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A PHARMACEUTICALLY ACTIVE SUBSTANCE

20220160812 · 2022-05-26

    Inventors

    Cpc classification

    International classification

    Abstract

    The invention relates to a pharmaceutically active substance comprising at least one peptide portion having the amino acid sequences m-v-v-y-f-r (first peptide portion), characterised in that the pharmaceutically active substance comprises at least additional one amino acid and/or peptide portion at the N-terminal end and/or at the C-terminal end of the first peptide portion (second peptide portion and/or third peptide portion) being directly bound to the peptide portion having the amino acid sequences m-v-v-y-f-r (first peptide portion). The invention further relates to a pharmaceutical composition and a drug for the treatment of cancer.

    Claims

    1. An pharmaceutically active substance comprising at least one peptide portion having the amino acid sequences m-v-v-y-f-r (first peptide portion), characterised in that wherein the pharmaceutically active substance comprises at least one additional amino acid and/or peptide portion at the N-terminal end and/or at the C-terminal end of the first peptide portion (second peptide portion and/or third peptide portion) being directly bound to the peptide portion having the amino acid sequences m-v-v-y-f-r (first peptide portion).

    2. The pharmaceutically active substance according to claim 1, wherein the second peptide portion and/or the third peptide portion comprises at least one alpha-amino acid within a sequence of 5 amino acid units from the first peptide portion, preferably within a sequence of 3 amino acid units from the first peptide portion, the additional amino acid, and/or the peptide portion.

    3. The pharmaceutically active substance according to claim 1, wherein the second peptide portion and/or the third peptide portion comprises at least one polar amino acid within a sequence of 5 amino acid units from the first peptide portion, preferably within a sequence of 3 amino acid units from the first peptide portion.

    4. The pharmaceutically active substance according to claim 3, wherein the second peptide portion and/or the third peptide portion comprises at least two, preferably at least 3, polar amino acids within a sequence of 5 amino acid units from the first peptide portion, preferably within a sequence of 3 amino acid units from the first peptide portion.

    5. The pharmaceutically active substance according to claim 1, wherein the second peptide portion and/or the third peptide portion comprises at least one basic amino acid within a sequence of 5 amino acid units from the first peptide portion, preferably within a sequence of 3 amino acid units from the first peptide portion.

    6. The pharmaceutically active substance according to claim 5, wherein the second peptide portion and/or the third peptide portion comprises at least two, preferably at least 3, basic amino acids within a sequence of 5 amino acid units from the first peptide portion, preferably within a sequence of 3 amino acid units from the first peptide portion.

    7. The pharmaceutically active substance according to claim 1, wherein the second peptide portion and/or the third peptide portion comprises more polar amino acids than nonpolar amino acids within a sequence of 5 amino acid units from the first peptide portion.

    8. The pharmaceutically active substance according to claim 1, wherein the second peptide portion and/or the third peptide portion comprises the same number or more of basic amino acids than acidic amino acids within a sequence of 5 amino acid units from the first peptide portion.

    9. The pharmaceutically active substance according to claim 1, wherein the pharmaceutically active substance comprises two additional amino acid and/or peptide portions, one at the N-terminal end and one at the C-terminal end of the peptide portion having the amino acid sequences m-v-v-y-f-r (second peptide portion and third portion) being directly bound to the peptide portion having the amino acid sequences m-v-v-y-f-r (first peptide portion).

    10. The pharmaceutically active substance according to claim 1, wherein the second peptide portion and/or the third peptide portion comprises at least one D-amino acid.

    11. The pharmaceutically active substance according to claim 10, wherein at least 50%, preferably at least 70%, of the second peptide portion and/or the third peptide portion are D-amino acids.

    12. The pharmaceutically active substance according to claim 1, wherein the pharmaceutically active substance comprises at least one peptide portion having the amino acid sequences TABLE-US-00018 w-m-v-v-y-f-r, k-m-v-v-y-f-r, m-v-v-y-f-r-w, m-v-v-y-f-r-k, W-m-v-v-y-f-r, K-m-v-v-y-f-r, m-v-v-y-f-r-W, m-v-v-y-f-r-K.

    13. The pharmaceutically active substance according to claim 12, wherein the pharmaceutically active substance comprises at least one peptide portion having the amino acid sequences TABLE-US-00019 k-w-m-v-v-y-f-r, w-k-m-v-v-y-f-r, k-k-m-v-v-y-f-r, w-w-m-v-v-y-f-r, m-v-v-y-f-r-k-w, m-v-v-y-f-r-w-k, m-v-v-y-f-r-k-k, m-v-v-y-f-r-w-w, K-W-m-v-v-y-f-r, W-K-m-v-v-y-f-r, K-K-m-v-v-y-f-r, W-W-m-v-v-y-f-r, m-v-v-y-f-r-K-W, m-v-v-y-f-r-W-K, m-v-v-y-f-r-K-K, m-v-v-y-f-r-W-W.

    14. The pharmaceutically active substance according claim 1, wherein the pharmaceutically active substance comprises at least one peptide portion having the amino acid sequences TABLE-US-00020 k-k-w-m-v-v-y-f-r, k-w-m-v-v-y-f-r-k or a sequence having a homology to said sequences TABLE-US-00021 k-k-w-m-v-v-y-f-r k-w-m-v-v-y-f-r-k of at least 30%, preferably at least 60%, based on the underlined amino acids.

    15. The pharmaceutically active substance according to claim 1, wherein the pharmaceutically active substance comprises at least one peptide portion having the amino acid sequences TABLE-US-00022 k-k-w-m-v-v-y-f-r-k, q-k-w-m-v-v-y-f-r-k or a sequence having a homology to said sequences TABLE-US-00023 k-k-w-m-v-v-y-f-r-k q-k-w-m-v-v-y-f-r-k of at least 30%, preferably at least 50%, more preferably at least 70%, based on the underlined amino acids.

