CANCER CHEMOTHERAPY SUPPORTING AGENT, FOOD, AND DRUG

Abstract

In order to provide a safe food-derived ingredient that reduces side effects of a cancer chemotherapeutic agent, and particularly to provide a food, a food ingredient (supplement), and a drug that reduce lethal toxic effects of a chemotherapeutic agent, a cancer chemotherapy supporting agent, a food, and a drug according to the present invention are supporting agents for a cancer chemotherapy in which streptozotocin etc., is administered, contain a lipopolysaccharide constituted of Pantoea bacteria LPS etc. as an active ingredient, and are orally administered.

Claims

1. A cancer chemotherapy supporting agent, food, or drug being a cancer chemotherapy supporting agent, food, or drug for reducing side effects of cancer chemotherapy and increasing the administration amounts of chemotherapeutic agents and containing a lipopolysaccharide as an active ingredient.

2. The cancer chemotherapy supporting agent, food, or drug according to claim 1, wherein the cancer chemotherapy is that in which an alkylating agent is administered.

3. The cancer chemotherapy supporting agent, food, or drug according to claim 2, wherein the alkylating agent is streptozotocin or cyclophosphamide.

4. The cancer chemotherapy supporting agent, food, or drug according to claim 1, wherein the cancer chemotherapy is that in which a platinating agent is administered.

5. The cancer chemotherapy supporting agent, food, or drug according to claim 4, wherein the platinating agent is cisplatin.

6. The cancer chemotherapy supporting agent, food, or drug according to claim 1, wherein the cancer chemotherapy is that in which an antimetabolite is administered.

7. The cancer chemotherapy supporting agent, food, or drug according to claim 6, wherein the antimetabolite is 5-fluorouracil.

8. The cancer chemotherapy supporting agent, food, or drug according to claim 1, wherein the supporting agent is orally administered.

9. The cancer chemotherapy supporting agent, food, or drug according to claim 1, wherein the lipopolysaccharide is derived from a bacterium belonging to family Enterobacteriaceae.

10. The cancer chemotherapy supporting agent, food, or drug according to claim 1, wherein the lipopolysaccharide is derived from a bacterium belonging to genus Pantoea or derived from a bacterium belonging to genus Enterobacter.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0048] FIG. 1 is a diagram showing results of an experiment of Example 1 of the present invention.

[0049] FIG. 2 is a diagram showing results of an experiment of Example 2 of the present invention.

[0050] FIG. 3 is a diagram showing results of an experiment of Example 5 of the present invention.

DESCRIPTION OF EMBODIMENTS

[0051] Examples of the present invention shall be described.

Example 1

[0052] Reduction of toxic effects of the chemotherapeutic agent streptozotocin by LPS oral administration

[0053] (1) Method

[0054] 1) Reagents [0055] LPS (LPSp) derived from Pantoea agglomerans belonging to genus Pantoea of family Enterobacteriaceae (mac0001 of Macrophi Inc.) [0056] Streptozotocin (STZ) (SAJ-S0130 of Sigma-Aldrich)

[0057] 2) Mice and Husbandry

[0058] Six-week-old male C57BL mice were used. Husbandry of the mice was carried out in a temperature and humidity controlled animal facility under environmental conditions of ad libitum food and water, and 12 hr light/12 hr dark. As food, the D12450B diet of Research Diets, Inc. was provided. After 1 week of preliminary rearing, the mice were divided into 3 groups of 6 mice each.

[0059] 3) Test

[0060] PBS administration group (PBS i.p.): 0.5 mL of phosphate buffer saline (PBS) were injected into the peritoneal cavity of each mouse.

[0061] STZ administration group (STZ i.p.): An STZ solution (250 mg/kg) was injected into the peritoneal cavity of each mouse.

[0062] STZ+LPS administration group (STZ i.p.+LPS): The STZ solution (250 mg/kg) was injected into the peritoneal cavity of each mouse and LPSp was mixed in drinking water such as to be of 100 μg/kg body weight/day and allowed to be ingested ad libitum.

