KR20230003314A - Pharmaceutical compositions and methods for the treatment of cancer - Google Patents

Abstract

tyrosine hydroxylase inhibitors; melanin, a melanin promoter, or a combination thereof; p450 3A4 promoter; and a leucine aminopeptidase inhibitor. Also provided are methods of treating cancer in a subject comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor. Also provided is a method of reducing cell proliferation in a subject comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor, a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor.

Description

Pharmaceutical compositions and methods for cancer treatment {PHARMACEUTICAL COMPOSITIONS AND METHODS FOR THE TREATMENT OF CANCER}

technical field

The present invention relates generally to compositions, kits and methods for reducing cell proliferation, such as in the treatment of cancer.

background technology

According to the U.S. National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database in 2008, the most recent year for which incidence data are available, 11,958,000 Americans have invasive cancer. Cancer is the second most common cause of death in the United States, behind heart disease, and accounts for 1 in 4 deaths. It is estimated that approximately 1600 Americans die of cancer every day. In addition to the pharmaceutical, emotional and psychological costs of cancer, cancer has significant financial costs to both industry and society. According to the National Institutes of Health, the total cost of cancer in 2010 was estimated at $263.8 billion. Moreover, it is estimated that another $140.1 billion of lost productivity is due to premature deaths.

Cancer treatments today include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapies, and combinations thereof. Surgical removal of the cancer was significantly advanced; However, a high probability of recurrence of the disease remains. Hormonal therapy with drugs such as aromatase inhibitors and luteinizing hormone-releasing hormone analogues and inhibitors is relatively effective in the treatment of prostate and breast cancer. Stereotactic proton beam radiotherapy, stereotactic radiosurgery, stereotactic radiotherapy, intraoperative radiotherapy, chemical modulators and radiosensitizers, radiation and related technologies are effective in killing cancer cells, but can also kill and transform surrounding normal tissues. can Chemotherapy drugs, both alone and in combination, such as aminopterin, cisplatin, methotrexate, doxorubicin, daunorubicin, etc., are often effective in killing cancer cells by modifying the process of DNA replication. Biological response modifier (BRM) therapy, biologic therapy, biotherapy or immunotherapy modifies cancer cell growth or influences the natural immune response and uses biologic agents such as interferons, interleukins and other cytokines and antibodies, e.g. Examples include administering cancer vaccines such as Rituximab and Trastuzumab and even Sipuleucel-T to patients.

Recently, new targeted therapies have been developed to combat cancer. Because chemotherapy works by killing both cancer and normal cells, their targeted therapies differ from chemotherapy in that they have a greater effect on cancer cells. Targeted therapies work by influencing the processes that regulate the growth, division and metastasis of cancer cells and the signals that naturally cause cancer cell death. One type of targeted therapy includes growth signal inhibitors such as trastuzumab, gefitinib, imatinib, cetuximab, dasatinib and nilotinib. Another type of targeted therapy includes angiogenesis inhibitors, such as bevacizumab, which prevent cancer from increasing the surrounding vasculature and blood supply. A final type of targeted therapy involves apoptosis-inducing drugs that can cause direct cancer cell death.

Although all of these treatments are effective to some extent, they all have drawbacks and limitations. Besides being expensive, many treatments are also often too imprecise or the cancer can adapt to them and become resistant.

Thus, there is a very great demand for additional cancer treatments. In particular, there is a demand for treatments for cancers that have become resistant to other forms of treatment.

[Prior art documents in which background art is disclosed]

US Application Publication No. 2013/0183263 (Publication date: 2013.07.18.)

US Patent Publication No. 8,481,498 (published on July 9, 2013)

summary

The present invention provides compositions, combination therapies, kits and methods for reducing excessive cell proliferation, including those associated with the treatment of cancer. In certain embodiments, the invention provides at least one tyrosine hydroxylase inhibitor; At least one kind of melanin, a melanin promoter or a combination thereof; at least one p450 3A4 promoter; at least one leucine aminopeptidase inhibitor; and optionally at least one growth hormone inhibitor. In another embodiment, the present invention provides kits comprising these components together with suitable packaging. Also provided are methods for reducing cell proliferation and/or an effective amount of at least one tyrosine hydroxylase inhibitor; At least one kind of melanin, a melanin promoter or a combination thereof; at least one p450 3A4 promoter; at least one leucine aminopeptidase inhibitor; and a method of treating cancer comprising administering any of at least one growth hormone inhibitor to a subject in need thereof.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The subject matter of the present invention may be more readily understood by reference to the following detailed description, which forms a part of this disclosure. The present invention is not limited to the specific products, methods, conditions or parameters described and/or shown herein, and the terminology used herein is intended to describe specific embodiments by way of example only and is not intended to limit the claimed invention. You have to understand.