    16. The pharmaceutically active substance according to claim 14, wherein the pharmaceutically active substance comprises at least one peptide portion having at least one of the amino acid sequences TABLE-US-00024 k-s-q-t-v-k-k-w-m-v-v-y-f-r-k, k-k-w-m-v-v-y-f-r-k-s-s-r, e-r-s-k-k-w-m-v-v-y-f-r-k, k-k-w-m-v-v-y-f-r-k-e-a-r, r-s-t-k-k-w-m-v-v-y-f-r-k, r-s-t-k-k-w-m-v-v-y-f-r, r-a-s-k-s-q-t-v-k-k-w-m-v-v-y-f-r-k-s-a-r, or a sequence having a homology to said sequences TABLE-US-00025 k-s-q-t-v-k-k-w-m-v-v-y-f-r-k, k-k-w-m-v-v-y-f-r-k-s-s-r, e-r-s-k-k-w-m-v-v-y-f-r-k, k-k-w-m-v-v-y-f-r-k-e-a-r, r-s-t-k-k-w-m-v-v-y-f-r-k, r-s-t-k-k-w-m-v-v-y-f-r, r-a-s-k-s-q-t-v-k-k-w-m-v-v-y-f-r-k-s-a-r, of at least 50%, preferably at least 70%, based on the underlined amino acids.

    17. The pharmaceutically active substance according to claim 14, wherein the pharmaceutically active substance comprises at least one peptide portion having at least one of the amino acid sequences TABLE-US-00026 k-s-q-t-v-q-k-w-m-v-v-y-f-r-k, s-q-t-v-q-k-w-m-v-v-y-f-r-k, s-q-t-v-q-k-w-m-v-v-y-f-r, or a sequence having a homology to said sequences TABLE-US-00027 k-s-q-t-v-q-k-w-m-v-v-y-f-r-k, s-q-t-v-q-k-w-m-v-v-y-f-r-k, s-q-t-v-q-k-w-m-v-v-y-f-r, of at least 50%, preferably at least 70%, based on the underlined amino acids.

    18. The pharmaceutically active substance according to claim 1, wherein the pharmaceutically active substance comprises at least one peptide portion having the amino acid sequence d-k-w-m-v-v-y-f-r-d, or a sequence having a homology to said sequence d-k-w-m-v-v-y-f-r-d of at least 30%, preferably at least 50%, more preferably at least 70%, based on the underlined amino acids.

    19. The pharmaceutically active substance according to claim 1, wherein the pharmaceutically active substance comprises a peptide chain being formed by the first peptide portion and the second and/or the third peptide portion and the peptide chain has a chain length of <100 amino acids.

    20. The pharmaceutically active substance according to claim 19, wherein the pharmaceutically active substance comprises a peptide chain being formed by the first peptide portion and the second and/or the third peptide portion and the peptide chain has a chain length of <50 amino acids.

    21. The pharmaceutically active substance according to claim 19, wherein the pharmaceutically active substance is a peptide that has a chain length of <100, preferably <50 amino acids.

    22. The pharmaceutically active substance according to claim 1, wherein the pharmaceutically active substance comprises two, three, four, five, or more of the first peptide portion, of the second peptide portion, and/or of the third peptide portion, preferably of peptide portions having one of the amino acid sequences TABLE-US-00028 w-m-v-v-y-f-r, k-m-v-v-y-f-r, m-v-v-y-f-r-w, m-v-v-y-f-r-k, W-m-v-v-y-f-r, K-m-v-v-y-f-r, m-v-v-y-f-r-W, m-v-v-y-f-r-K.

    23. A pharmaceutical composition, comprising at least one substance according to claim 1 or a pharmaceutically acceptable salt of this substance and a pharmaceutically acceptable carrier.

    24. The pharmaceutical composition according to claim 23, wherein the pharmaceutical composition comprises at least one further medicament active ingredient, preferably a cytostatic.

    25. Use of a substance according to claim 1 or of a pharmaceutically acceptable salt for preparation of a drug.

    26. The use of a substance according to claim 25 or of a pharmaceutically acceptable salt for preparation of a drug for the treatment of cancer disease.

    27. The use of a substance according to claim 26, wherein the cancer disease is related to cancer of head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, prostate, urinary bladder, uterine, cervix, breast, ovaries, testicles or other reproductive organs, skin, thyroid, blood, lymph nodes, kidney, liver, pancreas, brain, central nervous system, solid tumors, and blood-borne tumors.

    28. A drug for the treatment of cancer, comprising at least one substance according to claim 1 or a pharmaceutically acceptable salt of the pharmaceutically active substance and a pharmaceutically acceptable carrier.

    29. Set (kit) consisting of separate packs of (a) an effective amount of a pharmaceutically active substance according to claim 1 and/or pharmaceutically acceptable salts, tautomers, and stereoisomers thereof, including mixtures thereof in all ratios, and (b) an effective amount of a further medicament active ingredient.

    30. The substance according to claim 1, which substance is labelled.

    Description

    SHORT DESCRIPTION OF THE FIGURES

    [0459] FIG. 1a on the left side depicts the results of a typical FACS analysis as a 2D plot showing the region R-1 as a pentagon.

    [0460] FIG. 1b on the right side shows a histogram of the cell cycles including the SubG1 region (H-4) based on the region R-1 as shown in FIG. 1a.

    [0461] FIG. 1c shows a table of the results as given in FIG. 1b.

    [0462] FIG. 2 shows the induced cell death caused by apoptosis of A375 melanoma cells as given by the Comparative Example 1 and Examples 1 and 2. The concentration of the peptides is 100 μM and the incubation time is about 24 hours. FIG. 2 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above and below. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for all of the peptides evaluated. This high significance is marked by a superscript “a” in the Figure.

    [0463] FIG. 3 shows the induced cell death caused by apoptosis of A375 melanoma cells as given by the Comparative Examples 2 to 4 and Examples 3 to 11. The concentrations of the peptides are provided in the Figure and are 100 μM, 200 μM and 500 μM, respectively. The incubation time is about 24 hours. FIG. 3 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above and below. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for the peptides of the present invention evaluated compared to comparative peptide C1, at all three concentrations. This high significance is marked by a superscript “a” in the Figure.