[0063] (2) Results

[0064] The chemotherapeutic agent STZ is known to produce various toxic effects (nephropathy, myelosuppression (leukocytopenia, lymphocytopenia, neutropenia, thrombocytopenia, anemia, etc.), impaired glucose tolerance (hyperglycemia, increased blood insulin, increased insulin C peptide, and positive urine glucose), hepatopathy, etc. (NPL 10). On measuring the survival rate in the present test, it was found that on the 5th day, although there were no dead mice in the PBS administration group (PBS i.p.), 6 out of 6 mice died in the STZ administration group (STZ i.p.), and 4 out of 6 mice survived in the STZ+LPS administration group (STZ i.p.+LPS). On the 29th day, 1 out of 6 mice survived in the STZ+LPS administration group (Kaplan-Meier test: P<0.05). From the above, it was shown that LPSp administration has an effect of reducing the toxic effects of STZ (FIG. 1, Table 1).

TABLE-US-00001 TABLE 1 Survival rate (%) day PBS i.p. STZ i.p. STZ i.p. + LPS 3 100 66.7 83.3 4 100 33.3 83.3 4.5 100 33.3 66.7 5 100 0.0 66.7 9 100 0.0 50.0 11 100 0.0 33.3 21 100 0.0 16.7 29 100 0.0 16.7

[0065] Although prevention of side effects of a cancer chemotherapeutic agent by LPS oral administration was examined with Pantoea agglomerans-derived LPS (LPSp), this effect is obtained with all LPSs that can induce a protective action to tissue damage by activation of macrophages and is thus not limited to LPS derived from bacteria belonging to genus Pantoea.

Example 2

[0066] Reduction of toxic effects of the platinating agent cisplatin by LPS oral administration

[0067] (1) Method

[0068] 1) Reagents [0069] Pantoea agglomerans-derived LPS (LPSp) (mac0001 of Macrophi Inc.) [0070] Cisplatin (CDDP) (033-20091 of FUJIFILM Wako Pure Chemical Corporation)

[0071] 2) Mice and Husbandry

[0072] Four-week-old male ICR mice were used. Husbandry of the mice was carried out in a temperature and humidity controlled animal facility under environmental conditions of ad libitum food and water, and 12 hr light/12 hr dark. As food, CE-12 of CLEA Japan, Inc. was provided. After measuring the body weights at the time of delivery, the mice were divided into 3 groups of 6 mice each.

[0073] 3) Test

[0074] Physiological saline administration group (saline i.p.): 0.5 mL of physiological saline were injected into the peritoneal cavity of each mouse.

[0075] Cisplatin administration group (CDDP i.p.): A cisplatin solution (17.4 mg/kg) was injected into the peritoneal cavity of each mouse.

[0076] Cisplatin+LPS administration group (CDDP i.p.+LPS): The cisplatin solution (17.4 mg/kg) was injected into the peritoneal cavity of each mouse and LPSp was mixed in drinking water such as to be of 1 mg/kg body weight/day and allowed to be ingested ad libitum.

[0077] (2) Results

[0078] The chemotherapeutic agent cisplatin is known for various side effects (acute renal failure, abnormal BUN value, hematuria, etc.). On measuring the survival rate in the present test, it was found that by the 6th day from anticancer agent administration, although there were no dead mice in the physiological saline administration group (saline i.p.) and the cisplatin+LPS administration group (CDDP i.p.+LPS), 5 out of 6 mice died in the cisplatin administration group (CDDP i.p.). On the 14th day, 1 out of 6 mice survived in the cisplatin administration group and 5 out of 6 mice survived in the cisplatin+LPS administration group (Kaplan-Meier test: P<0.05). From the above, it was shown that LPSp administration has an effect of reducing the toxic effects of cisplatin (FIG. 2, Table 2).

TABLE-US-00002 TABLE 2 Survival rate (%) day Saline i.p. CDDP i.p. CDDP i.p. + LPS 5 100 50 100 6 100 16.7 100 7 100 16.7 83.3 14 100 16.7 83.3

Example 3

[0079] Reduction of toxic effects of the alkylating agent cyclophosphamide by LPS oral administration

[0080] (1) Method

[0081] 1) Reagents [0082] Pantoea agglomerans-derived LPS (LPSp) (mac0001 of Macrophi Inc.) [0083] Cyclophosphamide (CY) (030-12953 of FUJIFILM Wako Pure Chemical Corporation)

[0084] 2) Mice and Husbandry

[0085] Four-week-old male ICR mice were used. Husbandry of the mice was carried out in a temperature and humidity controlled animal facility under environmental conditions of ad libitum food and water, and 12 hr light/12 hr dark. As food, CE-12 of CLEA Japan, Inc. was provided. After measuring the body weights at the time of delivery, the mice were divided into 3 groups of 6 mice each.