Unless defined otherwise herein, scientific and technical terms used in connection with this application shall have the meanings commonly understood by one of ordinary skill in the art. Also, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

As used above and throughout this disclosure, unless otherwise indicated, the following terms and abbreviations will be understood to have the following meanings.

In this disclosure, the singular forms "a", "an" and "the" include plural references, and references to a particular number include at least that particular value unless the context clearly dictates otherwise. Thus, for example, a reference to “a compound” is a reference to one or more such compounds and equivalents thereof known to those skilled in the art, and the like. As used herein, the term "plurality" means more than one. Where a range of values is expressed, another embodiment includes from one particular value and/or to another particular value. Similarly, when values are expressed as approximations, by use of the preceding “about,” it is understood that the particular value forms another embodiment. All ranges are comprehensive and combinable.

As used herein, the terms "ingredient," "composition," "composition of a compound," "compound," "drug," "pharmacologically active agent," "active agent," "therapeutic," "therapy," "treatment, " or "agent" refers herein to a compound or composition of compounds or substances that, when administered to a subject (human or animal), elicits a desired pharmacological and/or physiological effect by local and/or systemic action. are used interchangeably in

As used herein, the term "treatment" or "therapy" (as well as its different forms) includes preventive (eg, prophylactic), curative or palliative treatment. As used herein, the term “treating” includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder. The condition, disease or disorder may be cancer.

As used above and throughout this disclosure, the term “effective amount” refers to an amount effective at a dosage and for a period of time necessary to achieve a desired result with respect to the treatment of a related disorder, condition or side effect. An effective amount of a component of the present invention depends not only on the particular compound, ingredient or composition selected, the route of administration and the ability of the ingredient to produce the desired result in the individual, but also the severity of the disease state or condition to be alleviated, the individual's hormone levels, age, sex , will vary from patient to patient due to factors such as weight, the condition of the patient and the severity of the pathological condition being treated, concomitant medications or special diets followed thereafter by the particular patient, and other factors recognized by those skilled in the art; the appropriate dosage is at the physician's discretion. It will be recognized that there is Dosage regimens may be adjusted to provide improved therapeutic response. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or detrimental effects of the ingredient.

“Pharmaceutically acceptable” means a compound, substance, within the scope of sound medical judgment, suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problematic complication commensurate with a reasonable benefit/risk ratio. , composition and/or dosage form.

In the present invention, the disclosed compounds can be prepared in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds, wherein the parent compound is modified by making acidic or basic salts thereof. Examples of pharmaceutically acceptable salts include inorganic or organic acid salts of basic moieties such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like, but are not limited thereto. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid , 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, and the like. Their physiologically acceptable salts can be prepared by methods known in the art, for example by dissolving the free amine base with an excess of acid in aqueous alcohol or by adding the free carboxylic acid to an alkali metal base such as a hydroxide. It can be prepared by neutralization with or with an amine.

The compounds described herein may be prepared in alternative forms. For example, many amino-containing compounds can be used or prepared as acid addition salts. Often these salts improve the separation and operability of the compound. For example, depending on reagents, reaction conditions, etc., the compounds described herein may be used or prepared as, for example, their hydrochloride or tosylate salts. Isomorphic crystalline forms, all chiral and racemic forms, N-oxides, hydrates, solvates and acid salt hydrates are also contemplated as being within the scope of this invention.

Certain acidic or basic compounds of the present invention may exist as zwitter ions. All forms of the compound, including free acids, free bases and zwitterions, are contemplated within the scope of this invention. It is well known in the art that compounds containing both amino and carboxyl groups often exist in equilibrium with their zwitterionic forms. Thus, any compounds described herein that contain, for example, both an amino group and a carboxy group also include reference to their corresponding zwitterion.