    [0464] FIG. 4 shows the induced cell death caused by apoptosis of A375 melanoma cells as given by the Comparative Examples 5 to 7 and Examples 12 to 20. The concentrations of the peptides are provided in the Figure and are 50 μM, 100 μM and 200 μM, respectively. The incubation time is about 24 hours. FIG. 4 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above and below. For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for all of the peptides evaluated. This high significance is marked by a superscript “a” in the Figure.

    [0465] FIG. 5 shows the induced cell death caused by apoptosis of A375 melanoma cells as given by the Examples 21 to 30. The concentrations of the peptides are provided in the Figure and are 100 μM and 200 μM, respectively. The incubation time is about 3 hours. FIG. 5 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above and below. For achieving an evaluation of the significance a fourfold chi square test is performed. Data show a high significance (p<0.01) for the Peptides SEQID NO 30, SEQID NO 32 and SEQID NO 33 evaluated. This high significance is marked by a superscript “a” in the Figure. The data obtained for Peptides SEQID No 27 and SEQID NO 31 show a lower significance and are marked by a superscript “b” in the Figure.

    [0466] FIG. 6 shows the induced cell death caused by apoptosis of A375 melanoma cells as given by the Examples 31 to 66. The concentrations of the peptides are provided in the Figure and are 100 μM, 200 μM and 300 μM, respectively. The incubation times are provided in the Figure and are about 1.5 h, 3 h, 6 h and 24 h, respectively. As shown in FIG. 6, the bars are arranged in groups depicting the incubation times, the concentration and the peptides, respectively. From the left to the right side the data provided the Peptides SEQID No 36, SEQID NO 37 and SEQID No 27. Furthermore, the data at a concentration of 300 μM are depicted on the left side for each peptide, while the data at a concentration of 100 μM are depicted on the right side for each peptide. For each concentration and each peptide the incubation times are ordered according to the incubation time wherein the data obtained at an incubation time of 24 h are provided at the left side and the data obtained at an incubation time of 1.5 h are provided at the right side. The data obtained at an incubation time of 6 h are provided at the right side of the 24 h data and the data obtained at an incubation time of 3 h are provided at the left side of the 1.5 h data. FIG. 6 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above and below. For achieving an evaluation of the significance a fourfold chi square test is performed. Data show a high significance (p<0.01) for incubation times of about 3 h and above. This high significance is marked by a superscript “a” in the Figure. The data obtained for an incubation time of about 1.5 h show significance (p<0.05) and are marked by a superscript “b” in the Figure.

    [0467] FIG. 7 shows the decrease of vitality of A375 melanoma cells as given by the Comparative Examples 8 to 10 and Examples 67 to 75. The concentrations of the peptides are provided in the Figure and are 100 μM, 200 μM and 500 μM, respectively. The incubation time is about 24 hours. As shown in FIG. 7, the bars are arranged in groups depicting the concentration and the peptides, respectively. From the bottom to the top the data provided the Peptides SEQ C1, SEQID NO 27, SEQID NO 39 and SEQID NO 38. Furthermore, the data at a concentration of 100 μM are depicted on the bottom for each peptide, while the data at a concentration of 500 μM are depicted on the top for each peptide. The data obtained at a concentration of 200 μM are provided in the middle of each peptide. FIG. 7 presents the percentage portion of surviving cells based on the percentage of cells in the region R-1 in the diagram (application Forward Scatter versus Sideward Scatter) as determined by the FACS method as mentioned above and below. The data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for all of the peptides evaluated. This high significance is marked by a superscript “a” in the Figure. As shown in FIG. 7, the peptides of the invention (SEQID NO 27, SEQID NO 39 and SEQID NO 38) provide a significantly greater decrease than the peptide of the prior art (Peptide SEQ C1).

    [0468] FIG. 8 shows the decrease of vitality of BxPC-3 human pancreatic cancer cells as given by the Comparative Examples 11 to 13 and Examples 76 to 87. The concentrations of the peptides are provided in the Figure and are 50 μM, 100 μM and 200 μM, respectively. The incubation time is about 24 hours. As shown in FIG. 8, the bars are arranged in groups depicting the concentration and the peptides, respectively. From the top to the bottom the data provided the Peptides SEQ C1, SEQID NO 27, SEQID NO 29, SEQID NO 36 and SEQID NO 37. Furthermore, the data at a concentration of 50 μM are depicted on the bottom for each peptide, while the data at a concentration of 200 μM are depicted on the top for each peptide. The data obtained at a concentration of 100 μM are provided in the middle of each peptide. FIG. 8 presents the percentage portion of surviving cells based on the percentage of cells in the region R-1 in the diagram (application Forward Scatter versus Sideward Scatter) as determined by the FACS method as mentioned above and below. For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for all of the peptides evaluated. This high significance is marked by a superscript “a” in the Figure. As shown in FIG. 8, the peptides of the invention (SEQID NO 27, SEQID NO 37, SEQID NO 36 and SEQID NO 29) provide a significantly greater decrease than the control peptide (C1).

    [0469] FIG. 9 shows the decrease of vitality of BxPC-3 human pancreatic cancer cells as given by the Comparative Example 14 and Examples 88 to 94. The concentration of the peptides is 100 μM and the incubation time is about 24 hours. From the bottom to the top the data provided concern the Peptides SEQ C1, SEQID NO 27, SEQID NO 25, SEQID NO 30, SEQID NO 31, SEQID NO 32, SEQID NO 33 and SEQID NO 34. FIG. 9 presents the percentage portion of surviving cells based on the percentage of cells in the region R-1 in the diagram (application Forward Scatter versus Sideward Scatter) as determined by the FACS method as mentioned above and below. The data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for all of the peptides evaluated. This high significance is marked by a superscript “*” in the Figure.