[0086] 3) Test

[0087] Physiological saline administration group (saline i.p.): 0.5 mL of physiological saline were injected into the peritoneal cavity of each mouse.

[0088] Cyclophosphamide administration group (CY i.p.): A cyclophosphamide solution (440 mg/kg) was injected into the peritoneal cavity of each mouse.

[0089] Cyclophosphamide+LPS administration group (CY i.p.+LPS): The cyclophosphamide solution (440 mg/kg) was injected into the peritoneal cavity of each mouse and LPSp was mixed in drinking water such as to be of 1 mg/kg body weight/day and allowed to be ingested ad libitum.

[0090] (2) Results

[0091] The chemotherapeutic agent cyclophosphamide is known for various side effects (leukocytopenia, vomiting, hair loss, etc.). On measuring the body weights in the present test, significant weight loss in comparison to the physiological saline administration group (saline i.p.) was seen with the cyclophosphamide administration group (CY i.p.) and the cyclophosphamide+LPS administration group (CY i.p.+LPS) on the 3rd day from anticancer agent administration. On the 11th day and 13th day from administration, although significant weight loss in comparison to the physiological saline administration group was seen with the cyclophosphamide administration group (Tukey's multiple comparison test: P<0.05), a significant difference was not seen with the cyclophosphamide+LPS administration group (Table 3). From the above, it was shown that LPSp administration has an effect of suppressing weight loss due to cyclophosphamide.

TABLE-US-00003 TABLE 3 Mice body weights after anticancer agent administration (relative value in % with body weights for saline i.p. being 100) 0 day 3 day 11 day 13 day Saline 100 ± 2.9 100 ± 3.3   100 ± 3.0  100 ± 2.4  i.p. CY i.p. 98.6 ± 3.0  80.3 ± 4.4 **  85.1 ± 3.2 * 84.8 ± 3.9 * CY i.p. + 100 ± 8.9 82.9 ± 13.3 ** 91.8 ± 13.1  92.3 ± 13.5  LPS * P < 0.05; ** P < 0.01 (with respect to saline i.p.)

Example 4

[0092] Reduction of toxic effects of the antimetabolite 5-fluorouracil by LPS oral administration

[0093] (1) Method

[0094] 1) Reagents [0095] Pantoea agglomerans-derived LPS (LPSp) (mac0001 of Macrophi Inc.) [0096] 5-fluorouracil (5-FU) (068-01401 of FUJIFILM Wako Pure Chemical Corporation)

[0097] 2) Mice and Husbandry

[0098] Four-week-old male ICR mice were used. Husbandry of the mice was carried out in a temperature and humidity controlled animal facility under environmental conditions of ad libitum food and water, and 12 hr light/12 hr dark. As food, CE-12 of CLEA Japan, Inc. was provided. After measuring the body weights at the time of delivery, the mice were divided into 3 groups of 6 mice each.

[0099] 3) Test

[0100] Physiological saline administration group (saline i.p.): 0.5 mL of physiological saline were injected into the peritoneal cavity of each mouse.

[0101] 5-fluorouracil administration group (5-FU i.p.): A 5-fluorouracil solution (360 mg/kg) was injected into the peritoneal cavity of each mouse.

[0102] 5-fluorouracil+LPS administration group (5-FU i.p.+LPS): The 5-fluorouracil solution (360 mg/kg) was injected into the peritoneal cavity of each mouse and LPSp was mixed in drinking water such as to be of 1 mg/kg body weight/day and allowed to be ingested ad libitum.

[0103] (2) Results

[0104] The chemotherapeutic agent 5-fluorouracil is known for various side effects (leukocytopenia, diarrhea, melena, dysorexia, etc.). On measuring the body weights in the present test, on the 3rd day from anticancer agent administration, whereas a comparison of the physiological saline administration group (saline i.p.) and the 5-fluorouracil administration group (5-FU i.p.) showed a significant weight loss in the 5-fluorouracil administration group (5-FU i.p.) (Tukey's multiple comparison test: P<0.05), a significant difference was not seen between the physiological saline administration group (saline i.p.) and the 5-fluorouracil+LPS administration group (5-FU i.p.+LPS).