The term “stereoisomers” refers to compounds that have the same chemical makeup, but differ with respect to the arrangement of their atoms or groups in space.

The term “administering” means either directly administering a compound or composition of the present invention or administering a precursor, derivative or analog that will form an equivalent amount of the active compound or substance in the body.

The terms "subject," "individual," and "patient" are used interchangeably herein and refer to an animal, such as a human, for whom treatment is being provided, including prophylactic treatment, with a pharmaceutical composition according to the present invention. . As used herein, the term “subject” refers to human and non-human animals. The terms “non-human animal” and “non-human mammal” are used interchangeably herein and include all vertebrates, including mammals, including non-human primates, (particularly higher primates), sheep, dogs, rodents, (eg mice or rats), guinea pigs, goats, pigs, cats, rabbits, cows, horses and non-mammals such as reptiles, amphibians, chickens and turkeys.

As used herein, the term "inhibitor" includes compounds that inhibit the expression or activity of a protein, polypeptide or enzyme and do not necessarily imply complete inhibition of expression and/or activity. Rather, inhibition includes inhibition of the expression and/or activity of a protein, polypeptide or enzyme to a sufficient extent and for a sufficient time to produce the desired effect.

As used herein, the term "promoter" includes compounds that promote the expression or activity of a protein, polypeptide or enzyme, but do not necessarily imply complete promotion of expression and/or activity. Rather, promotion includes promotion of the expression and/or activity of a protein, polypeptide or enzyme to a degree and for a time sufficient to produce the desired effect.

In one embodiment, the present invention provides combination therapies that modify the defense of cancer cells against oxidative stress. One class of these therapies increases the availability of free radicals to cancer cells. Representative subclasses of such therapy include administration of a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor, melanin or a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor and any growth hormone inhibitor. Another subclass includes the administration of pharmaceutical compositions comprising melanin and tyrosine hydroxylase inhibitors, respectively. Specific components of the pharmaceutical composition are described below.

While not intending to be limited to any specific mechanism of action, the tyrosine hydroxylase inhibitors according to the present invention function by accumulating in cancer cells and preventing them from forming a coating of lipids or hyaluronan. It is believed that by preventing cancer cells from forming a coating of lipids or hyaluronic acid, cancer cells are made more accessible to oxidative stress. Representative tyrosine hydroxylase inhibitors include tyrosine derivatives that are typically rapidly absorbed by most cancers and inflamed tissues. Representative tyrosine derivatives include one or more of methyl (2R)-2-amino-3-(2-chloro-4-hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2-amino-3 -(2,6-dichloro-3,4-dimethoxyphenyl)propanoate HD-Tyr(TBU)-allyl ester HCl, methyl (2R)-2-amino-3-(3-chloro-4,5- Dimethoxyphenyl) Propanoate, Methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) Propanoate, Methyl (2R)-2-amino-3- (4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propano Eight, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2 -chloro-6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3- (3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino- 3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl ) Propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr -OME HCl, HD-3,5-diiodo-tyr-OME HCl, HD-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, HD -tyr-OMe HCl, D-tyrosine methyl ester HCl, HD-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3 -(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-( 4-hydroxyphenyl) propanoate hydrochloride, 3-chloro-L- Tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL- m -tyrosine, DL- o -tyrosine, Boc-Tyr (3,5-I ₂ )-OSu, Fmoc- tyr(3-NO ₂ )-OH and α-methyl-DL-tyrosine (also known as DL-2-methyl-3-(4-hydroxyphenyl) alanine).

The present invention includes the use of at least one type of melanin, a melanin promoter or a combination thereof. Thus, melanin may be used, more than one melanin promoter may be used, and both melanin and more than one melanin promoter may be used (either in separate dosage forms or in the same dosage form). The melanin promoter according to the present invention is a chemical compound that increases the production and/or activity of melanin. It is believed that increased melanin levels reduce inflammation (eg, through inhibition of TNF) and exclude the sequestered lymphatic system. Melanin is a photocatalyst and can therefore promote chemical reactions that generate free radicals, ie, become accessible to cancer cells. Representative melanin promoters are methoxsalen and melanotan II.