    [0470] FIG. 10 shows the induced cell death caused by apoptosis of BxPC-3 human pancreatic cancer cells as given by the Comparative Examples 15 to 17 and Examples 95 to 106. The concentrations of the peptides are provided in the Figure and are 50 μM, 100 μM and 200 μM, respectively. As shown in FIG. 10, the bars are arranged in groups depicting the concentration and the peptides, respectively. From the top to the bottom the data provided the Peptides SEQ C1, SEQID NO 27, SEQID NO 29, SEQID NO 36 and SEQID NO 37. Furthermore, the data at a concentration of 50 μM are depicted on the bottom for each peptide, while the data at a concentration of 200 μM are depicted on the top for each peptide. The data obtained at a concentration of 100 μM are provided in the middle of each peptide. The incubation time is about 24 hours. FIG. 10 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above and below. The data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for a comparison of Peptide SEQ Cl versus peptide SEQID NO 27 at 50 μM, 100 μM and 200 μM, respectively. This high significance is marked by a superscript “a” in the Figure. The data show a high significance (p<0.01) for a comparison of Peptide SEQ Cl versus Peptide SEQID No 36 at 50 μM, 100 μM and 200 μM, respectively. This high significance is marked by a superscript “b” in the Figure. The data show a high significance (p<0.01) for a comparison of Peptide SEQ Cl versus Peptide SEQID No 29 at 50 μM, 100 μM and 200 μM, respectively. This high significance is marked by a superscript “b” in the Figure. The data show a high significance (p<0.01) for a comparison of Peptide SEQ Cl versus Peptide SEQID No 37 at 100 μM and 200 μM, respectively. This high significance is marked by a superscript “c” in the Figure.

    [0471] FIG. 11 shows the decrease of vitality of human B-chronic lymphocytic leukaemia cells (MEC-1) and human peripheral blood mononuclear cells (Lymphocyte, -PBMC″) as given by the Examples 111 to 152, respectively. The concentrations of the peptides are provided in the Figure and are 50 μM, 100 μM and 200 μM, respectively. As shown in FIG. 11, the bars are arranged in groups depicting the cell type, the concentration and the peptides, respectively. From the left to the right side the data provided the peptides SEQID NO 27, SEQID NO 25, SEQID NO 26, SEQID NO 30, SEQID NO 31, SEQID NO 32 and SEQID NO 33. The Figure depicts the data for each peptide by six bars. The three bars on the left side of each peptide concerns the data for the MEC-1 cancer cells (bars having stripes) while the three bars on the right side of each peptide concerns the data obtained with healthy Lymphocyte (PBMC cells; filled bars). Furthermore, the data at a concentration of 50 μM are depicted on the left side for each peptide and each cell type, while the data at a concentration of 200 μM are depicted on the right side for each peptide and each cell type. For cell type and each peptide the data at a concentration of 100 μM are provided in the middle. The incubation time is about 2 hours. FIG. 11 presents the percentage portion of surviving cells based on the percentage of cells in the region R-1 in the diagram (application Forward Scatter versus Sideward Scatter) as determined by the FACS method as mentioned above and below. The data achieved considers the data as measured for the solvent alone (DMSO).

    [0472] FIG. 12 shows the decrease of vitality of human breast carcinoma cells (MDA-MB-231) as given by the Examples 153 to 170, respectively. The concentrations of the peptides are provided in the Figure and are 50 μM, 100 μM and 200 μM, respectively. As shown in FIG. 12, the bars are arranged in groups depicting the peptides, the concentration and the treatment time, respectively. From the left to the right side the data provided the peptides SEQID NO 36, SEQID NO 37 and SEQID NO 27. The Figure depicts the data for each peptide by six bars. The bars on the left side of each peptide concerns the data for a concentration of 200 μM while the bars on the right side of each peptide concerns the data obtained for a concentration of 50 μM. The data obtained for a concentration of 100 μM are depicted in the middle of the data for each peptide. Furthermore, the data obtained with a treatment time of 48 h are depicted on the left side for each peptide and each concentration (filled bars), while the data obtained with a treatment time of 24h are depicted on the right side for each peptide and each concentration (bars having stripes). FIG. 12 presents the percentage portion of surviving cells based on the respiration activity method as mentioned above and below. The data achieved considers the data as measured for the solvent alone (DMSO).

    [0473] FIG. 13 shows the induced cell death caused by apoptosis of human breast carcinoma cells (MDA-MB-231). The concentrations of all peptides used are 200 μM. The incubation time is about 24 hours. FIG. 13 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for all of the peptides evaluated compared to comparative peptide C1.

    [0474] Addition of one amino acid at the carboxy terminus (SEQ No 3 and SEQ No 4) or at the amino terminus (SEQ No 1 and SEQ No 2) leads to an increased apoptosis-inducing activity compared to the peptide SEQ C1. Adding one additional nonpolar amino acid to peptide SEQID No 1 leading to SEQID No 12 causes a slightly decreased activity compared to peptide SEQID No 1. Nevertheless, peptide SEQID No 12 shows a remarkably improved efficiency than SEQ C1. However, the improvement of SEQID No 12 is smaller than the improvement of peptide SEQID No 1. As shown in FIG. 2, adding one additional polar amino acid to peptide SEQID No 1 leading to peptide SEQID No 9 causes a extraordinary increased activity compared to peptide SEQ C1.

    [0475] FIG. 14 shows the induced cell death caused by apoptosis of BxPC-3 pancreas cancer cells. The concentrations of all peptides used was 100 μM. The incubation time is about 24 hours. FIG. 14 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for all of the peptides evaluated compared to comparative peptide C1.

    [0476] Adding one amino acid (SEQID No 1, -2 and -3) or two amino acids (SEQID No 9 and -12) leads to a stronger apoptosis induction compared to SEQ C1. Adding one additional polar amino acid to peptide SEQID No 1 leading to SEQID No 9 causes an strongly improved activity compared to peptide SEQID No 1.

    [0477] FIG. 15 shows the induced cell death caused by apoptosis of human breast carcinoma cells (MDA-MB-231). The concentrations of all peptides used was 100 μM. The incubation time is about 24 hours. FIG. 15 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). An exchange of the amino-terminal amino acid from k in SEQID No 27 to q in SEQID No 28 leads to a higher apoptosis-inducing activity. For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for the peptide SEQID No 27 evaluated compared to peptide SEQID No 28.