[0105] Also, on the 6th day, a comparison of the 5-fluorouracil administration group (5-FU i.p.) and the 5-fluorouracil+LPS administration group (5-FU i.p.+LPS) showed the 5-fluorouracil administration group (5-FU i.p.) to be significantly low (Tukey's multiple comparison test: P<0.05). From the above, it was shown that LPSp administration has an effect of reducing the toxic effects of 5-fluorouracil (Table 4).

TABLE-US-00004 TABLE 4 Mice body weights after anticancer agent administration (relative value in % with body weights for saline i.p. being 100) 0 day 3 day 6 day Saline i.p. .sup. 100 ± 5.7 100 ± 6.2  100 ± 10.7 5-FU i.p. 102.0 ± 2.4 91.8 ± 4.1 * 94.5 ± 2.6.sup.  5-FU i.p. + LPS 106.1 ± 5.7 98.1 ± 5.6.sup.  106.4 ± 5.9 ** * P < 0.05 (with respect to saline i.p.) ** P < 0.05 (with respect to 5-FU i.p.)

Example 5

[0106] Reduction of toxic effects of the alkylating agent streptozotocin by LPS oral administration

[0107] (1) Method

[0108] 1) Reagents [0109] LPS (LPSea) derived from Enterobacter asburiae belonging to genus Enterobacter of family Enterobacteriaceae (Macrophi Inc.) [0110] Streptozotocin (STZ) (SAJ-S0130 of Sigma-Aldrich)

[0111] 2) Mice and Husbandry

[0112] Six-week-old male C57BL mice were used. Husbandry of the mice was carried out in a temperature and humidity controlled animal facility under environmental conditions of ad libitum food and water, and 12 hr light/12 hr dark. As food, the D12450B diet of Research Diets, Inc. was provided. After measuring the body weights at the time of delivery, the mice were divided into 3 groups of 6 mice each.

[0113] 3) Test

[0114] Physiological saline administration group (saline i.p.): 0.5 mL of physiological saline were injected into the peritoneal cavity of each mouse.

[0115] STZ administration group (STZ i.p.): An STZ solution (313 mg/kg) was injected into the peritoneal cavity of each mouse.

[0116] STZ+LPS administration group (STZ i.p.+LPSea): The cisplatin solution (313 mg/kg) was injected into the peritoneal cavity of each mouse and LPSea was mixed in drinking water such as to be of 1 mg/kg body weight/day and allowed to be ingested ad libitum.

[0117] (2) Results

[0118] On measuring the survival rate in the present test, it was found that by the 4th day from anticancer agent administration, although there were no dead mice in the physiological saline administration group (saline i.p.) and the STZ+LPS administration group (STZ i.p.+LPSea), 1 out of 6 mice died in the STZ administration group (STZ i.p.). From the above, it was shown that LPSea administration has an effect of reducing the toxic effects of streptozotocin (FIG. 3, Table 5).

TABLE-US-00005 TABLE 5 Survival rate (%) day Saline i.p. STZ i.p. STZ i.p. + LPSea 3 100 100 100 4 100 83.33 100 8 100 83.33 100

[0119] In NPL 11, it is stated that in comparison to using the anticancer agent doxorubicin alone, there is an increase in IFN-γ etc., that contribute to cancer treatment when IP-PA1, which is a Pantoea agglomerans-derived LPS, is used in combination, that is, cancer treatment effects are improved by combined use of Pantoea agglomerans-derived LPS with doxorubicin.

[0120] On the other hand, the present invention suppresses the side effects of anticancer agents and can therefore improve the quality of medical treatment life to provide opportunities for treatment by anticancer agents to a larger number of patients and further enables larger amounts of anticancer agents to be administered to patients.

[0121] The disclosure of Japanese Patent Application No. 2019-156220 filed on Aug. 29, 2019 that includes a description, claims, and drawings is incorporated herein by reference in its entirety.

[0122] All publications, patents, and patent applications cited in this Description are incorporated herein by reference in their entirety.