In some cases, the tyrosine hydroxylase inhibitor is mixed into the same dosage form as melanin. It is believed that this association of melanin with tyrosine hydroxylase inhibitors facilitates melanin uptake in cancer cells because tyrosine hydroxylase inhibitors are more readily uptake by these cells. In certain embodiments melanin is dissolved in a solubilizing agent and then mixed with a tyrosine hydroxylase inhibitor by methods known in the art. Solubilizers can be removed by standard techniques, such as evaporation, drying, and the like. The solubilizer may be a non-toxic solubilizer, such as hydrogen peroxide or other solubilizers commonly known in the art. Melanin and/or the pharmaceutical composition may be further processed to optimize the effect of the pharmaceutical composition on cancer cells. In another embodiment the pharmaceutical composition may include additional active agents and/or pharmaceutical excipients.

The pharmaceutical composition of the present invention also includes the p450 3A4 promoter. "Cytochrome p450 3A4" (which may be abbreviated to "p450 3A4") is an enzyme belonging to the cytochrome p450 superfamily and is a mixed-function oxidase involved in xenobiotic metabolism in the body. It has the widest range of substrates of all cytochromes. The function of the p450 3A4 promoter in the pharmaceutical composition of the present invention is to increase the expression and/or activity of p450 3A4. It is believed that increased p450 3A4 expression and/or activity reduces cortisone and estrogen levels in patients. Additionally, it is believed that increased p450 3A4 expression and/or activity also slightly reduces blood pH, which helps preserve and enhance melanin activity. Representative p450 3A4 promoters are 5,5-diphenylhydantoin (eg, sold commercially as Dilantin), valproic acid, and carbamazepine, which are believed to drive expression of the p450 3A4 enzyme. .

The pharmaceutical composition further comprises a leucine aminopeptidase inhibitor (otherwise known as a leucyl aminopeptidase inhibitor). Leucine aminopeptidases are enzymes that preferentially catalyze the hydrolysis of the N-terminal leucine residues of peptides and/or proteins. Inhibiting the expression and/or activity of leucine aminopeptidase is believed to increase cholesterol transport to the liver to aid in tumor resorption. It is generally believed that aminopeptidase inhibitors, including aminopeptidase inhibitors, deplete tumor cells that are sensitive to certain amino acids by preventing protein recycling, thus producing an antiproliferative effect. Representative leucine aminopeptidase inhibitors are N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine and rapamycin.

The pharmaceutical composition also optionally includes a growth hormone inhibitor. Growth hormone (eg, pancreatic growth hormone) triggers cell replication. It is believed that inhibition of the expression and/or activity of growth hormone allows cancer cells to continue rapid replication to incorporate tyrosine derivatives while excluding normal cells from rapid replication. Representative growth hormone inhibitors are octreotide, somatostatin and seglitide.

A pharmaceutical composition of the present invention may further comprise D-leucine. D-leucine is a stereoisomer of naturally occurring L-leucine, a form of leucine that is incorporated into polypeptides and proteins. D-leucine cannot be incorporated into polypeptides and/or proteins. In combination with leucine aminopeptidase inhibitors, D-leucine is believed to create a physiological environment similar to leucine deficiency. Thus, the presence of D-leucine permits the use of lower doses of the leucine aminopeptidase inhibitor in pharmaceutical compositions.

Also provided herein are kits comprising combination therapies that create alterations in the defense of cancer cells against oxidative stress. An intended suitable embodiment is a kit comprising a combination therapy that increases the availability of free radicals to cancer cells. An exemplary kit includes a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor and, optionally, a growth hormone inhibitor of the type described above, together in the same packaging. A kit may include one or more separate containers, dividers or compartments and optionally an informational medium, such as instructions for administration. For example, each inhibitor or promoter (or various combinations thereof) can be contained in a bottle, vial or syringe and the informational media can be contained in or labeled in a plastic sleeve or packet. In some embodiments, a kit comprises a plurality of separate containers (eg, packs) each containing one or more unit dosage forms of a compound described herein. For example, a kit may include a plurality of syringes, ampoules, foil packets, or blister packs, each containing a single unit dose of a compound described herein or any of the various combinations thereof. Containers of the kit may be airtight, waterproof ( eg, not subject to change or evaporation of moisture), and/or shielded from light. The kit optionally includes a suitable device for administration of the composition, such as a syringe, inhaler, pipette, tweezers, measuring spoon, dropper ( eg, eye dropper), cotton swab ( eg, cotton swab or wooden swab), or Any such delivery device is included.