    [0478] FIG. 16 shows the induced cell death caused by apoptosis of human breast carcinoma cells (MDA-MB-231). The concentrations of the peptides used was 100 μM. The incubation time is about 24 hours. FIG. 16 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). An exchange of one amino acid from k to q at position 4 of peptide SEQID No 33 results in peptide SEQID No 40 which shows a similar activity in the subG1 apoptosis assay system measuring the effect to MDA-MB-231 cells. In FIG. 16 SEQID 40 shows a slightly smaller efficiency than SEQID No 33. However, an evaluation of the significance a fourfold chi square test is performed. The data show a low significance (p>0.1) for the peptide SEQID No 33 evaluated compared to peptide SEQID No 40.

    [0479] FIG. 17 shows the induced cell death caused by apoptosis of BxPC-3 pancreas cancer cells. The concentrations of the peptides used was 100 μM. The incubation time is about 24 hours. FIG. 17 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for the peptide SEQID No 33 evaluated compared to peptide SEQID No 40.

    [0480] An exchange of one amino acid from k to q at position 4 of peptide SEQID No 33 results in peptide SEQID No 40 which shows a weaker activity in the subG1 apoptosis assay system measuring the effect to BxPC-3 cells.

    [0481] FIG. 18 shows the induced cell death caused by apoptosis of human breast carcinoma cells (MDA-MB-231). The concentrations of peptides SEQID No 28 and SEQID No 1 used was 100 μM, the concentration of the peptide SEQID No 41 which contains two active peptide motifs with the sequence mvvyfr used was 50 μM. The incubation time is about 24 hours. FIG. 18 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a high significance (p<0.01) for the peptide SEQID No 41 evaluated compared to peptide SEQID No 28. However, the data show a low significance (p>0.1) for the peptide SEQID No 1 evaluated compared to peptide SEQID No 28.

    [0482] The dimeric peptide which is applied at half the concentration of the monomeric peptides, thereby resulting in an identical concentration of the active peptide motif, yields a more than two-fold apoptosis-inducing activity than the peptides SEQID No 28 and SEQID No 1. FIG. 18 clearly shows that a peptide having two, three, four or more amino acid sequences m-v-v-y-f-r (first peptide portion) have a superior efficiency. Based on the fact that the molar concentration of the binding motif mvvyfr are the same in the examples, the use of a peptide having two, three, four or more amino acid sequences m-v-v-y-f-r (first peptide portion) provides a synergistic effect.

    [0483] FIG. 19 shows the induced cell death caused by apoptosis of BxPC-3 pancreas cancer cells. The concentrations of peptides SEQID No 28 and SEQID No 27 used was 100 μM, the concentration of the peptide peptide SEQID No 41 which contains two active peptide motifs with the sequence mvvyfr used was 50 μM. The incubation time is about 24 hours. FIG. 19 presents the percentage portion of cells in the subG1 area of the cell cycle as determined by the FACS method as mentioned above. The apoptosis data achieved considers the data as measured for the solvent alone (DMSO). For achieving an evaluation of the significance a fourfold chi square test is performed. The data show a very high significance (p<0.001) for the peptide SEQID No 41 evaluated compared to peptide SEQID No 28. Additionally, the data show a high significance (p<0.01) for the peptide SEQID No 27 evaluated compared to peptide SEQID No 28.

    [0484] The dimeric peptide which is applied at half the concentration of the monomeric peptides, thereby resulting in an identical concentration of the active peptide motif, yields a more than two-fold apoptosis-inducing activity than the peptides SEQID No 28 and SEQID No 27.

    COMPARATIVE EXAMPLE 1

    [0485] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 2.

    [0486] The Comparative Example 1 has been repeated for an incubation time of about 24 hours and 6 hours and shows essentially the same results.

    Example 1

    [0487] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID No 9 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 2.

    Example 2

    [0488] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 2.

    [0489] The Example 2 has been repeated for an incubation time of about 24 hours and 6 hours and shows essentially the same results.

    [0490] The Examples 1 and 2 and the Comparative Example 1 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0491] The evaluation of Comparative Example 1 and Examples 1 and 2 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially Example 2 demonstrates an at least sevenfold efficiency of peptide SEQID NO 27 in view of Peptide SEQ C1.

    COMPARATIVE EXAMPLE 2

    [0492] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    COMPARATIVE EXAMPLE 3

    [0493] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    COMPARATIVE EXAMPLE 4

    [0494] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 500 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 3

    [0495] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 4

    [0496] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 5

    [0497] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 500 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 6

    [0498] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 39 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 7

    [0499] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 39 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 8

    [0500] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 39 is measured using the subG1 method mentioned above at a concentration of the peptide of about 500 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 9

    [0501] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 38 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 10

    [0502] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 38 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    Example 11

    [0503] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 38 is measured using the subG1 method mentioned above at a concentration of the peptide of about 500 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 3.

    [0504] The Examples 3 to 11 and the Comparative Examples 2 to 4 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0505] The evaluation of Comparative Examples 2 to 4 and Examples 3 to 11 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially Examples 9 to 11 demonstrate an at least tenfold efficiency of Peptide SEQID No 38 in view of Peptide SEQ Cl at any concentration. Additionally, the Peptide SEQID No 38 provides a clear improvement over peptide SEQID NO 27 at a concentration below 500 μM and over Peptide SEQID NO 39 at a concentration above 100 μM.

    COMPARATIVE EXAMPLE 5

    [0506] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    COMPARATIVE EXAMPLE 6

    [0507] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    COMPARATIVE EXAMPLE 7

    [0508] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 12

    [0509] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 13

    [0510] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 14

    [0511] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 15

    [0512] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 16

    [0513] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 17

    [0514] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 18

    [0515] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 19

    [0516] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    Example 20

    [0517] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 4.

