Cancer starvation therapy

Abstract

The present invention is a glutamine compound having a high Z element attached via a ligand, which enters the mitochondrion and is subsequently exposed to ionizing radiation. When exposed to ionizing radiation, the present invention damages mitochondrial (as well as other) substructures such as mtDNA, the outer membrane, the inner membrane, cristae, ribosomes, etc., and causes the effective destruction of such mitochondrion. Tumorigenic cells without mitochondria cannot produce the energy they need to subsist and replicate, effectively starving them of energy and causing their destruction.

Claims

1. A method for treating tumorigenic cells by targeting the cells mitochondria comprising: treating the tumorigenic cells with a radiosensitizing containing glutamine-ligand-high Z element compound and also treating the tumorigenic cells with a high energy radiation, wherein the glutamine-ligand-high Z element compound is selected from the group consisting of the compounds having the Formula IB, IIA, IIB, IIIA, IIIB, IVA, IVB, VA or VB; wherein m=1-50 (1-5, 1-10) and wherein Z is iodine ##STR00001## ##STR00002##

2. The method of claim 1 wherein the high energy radiation is selected from the group of x-rays, gamma rays, microwaves, alpha particles, protons, and neutrons.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The accompanying drawings which are incorporated herein constitute part of the specifications and illustrate the preferred embodiment of the invention.

(2) FIG. 1 shows a collision probability equation.

(3) FIG. 2 shows a Compton interaction model.

(4) FIG. 3 shows the collision stopping power equation for electrons.

(5) FIG. 4 shows a radiative stopping power equation.

(6) FIG. 5 shows a radiation yield equation.

(7) FIG. 6 shows the amount of charged particle amplification formula.

(8) FIG. 7 shows relative amount of charged particle amplification formula when binding high Z-atoms.

(9) FIG. 8 shows plotted values of FIG. 7 equation for different values of Z.

(10) FIG. 9 shows an equation to estimate the mean of ionization potential and polarization correction.

(11) FIG. 10 shows the structure of glutamine, chemical formula C.sub.5H.sub.10N.sub.2O.sub.3.

(12) FIGS. 11A-11B shows a structural analogue of present invention with single replacement.

(13) FIGS. 12A-12B shows a structural analogue of present invention with 2 carbon replacement.

(14) FIGS. 13A-13B shows a structural analogue of present invention with 3 carbon replacement.

(15) FIG. 14A represents glutamine. FIG. 14B represents the sites of modification (A, B, C, D or E) of glutamine to which groups with high Z elements can be attached with a ligand.

(16) FIG. 15A shows representative compounds of formulas IA and IB.

(17) FIG. 15B shows representative compounds of formulas IIA and IIB.

(18) FIG. 15C shows representative compounds of formulas IIIA and IIIB.

(19) FIG. 15D shows representative compounds of formulas IVA and IVB.

(20) FIG. 15E shows representative compounds of formulas VA and VB.

(21) FIG. 16 provides examples of Formula I.

(22) FIG. 17 provides examples of Formula II.

(23) FIG. 18 provides examples of Formula III.

(24) FIG. 19 provides examples of Formula IV.

(25) FIG. 20 provides examples of Formula V.

(26) FIG. 21 provides a diagram of the cell cycle.

DESCRIPTION OF THE INVENTION

(27) The present invention is directed to a glutamine analogue composition, wherein said composition is design to be exposed and enter the mitochondrion, more particularly the mitochondria of not-healthy cells, such as but not limited to cancer cells. Subsequently the not-healthy cells become a target, wherein said targeted cells are exposed to ionizing radiation. When exposed to ionizing radiation, the present composition, having metallic particles, reacts in such way that damages mitochondrial (as well as other) substructures such as mtDNA, the outer membrane, the inner membrane, cristae, ribosomes, etc., and causes the effective destruction of such mitochondrion. The destruction of the mitochondria starts the programmed cell death of Tumorigenic cells for the reason that without mitochondria Tumorigenic cells cannot produce the energy they need to subsist and replicate, effectively starving mitochondria damaged cells of energy and causing their destruction.