Methods of treating cancer in a subject are also provided as methods of reducing excessive cell proliferation. Such methods may include administering an effective amount of the combination therapy to promote alteration of the cancer cell's defenses against oxidative stress. Representative methods of treating cancer include administering an effective amount of a combination therapy that increases the availability of free radicals to cancer cells. A suitable embodiment is a method comprising administering an effective amount of an above-described tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter, a leucine aminopeptidase inhibitor and optionally a growth hormone inhibitor. Another suitable method involves administering an effective amount of a melanin and tyrosine hydroxylase inhibitor.

A suitable method is the simultaneous administration of at least two tyrosine hydroxylase inhibitors, melanin or a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor, at least three of these or each of them (in each case, optionally with a growth hormone inhibitor). or at least co-administration. It is believed that effective concentrations of these moieties are contemporaneously present in the subject's bloodstream, and any dosing regimen that achieves this is within the scope of this invention. The desired number of inhibitors and promoters may be provided in any desired number of dosage forms including single dosage forms or separate dosage forms. Representative dosage forms include tablets, capsules, dragees, sterile aqueous or organic solutions, reconstitutable powders, elixirs, liquids, colloidal or other types of suspensions, emulsions, beads, beadlets, granules, microparticles, nanoparticles, and combinations thereof. include The amount of composition administered will, of course, depend on the subject being treated, the weight of the subject, the severity of the condition being treated, the method of administration and the judgment of the prescribing physician.

Administration of melanin, promoters and/or inhibitors can be via a variety of routes, including orally, intranasally, subcutaneously, intravenously, intramuscularly, transdermally, vaginally, rectally, or any combination thereof. Transdermal administration can be effected using, for example, oleic acid, 1-methyl-2-pyrrolidone or dodecylnonaoxyethylene glycol monoether.

The melanin, promoters and/or repressors may be administered during a cycle consisting of 5 to 7 days of administration of melanin, promoters and/or repressors and 1 to 2 days of no melanin, promoters and/or repressors. Melanin, promoters and/or repressors may be administered over at least 6 of these cycles. It may be desirable to administer these ingredients about 2 hours between meals to facilitate intake.

A subject to whom the present composition is administered may be a mammal, preferably a human.

In one exemplary method, 60 mg of a tyrosine derivative is administered orally and 0.25 mL of a suspension of a 2 mg/mL tyrosine derivative is administered subcutaneously; 10 mg of methoxsalen is administered orally and 0.25 mL of a 1 mg/mL suspension of methoxsalen is administered subcutaneously; 30 mg of 5,5-diphenylhydantoin is administered orally; Then, 20 mg of N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is orally administered.

In certain embodiments, the combination therapy comprises: (i) a dosage form comprising melanin (50 meg) and α-methyl-DL-tyrosine (75 mg); (ii) a dosage form comprising 5,5-diphenylhydantoin (15 mg) and α-methyl-DL-tyrosine (75 mg); (iii) a dosage form comprising 3-amino-2-hydroxy-4-phenylbutyryl-L-leucine (50 meg) and α-methyl-DL-tyrosine (75 mg); (iv) administration comprising 3-amino-2-hydroxy-4-phenylbutyryl-L-leucine (5 meg), melanotan II (10 meg) and 5,5-diphenylhydantoin (2 mg) brother; and (v) α-methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic water. In another embodiment, the combination therapy comprises: (i) a dosage form comprising melanin (50 meg) and α-methyl-DL-tyrosine (75 mg); (ii) a dosage form comprising 5,5-diphenylhydantoin (15 mg) and α-methyl-DL-tyrosine (75 mg); (iii) a dosage form comprising rapamycin (0.2 mg) and α-methyl-DL-tyrosine (75 mg); (iv) a dosage form comprising rapamycin (0.15 meg), melanotan II (10 meg) and 5,5-diphenylhydantoin (2 mg); and (v) α-methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic water. Doses greater than 2-fold and even greater than 4-fold are believed to be safe and effective.