    [0518] The Examples 12 to 20 and the Comparative Examples 5 to 7 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0519] The evaluation of Comparative Example 5 and Examples 12 to 20 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially Examples 15 to 17 demonstrate at 100 μM an at least fivefold efficiency and at 200 μM an at least tenfold efficiency of Peptide SEQID No 36 in view of Peptide SEQ C1. Additionally, the Peptide SEQID No 36 provides a clear improvement over Peptides SEQID NO 37 and SEQID NO 29 at any concentration. Furthermore, the Peptide SEQID No 29 shows higher efficiency at 200 μM in view of Peptide SEQID No 37.

    Example 21

    [0520] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 22

    [0521] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 23

    [0522] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 30 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 24

    [0523] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 30 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 25

    [0524] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 26

    [0525] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 27

    [0526] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 28

    [0527] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 29

    [0528] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    Example 30

    [0529] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 5.

    [0530] The Examples 21 to 30 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0531] The evaluation of Examples 21 to 30 clearly shows a high apoptosis efficiency of the inventive pharmaceutically active substances. At a concentration of 200 μM the Peptides SEQID No 30 and SEQID NO 33 exhibit an improvement over the peptides SEQID NO 27, SEQID NO 31 and SEQID NO 32, while the Peptide SEQID No 32 provides a higher efficiency than peptides SEQID NO 27 and SEQID NO 31. Furthermore, the Peptide SEQID No 30 shows higher efficiency at 100 μM in view of peptides SEQID NO 27 and SEQID NO 31. In addition thereto, the Peptides SEQID No 31 and SEQID NO 32 have an improved apoptosis level in view of peptide SEQID NO 27.

    Example 31

    [0532] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 32

    [0533] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 33

    [0534] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 34

    [0535] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 35

    [0536] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 36

    [0537] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 37

    [0538] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 38

    [0539] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 39

    [0540] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 40

    [0541] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 41

    [0542] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 42

    [0543] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 43

    [0544] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 44

    [0545] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 45

    [0546] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 46

    [0547] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 47

    [0548] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 48

    [0549] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 49

    [0550] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 50

    [0551] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 51

    [0552] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 52

    [0553] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 53

    [0554] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 54

    [0555] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 55

    [0556] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 56

    [0557] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 57

    [0558] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 58

    [0559] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 59

    [0560] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 60

    [0561] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 61

    [0562] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 62

    [0563] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    Example 63

    [0564] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 1.5 hours. The data obtained are depicted FIG. 6.

    Example 64

    [0565] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 3 hours. The data obtained are depicted FIG. 6.

    Example 65

    [0566] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 6 hours. The data obtained are depicted FIG. 6.

    Example 66

    [0567] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 300 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 6.

    [0568] The Examples 31 to 66 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0569] The evaluation of Examples 31 to 66 clearly shows a high apoptosis efficiency of the inventive pharmaceutically active substances. Please note the high apoptosis level at an incubation time of about 3 hours at a peptide concentration of 200 OA and above regarding the highly efficient Peptide SEQID No 36. It seems that surviving cells are dividing and leading to such result. At a concentration of 300 OA the Peptide SEQID No 36 provides an improvement with regard to all incubation times over Peptides SEQID NO 37 and SEQID NO 27. At a concentration of 200 OA the peptide provides an improvement over Peptides SEQID NO 37 and SEQID NO 27 at incubation times of 1.5 h, 3 h and 6 h while at an incubation time of 24 h the Peptide SEQID No 37 shows the best results. At a concentration of 100 OA the Peptides SEQID NO 37 and SEQID NO 36 show a slightly improved apoptosis level in view of peptide SEQID NO 27.

    COMPARATIVE EXAMPLE 8

    [0570] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    COMPARATIVE EXAMPLE 9

    [0571] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    COMPARATIVE EXAMPLE 10

    [0572] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the cell vitality method mentioned above at a concentration of the peptide of about 500 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 67

    [0573] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 68

    [0574] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 69

    [0575] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 500 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 70

    [0576] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 39 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 71

    [0577] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 39 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 72

    [0578] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 39 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 500 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 73

    [0579] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 38 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 74

    [0580] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 38 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    Example 75

    [0581] As mentioned above A375 melanoma cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 38 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 500 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 7.

    [0582] The Examples 67 to 75 and the Comparative Examples 8 to 10 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0583] The evaluation of Comparative Examples 8 to 10 and Examples 67 to 75 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially Examples 73 to 75 demonstrate an at least threefold efficiency of Peptide SEQID No 38 in view of Peptide SEQ Cl at 200 μM, and an at least tenfold efficiency at 500 μM. Additionally, the Peptide SEQID No 38 provides a clear improvement over peptides SEQID NO 27 and SEQID NO 39 at any concentration. Furthermore, the peptide SEQID NO 27 shows higher efficiency at 500 μM in view of peptide SEQID NO 39 while peptide SEQID NO 39 shows a higher apoptosis rate at a concentration of 100 μM as peptide SEQID NO 27.

    COMPARATIVE EXAMPLE 11

    [0584] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    COMPARATIVE EXAMPLE 12

    [0585] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    COMPARATIVE EXAMPLE 13

    [0586] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 76

    [0587] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 77

    [0588] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 78

    [0589] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 79

    [0590] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 80

    [0591] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 81

    [0592] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 82

    [0593] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 83

    [0594] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 84

    [0595] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 85

    [0596] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 86

    [0597] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    Example 87

    [0598] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 8.

    [0599] The Examples 76 to 87 and the Comparative Examples 11 to 13 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0600] The evaluation of Comparative Examples 11 to 13 and Examples 76 to 87 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially Examples 82 to 84 demonstrate an at least fourfold efficiency of Peptide SEQID No 36 in view of Peptide SEQ Cl at 50 μM concentration, and an at least sevenfold efficiency of Peptide SEQID No 36 in view of Peptide SEQ Cl at 100 and 200 μM concentration. Additionally, the Peptide SEQID No 36 provides a clear improvement over peptides SEQID NO 27, SEQID NO 37 and SEQID NO 29 at a concentration of 50 μM. At a concentration of 100 μM the Peptides SEQID No 36 and SEQID NO 29 exhibit a very high efficiency. At a concentration of 200 μM the Peptides SEQID NO 37, SEQID NO 36 and SEQID NO 29 exhibits an astonishing high efficiency. Furthermore, the peptide SEQID NO 27 shows a lower efficiency at all concentrations than the Peptides SEQID NO 37, SEQID NO 36 and SEQID NO 29.