(28) The invention provides a glutamine-ligand-high Z element compound for treating tumorigenic cells in combination with a high energy radiation. The glutamine-ligand-high Z element compound is selected from the group of compounds having the Formula I, II, III, IV and V (as provided in FIGS. 15A-15E). This molecule (has been termed by the inventor as the “Cancer Starvation Molecule” and the cancer treatment therapies using these compounds (along with high energy radiation) has been termed Cancer Starvation Therapy.”

(29) The Cancer Starvation Molecule was morphed from the convergence of observation of simple facts, starting by simple observation of radiation toxicity for head and neck patients, tumor microenvironment and resistance to conventional therapies, to more elaborate ideas. To date, all novel cancer approaches have helped strengthen the idea that treatments directed to the tumor metabolic pathways are the next step that could help us win the battle against cancer.

(30) The fact is that radiation therapy mainly works by damaging the DNA, which is more vulnerable in the parts of the cancer cell cycle that are also the shortest, specifically G2 and Mitosis. See FIG. 21. Even this handicap has not deterred scientists from making big strides in the battle against cancer, but there is a whole ocean of possibilities in the rest of the cancer cell cycle where conventional therapies are weak. Within the big ocean of possibilities is where the therapeutic ratio (increase cancer killing capacity with less damage possible to the patient) can improve exponentially with a Cancer Starvation Molecule (CSM) and Cancer Starvation Therapy (CST).

(31) Cancer Starvation Molecule is an organometallic molecule nonexistent in nature and capable of crossing the blood brain barrier. It was designed to enter inside the cancer cell mitochondria with predilection for tissue with low oxygen concentration (hypoxic tissue) and to be activated by a physical reaction or radiation. Therefore it is designed to work at the parts of the cancer cell cycle were chemotherapy and radiation therapy notoriously, are known to fail.

(32) It is believed that CSM and CST is suited for treating tumor culture cells like Glioblastoma multiforme (GBM). GBM are tumors that arise from glial cells or brain supporting cells, characterized by an impressive growth rate and high lethality. The landmarks that define GBM as a resistant disease reside in the fact that this tumor microenvironment is highly associated with low oxygen concentrations or hypoxia and that the tumor extends beyond what is visible by the currently available diagnostic technologies.

(33) Tumors in hypoxic environments survived by changing their metabolism from aerobic to anaerobic, which are associated by an increased presence of lactate and increased consumption of glutamine. CSM is an organometallic composed of glutamine for selective transport of a heavy metal that is the source use to increase scattered radiation inside the cancer cell mitochondria. Hypoxic microenvironment is a harsh environment, also blamed to induce the formation of cancer stem cells or cancer immortal cells. The fact that these cancer stem cells are fast dividing cells in an environment notoriously resistant to conventional therapy is what makes it a perfect target for CST.

(34) In the past therapies have attempted to conquer the battle against GBM through brute force, by increasing the radiation dose to a better defined target using Stereotactic Radio Surgery (SRS), Neutron therapy and Proton therapy. All these approaches failed because they cannot treat what cannot be seen by the available radiologic technologies. GBM is well known to be present 2-3 cm beyond what is the radiographically visible disease and using brute force therapies could kill more disease but also kills the patient. CST is designed as a Trojan's horse to be trapped by the cancer cell at the mitochondria, or the cell power house and be activated via conventional radiation therapy. By selectively damaging or even destroying the cancer cells mitochondria we cripple the cancer cell capacity to heal sub-lethal damage cause by conventional therapies, leading to damage similar to the brute force technologies but in a space that is controlled by the tumor itself.

(35) Other cancers that could benefit for Cancer Starvation Therapy include lung cancer, head and neck cancer, melanoma, rectal cancer, pancreatic cancer, esophageal cancer, cervical cancer and bladder cancers among many others.