Representative methods include those where the cancer is non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is stage 4 non-small cell lung cancer. In another embodiment, the cancer is ovarian cancer, breast cancer, cervical cancer, pancreatic cancer, stomach cancer, brain cancer, liver cancer, testicular cancer, leukemia, lymphoma, appendix cancer, cholangiocarcinoma, cholangiocarcinoma, colorectal cancer, colon cancer, germ cell tumor, glioma, tiger Hodgkin's lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, thyroid cancer, tongue cancer, tonsillar squamous cell carcinoma or urothelial cell carcinoma.

In certain embodiments, one or more tyrosine hydroxylase inhibitors; melanin promoter; p450 3A4 promoter; and leucine aminopeptidase inhibitors are fragments of nucleic acids, proteins, antibodies or antigen-binding antibodies.

In addition to the disclosed administering steps, the method may also include assessing progression of the cancer in the subject and/or extent of cell proliferation. The evaluating step can be performed before or after the administering step.

A suitable embodiment may include a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor. The pharmaceutical composition may further include a growth hormone inhibitor. The growth hormone may be pancreatic growth hormone. The growth hormone inhibitor may be octreotide or somatostatin. The tyrosine hydroxylase inhibitor may be a tyrosine derivative. Tyrosine derivatives can be selected from one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2-amino-3-( 2,6-dichloro-3,4-dimethoxyphenyl) propanoate HD-Tyr(TBU)-allyl ester HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxy phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4 -[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate, Methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro -6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3- (3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3- (3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl) pro Panoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, HD-3,5-diiodo-tyr-OME HCl, HD-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, HD-tyr -OMe HCl, D-tyrosine methyl ester HCl, HD-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-( 4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4- hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL- m -tyrosine, DL- o -tyrosine, Boc-Tyr (3,5-I ₂ )-OSu, Fmoc-tyr( 3-NO ₂ )-OH and α-methyl-DL-tyrosine. The melanin promoter may be methoxsalen or melanotan II. The p450 3A4 promoter may be 5,5-diphenylhydantoin. The p450 3A4 promoter may be valproic acid or carbamazepine. The leucine aminopeptidase inhibitor may be N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or rapamycin. A pharmaceutical composition of the present invention may further comprise D-leucine.

Also provided herein is a kit comprising a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor together in the same package. The kit may further include a growth hormone inhibitor. The growth hormone may be pancreatic growth hormone. The growth hormone inhibitor may be octreotide or somatostatin. The tyrosine hydroxylase inhibitor may be a tyrosine derivative. Tyrosine derivatives can be selected from one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2-amino-3-( 2,6-dichloro-3,4-dimethoxyphenyl) propanoate HD-Tyr(TBU)-allyl ester HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxy phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4 -[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate, Methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro -6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3- (3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3- (3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl) pro Panoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, HD-3,5-diiodo-tyr-OME HCl, HD-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, HD-tyr -OMe HCl, D-tyrosine methyl ester HCl, HD-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-( 4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride methyl (2R)-2-azanyl-3-(4-hydroxy oxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3 -nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL- m -tyrosine, DL- o -tyrosine, Boc-Tyr (3,5-I ₂ )-OSu, Fmoc-tyr(3 -NO ₂ )-OH and α-methyl-DL-tyrosine. The melanin promoter may be methoxsalen or melanotan II. The P450 3A4 promoter may be 5,5-diphenylhydantoin, valproic acid or carbamazepine. The leucine aminopeptidase inhibitor may be N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine or rapamycin. The kits of the present invention may further include D-leucine.