    COMPARATIVE EXAMPLE 14

    [0601] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQ Cl is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    Example 88

    [0602] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    Example 89

    [0603] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID NO 25 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    Example 90

    [0604] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID No 30 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    Example 91

    [0605] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID No 31 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    Example 92

    [0606] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID No 32 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    Example 93

    [0607] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID No 33 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    Example 94

    [0608] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID No 34 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 9.

    [0609] The Examples 88 to 94 and the Comparative Example 14 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0610] The evaluation of Comparative Example 14 and Examples 88 to and 94 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Regarding the inventive pharmaceutically active substances, the Peptide SEQID NO 25 shows the lowest level of apoptosis while the Peptides SEQID No 32 and SEQID NO 33 induce the highest level of apoptosis.

    COMPARATIVE EXAMPLE 15

    [0611] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    COMPARATIVE EXAMPLE 16

    [0612] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    COMPARATIVE EXAMPLE 17

    [0613] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 95

    [0614] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 96

    [0615] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 97

    [0616] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 98

    [0617] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 99

    [0618] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 100

    [0619] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 37 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 101

    [0620] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 102

    [0621] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 103

    [0622] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 36 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 104

    [0623] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 105

    [0624] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    Example 106

    [0625] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 29 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 10.

    [0626] The Examples 95 to 106 and the Comparative Examples 15 to 17 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0627] The evaluation of Comparative Examples 15 to 17 and Examples 95 to 106 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially Examples 101 to 103 demonstrate an at least fourfold efficiency of Peptide SEQID No 36 in view of Peptide SEQ Cl at any concentration. Additionally, the Peptides SEQID NO 37 and SEQID NO 36 provide a clear improvement over peptides SEQID NO 27 and SEQID NO 29 at a concentration of 200 μM. Furthermore, the Peptide SEQID No 29 shows higher efficiency at 100 μM in view of Peptides SEQID NO 27, SEQID NO 37 and SEQID NO 36. At a concentration of 50 μM the Peptides SEQID No 36 and SEQID NO 29 provide a slight improvement over peptides SEQID NO 27 and SEQID NO 37.

    Example 107

    [0628] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID No 33 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours.

    Example 108

    [0629] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID No 33 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours.

    Example 109

    [0630] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID NO 35 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours.

    Example 110

    [0631] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQID NO 35 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours.

    [0632] The data obtained in Examples 109 to 110 show that both peptides impart a considerable efficiency to induce apoptosis in pancreatic cancer cells. The peptide sequence SEQID NO 35 provides a slightly higher apoptosis than the peptide sequence SEQID NO 33.

    Example 111

    [0633] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 112

    [0634] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 113

    [0635] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 114

    [0636] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 115

    [0637] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 116

    [0638] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 117

    [0639] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 25 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 118

    [0640] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 25 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 119

    [0641] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 25 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 120

    [0642] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 25 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 121

    [0643] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 25 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 122

    [0644] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID NO 25 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 123

    [0645] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 26 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 124

    [0646] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 26 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 125

    [0647] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 26 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 126

    [0648] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 26 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 127

    [0649] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 26 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 128

    [0650] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 26 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 129

    [0651] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 30 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 130

    [0652] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 30 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 131

    [0653] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 30 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 132

    [0654] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 30 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 133

    [0655] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 30 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 134

    [0656] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 30 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 135

    [0657] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 136

    [0658] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 137

    [0659] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 138

    [0660] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 139

    [0661] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 140

    [0662] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 31 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 141

    [0663] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 142

    [0664] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 143

    [0665] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 144

    [0666] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 145

    [0667] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 146

    [0668] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 32 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 147

    [0669] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 148

    [0670] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 149

    [0671] As mentioned above MEC-1 cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 150

    [0672] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 151

    [0673] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    Example 152

    [0674] As mentioned above healthy Lymphocyte (PBMC) cells are cultivated, harvested and evaluated using the Protocol A. The apoptosis efficiency of Peptide SEQID No 33 is measured using the cell vitality method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 11.

    [0675] The Examples 111 to 152 have been performed using cells being obtained with one cultivation approach which has been split up for the tests.

    [0676] The evaluation of Examples 111 to 152 clearly shows a high apoptosis efficiency of the inventive pharmaceutically active substances with regard to the cancer cells. Furthermore the Examples show that healthy Lymphocyte (PBMC) cells tolerate high levels of the inventive pharmaceutically active substances. That is, based on the pharmaceutical mechanism of action of the peptides cells being not prone to apoptosis are not remarkably damaged by the peptides of the present invention. This is especially true with regard to the peptides SEQID NO 27, SEQID NO 30, SEQID NO 31, SEQID NO 32 and SEQID NO 33. Regarding the depicted data, please consider that the solvent DMSO may have a considerable toxic effect to the cells and, hence, even at low levels a measurable degree of vitality is seen in the Figure.

    [0677] The Peptides SEQID No 30 and SEQID NO 33 show a very high level of induced apoptosis to the cells, while being well tolerated. That is, these Peptides SEQID No 30 and SEQID NO 33 have an astonishingly high selectivity. This is especially true at concentrations of 100 μM and above. The Peptide SEQID No 32 shows the same efficiency as Peptide SEQID No 30 at a concentration of 200 μM and a higher selectivity (lower effect with regard to healthy cells). The peptide SEQID NO 27 is very good tolerated by the healthy cells (low toxic effect). However, the ability to induce apoptosis is lower than the effect of Peptides SEQID No 30, SEQID NO 31, SEQID NO 32 and SEQID NO 33 at any concentration. The Peptides SEQID NO 25 and SEQID NO 26 are not so well tolerated by the healthy cells than the Peptides SEQID NO 27, SEQID NO 30, SEQID NO 31, SEQID NO 32 and SEQID NO 33

    Example 153

    [0678] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 154

    [0679] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 155

    [0680] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 156

    [0681] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 157

    [0682] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 158

    [0683] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 27 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 159

    [0684] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 37 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 160

    [0685] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 37 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 161

    [0686] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 37 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 162

    [0687] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 37 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 163

    [0688] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 37 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 164

    [0689] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 37 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 165

    [0690] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 36 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 166

    [0691] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 36 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 167

    [0692] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 36 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 12.