(36) In the oncology arena lung cancer is the number one killer in developed countries. Tumor control is limited by disease volume, disease location, patient's performance status and radiation treatment doses. Local treatment failure is a major pattern of failure and although the cancer starvation molecule does not distinguish between cancers of glandular or epidermal origin, it can easily distinguish between normal and abnormal cells and could potentially be used for treatment of patients with few metastasis or oligo metastasis. This approach can take us closer to make cancer a chronic disease.

(37) For patients with head and neck cancers local failure leads to permanent surgical mutilation. Imagine that you or someone you love losses their tongue and now they cannot verbalize their thoughts and cannot swallow food, or the ones that loss the larynx and now even bathing become a very risky activity.

(38) Melanomas are known to be highly resistant to radiation because the melanoma cancer cells are known to contain high levels of antioxidants. With CST, melanoma will not only meet its match but very importantly the dramatic hike in the cost of melanoma medical care can be reduced. New melanoma medications can be as expensive as $300,000 a year, and yet they still are only a palliative approach. Our economically crumbling medical system cannot tolerate this nonsense. CST is about killing cancer stem cells and is about getting closer to achieve the abscopal effect.

(39) For some years there have been a trend to treat rectal cancers with chemoradiation and then to delay definite surgery until there is evidence of local failure. When we analyze the percentage of rectal cancer patients were surgery can be left out of the curative approach, then is easy to realize that is about the same percentage of patients anticipated to achieve a complete pathological response with preoperative chemoradiation. Having a permanent colostomy is deleterious to the patient quality of life and local progression of disease leads to metastasis and death. CST can easily double or triple a pathological complete response for patients treated with preoperative chemoradiation, leading to a decrease utilization of surgery, decrease medical care cost and a more social and psychologically empowered patient, more willing to return to the labor force and more willing to live with purpose.

(40) Having a pancreatic cancer diagnosis is very much consonant with a death sentence. Imagine that local and regional recurrence after successful surgery could be as high as 90%. Many other malignancies could be treated using the principles above described.

(41) FIG. 10 shows glutamine, wherein said glutamine is composed of a chain of three carbon atoms, Z=6, attached on either end to an additional atom of carbon. The present composition as mentioned consists in the replacement the core carbon atoms with high Z elements, such as gold atoms, Z=79. FIGS. 11-13 disclose several embodiments for the present invention. The present composition is generated, for example by replacing the carbon atoms. Further the present composition acts as a glutamine analogue compound that accesses the mitochondria. However due to the replacement of glutamine atoms for other high Z elements, such as but not limited to gold or copper, the properties of the element change providing a composition susceptible to radiation, as mentioned before.

(42) FIG. 11A, as an example, shows a first generic embodiment of the present invention compound wherein the structural analogue of glutamine, more particularly the amine functional group NH.sub.2 is replaced with a high z element, and in this generic case, three Hydrogen atoms. The Nitrogen atom may also be replaced with any high z element that would require 2 (or any number) hydrogen atoms to bind with it, in which case such generic substitution would take the form ZH.sub.2, where Z is any high z element as previously defined. Such general first embodiment is denoted with the generic chemical formula C.sub.5H.sub.11ZNO.sub.3.

(43) FIG. 11B provides a more specific embodiment of the first general embodiment presented in FIG. 11A above. As disclosed above the first embodiment consists of a structural analogue of glutamine where the amine functional group NH.sub.2 is replaced with a high z element and three Hydrogen atoms such as AuH.sub.3. The chemical formula for this specific compound is C.sub.5H.sub.11AuNO.sub.3.

(44) FIG. 12A, as an example, shows an second embodiment of the present invention, wherein a structural analogue of glutamine, more particularly two carbon atoms are replaced with high z elements. Z is any high z element as previously defined, wherein said general second embodiment is denoted with the generic chemical formula C.sub.3H.sub.10Z.sub.2N.sub.2O.sub.3.

(45) FIG. 12B provides a more specific second embodiment of the general embodiment presented in FIG. 12a above. The present second embodiment consists of a structural analogue of glutamine where two carbon atoms are replaced with Cu atoms. The chemical formula for this specific compound is C.sub.3H.sub.10Cu.sub.2N.sub.2O.sub.3.