    Example 168

    [0693] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 36 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 169

    [0694] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 36 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    Example 170

    [0695] As mentioned above MDA-MB-231 cells are cultivated, harvested and evaluated as mentioned above concerning the concerning the respiration activity (ATP). The apoptosis efficiency of peptide SEQID NO 36 is measured using the cell respiration activity method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 48 hours. The data obtained are depicted FIG. 12.

    [0696] The evaluation of Examples 153 to 170 clearly shows a high apoptosis efficiency of the inventive pharmaceutically active substances with regard to the cancer cells. Please note that the respiration activity method measures the presence of ATP which is an energy source in the cells. At a low cell activity the cells show only a low decrease of ATP and the ATP is rather stable and, hence, although the cells itself are killed by the inventive pharmaceutically active substances at a very high speed as shown above, the decrease measured by ATP concentration shows a delay.

    COMPARATIVE EXAMPLE 18

    [0697] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 13.

    Example 171

    [0698] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 1 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 13.

    Example 172

    [0699] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 2 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 13.

    Example 173

    [0700] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 3 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 13.

    Example 174

    [0701] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 4 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 13.

    Example 175

    [0702] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 12 is measured using the subG1 method mentioned above at a concentration of the peptide of about 200 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 13.

    [0703] The evaluation of Comparative Example 18 and Examples 171 to 175 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances.

    COMPARATIVE EXAMPLE 19

    [0704] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of Peptide SEQ Cl is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 14.

    Example 176

    [0705] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 1 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 14.

    Example 177

    [0706] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 2 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 14.

    Example 178

    [0707] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 3 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 14.

    Example 179

    [0708] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 9 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 OA and an incubation time of about 24 hours. The data obtained are depicted FIG. 14.

    Example 180

    [0709] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 12 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 14.

    [0710] The evaluation of Comparative Example 19 and Examples 176 to 180 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially Example 179 demonstrates an at least fourfold efficiency of Peptide SEQID No 9 in view of Peptide SEQ C1. Furthermore, Example 179 demonstrates an at least threefold efficiency of Peptide SEQID No 9 in view of Peptide SEQ No 12. This clearly shows an unexpected improvement of peptides having a polar amino acid, preferably a basic amino acid within a sequence of 5 amino acid units from the first peptide portion. That is, a peptide comprising at least additional one amino acid and/or peptide portion at the N-terminal end and/or at the C-terminal end of the first peptide portion (second peptide portion and/or third peptide portion) being directly bound to the peptide portion having the amino add sequences m-v-v-y-f-r (first peptide portion) wherein the second peptide portion and/or third peptide portion comprising at least one polar amino acid within a sequence of 5 amino acid units from the first peptide portion, preferably within a sequence of 3 amino acid units from the first peptide portion is preferred over a peptide having only nonpolar amino acid within a sequence of 5 amino acid units from the first peptide portion.

    Example 181

    [0711] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 15.

    Example 182

    [0712] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 28 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 15.

    [0713] The evaluation of Examples 181 and 182 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances.

    [0714] Additionally, SEQID NO 28 shows an improvement over SEQID NO 27 regarding MDA-MB-231 cells.

    Example 183

    [0715] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 33 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 16.

    Example 184

    [0716] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 40 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 16.

    [0717] The evaluation of Examples 181 and 182 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Additionally, SEQID NO 33 shows about the same efficiency as SEQID NO 40 concerning the apoptosis of MDA-MB-231 cells.

    Example 185

    [0718] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 33 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours.

    [0719] The data obtained are depicted FIG. 17.

    Example 186

    [0720] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 40 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 17.

    [0721] The evaluation of Examples 185 and 186 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Additionally, SEQID NO 33 shows an improvement over SEQID NO 40 concerning the apoptosis of BxPC-3 cells.

    Example 187

    [0722] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 1 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 18.

    Example 188

    [0723] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 28 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 18.

    Example 189

    [0724] As mentioned above MDA-MB-231 cells are cultivated and harvested. The apoptosis efficiency of peptide SEQID NO 41 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 18.

    [0725] The evaluation of Examples 187 to 189 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially, Example 189 demonstrates an at least double efficiency of Peptide SEQID No 41 in view of Peptide SEQ No 1 and Peptide SEQ No 28 although the same molar amount of binding sites are present. This clearly shows an unexpected improvement of peptides comprising two, three, four, five or more of the first peptide portion, of the second peptide portion and/or of the third peptide portion, especially comprising two, three, four, five or more of the first peptide portion.

    Example 190

    [0726] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 27 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 19.

    Example 191

    [0727] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 28 is measured using the subG1 method mentioned above at a concentration of the peptide of about 100 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 19.

    Example 192

    [0728] As mentioned above BxPC-3 cells are cultivated, harvested and evaluated using the Protocol B. The apoptosis efficiency of peptide SEQID NO 41 is measured using the subG1 method mentioned above at a concentration of the peptide of about 50 μM and an incubation time of about 24 hours. The data obtained are depicted FIG. 19.

    [0729] The evaluation of Examples 190 to 192 clearly shows an astonishing improvement of the apoptosis efficiency of the inventive pharmaceutically active substances. Especially, Example 192 demonstrates an at least double efficiency of Peptide SEQID No 41 in view of Peptide SEQ No 27 and Peptide SEQ No 28 although the same molar amount of binding sites are present. This clearly shows an unexpected improvement of peptides comprising two, three, four, five or more of the first peptide portion, of the second peptide portion and/or of the third peptide portion, especially comprising two, three, four, five or more of the first peptide portion.