(46) FIG. 13A, as an example, shows a third embodiment of the present invention, wherein structural analogues of glutamine, more particularly three carbon atoms are replaced with high z elements. Again Z is any high z element as previously defined, such general third embodiment is denoted with the generic chemical formula C.sub.2H.sub.10Z.sub.3N.sub.2O.sub.3.

(47) FIG. 13B provides a more specific embodiment of the general embodiment presented in FIG. 13A above. The present third embodiment consists of a structural analogue of glutamine where three carbon atoms are replaced with Au atoms. The chemical formula for this specific compound is C.sub.2H.sub.10Au.sub.3N.sub.2O.sub.3.

(48) FIG. 14A represents glutamine. Cancer starvation molecules of the invention provide glutamine molecules having high Z elements attached via a side chain or ligand to the glutamine. The side chain or ligand may be a linker of (CH.sub.2)n-X, or [(CH.sub.2CH.sub.2).sub.mX].sub.n where X═O, S, or NH, where m and n are integers, and independently range from 1-50, from 1-15 or from 1-10. For example, FIG. 14B represents the sites of modification (A, B, C, D or E) of glutamine to which groups with high Z elements can be attached.

(49) FIG. 15A shows generic formulas of each of the sites of modification to which structures with Z elements can be attached. In FIGS. 15A-15E, “Z” represents a group that either is, or contains high Z elements. In the same figure, group “X” can be O, S or NH, to which “Z” can be attached directly or via a “linker.” The “linker” should be understood as a short connector consisting of a chain of CH.sub.2 groups that can have O, S, or NH groups incorporated.

(50) FIGS. 16-20 represents structures of specific examples of possible modifications on each of the sites A, B, C, D or E. The structures of FIGS. 16-20 should be considered as non limiting examples.

(51) FIG. 16 shows compounds having groups with high Z elements attached to the carboxylic acid group of glutamine.

(52) FIG. 17 shows compounds having groups with high Z elements connected to the amino group of glutamine.

(53) FIG. 18 shows compounds having groups with high Z elements connected to the primary amide group of glutamine.

(54) FIG. 19 shows compounds that maintain the three functional groups of glutamine (A, B and C), and the high Z elements are connected to the side chain β-carbons.

(55) FIG. 20 shows compounds that maintain the three functional groups of glutamine (A, B and C), and the high Z elements are connected to the side chain γ-carbons respectively.

(56) As mentioned, the present compounds are designed to access the mitochondria, wherein the estimated charged particle density from interactions in the area immediately surrounding present invention compound increases dramatically relative to the glutamine it substitutes. For example, as previously mentioned, for a 6 MV photon beam, three gold atoms (Z=79) in such an analogue would yield a factor of 17×3=51:1 higher fluence rate than three carbon atoms they replace. The same replacement would yield a factor of 136:1 and 82:1 for 500 keV photons and an 18 MV beam, respectively.

(57) While the invention has been described as having a preferred design, it is understood that many changes, modifications, variations and other uses and applications of the subject invention will, however, become apparent to those skilled in the art without materially departing from the novel teachings and advantages of this invention after considering this specification together with the accompanying drawings. Accordingly, all such changes, modifications, variations and other uses and applications which do not depart from the spirit and scope of the invention are deemed to be covered by this invention as defined in the following claims and their legal equivalents. In the claims, means-plus-function clauses, if any, are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures.

(58) All of the patents, patent applications, and publications recited herein, and in the Declaration attached hereto, if any, are hereby incorporated by reference as if set forth in their entirety herein. All, or substantially all, the components disclosed in such patents may be used in the embodiments of the present invention, as well as equivalents thereof. The details in the patents, patent applications, and publications incorporated by reference herein may be considered to be incorporable at applicant's option, into the claims during prosecution as further limitations in the claims to patentable distinguish any amended claims from any applied prior art.