Also provided is a method of treating cancer in a subject comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor, melanin and/or a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor. In suitable embodiments, the method of treating cancer may further include a growth hormone inhibitor. In certain embodiments, at least two components ( ie, melanin, promoter and/or repressor) are administered simultaneously. In other embodiments, at least three components are administered simultaneously. Each component may be administered simultaneously. In a suitable embodiment, the component is administered orally, subcutaneously, intravenously, transdermally, vaginally, rectally, or optionally a combination thereof. Transdermal administration can be with oleic acid, 1-methyl-2-pyrrolidone or dodecylnonaoxyethylene glycol monoether. In another embodiment, the component is administered during a cycle consisting of 5 to 7 days with administration of the component and 1 to 2 days without administration of the component. A component may be administered over at least 6 such cycles. The tyrosine hydroxylase inhibitor may be a tyrosine derivative. Tyrosine derivatives can be selected from one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2-amino-3-( 2,6-dichloro-3,4-dimethoxyphenyl) propanoate HD-Tyr(TBU)-allyl ester HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxy phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4 -[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate, Methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro -6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3- (3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3- (3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl) pro Panoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, HD-3,5-diiodo-tyr-OME HCl, HD-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, HD-tyr -OMe HCl, D-tyrosine methyl ester HCl, HD-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-( 4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4- hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL- m -tyrosine, DL- o -tyrosine, Boc-Tyr (3,5-I ₂ )-OSu, Fmoc-tyr( 3-NO ₂ )-OH and α-methyl-DL-tyrosine. In a suitable embodiment of the method, 60 mg of the tyrosine derivative is administered orally and 0.25 mL of a suspension of the 2 mg/mL tyrosine derivative is administered subcutaneously. The melanin promoter may be methoxsalen. In another suitable method, 10 mg of methoxsalen is administered orally and 0.25 mL of a 1 mg/mL suspension of methoxsalen is administered subcutaneously. The melanin promoter may also be melanotan II. The P450 3A4 promoter may be 5,5-diphenylhydantoin. In another suitable method, 30 mg of 5,5-diphenylhydantoin is administered orally. The P450 3A4 promoter may also be valproic acid or carbamazepine. The leucine aminopeptidase inhibitor may be N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. In another suitable method, 20 mg of N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is administered orally. The leucine aminopeptidase inhibitor may also be rapamycin. The growth hormone may be pancreatic growth hormone. The growth hormone inhibitor may be octreotide. The method may further include administering an effective amount of D-leucine. The subject may be a mammal and the mammal may be a human. Representative methods include those where the cancer is non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is stage 4 non-small cell lung cancer. In other embodiments, the cancer is ovarian cancer, breast cancer, cervical cancer, cancer of the pancreas, stomach cancer, brain cancer, liver cancer, testicular cancer, leukemia, lymphoma, appendix cancer, cholangiocarcinoma, cholangiocarcinoma, colorectal cancer, colon cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, thyroid cancer, tongue cancer, tonsillar squamous cell carcinoma or urothelial cell carcinoma. In other suitable embodiments, the tyrosine hydroxylase inhibitor, melanin promoter, p450 3A4 promoter and leucine aminopeptidase inhibitor are fragments of one or more nucleic acids, proteins, antibodies or antigen-binding antibodies. Another suitable embodiment further comprises assessing progression of said cancer in said subject. The evaluation step may be performed before the administration step or the evaluation step may be performed after the administration step.

an effective amount of a tyrosine hydroxylase inhibitor; melanin and/or melanin promoter; p450 3A4 promoter; and methods of reducing cell proliferation in a subject comprising administering a leucine aminopeptidase inhibitor to a subject in need thereof. In suitable embodiments, the method of treating cancer may further include a growth hormone inhibitor. In certain embodiments, at least two compounds ( ie , melanin, promoter and/or repressor) are administered simultaneously. In another embodiment, at least three compounds are administered simultaneously. Each component may be administered simultaneously. In a suitable embodiment, the component is administered orally, subcutaneously, intravenously, transdermally, vaginally, rectally, or any combination thereof. Transdermal administration may be with oleic acid, 1-methyl-2-pyrrolidone or dodecylnonaoxyethylene glycol monoether. In another embodiment, the component is administered during a cycle consisting of 5 to 7 days with administration of the component and 1 to 2 days without administration of the component. A component may be administered over at least 6 such cycles. The tyrosine hydroxylase inhibitor may be a tyrosine derivative. Tyrosine derivatives can be selected from one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2-amino-3-( 2,6-dichloro-3,4-dimethoxyphenyl) propanoate HD-Tyr(TBU)-allyl ester HCl, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxy phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4 -[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3,4-dimethoxyphenyl) propanoate, Methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro -6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3- (3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3- (3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6-dichloro-3-hydroxy-4-methoxyphenyl) pro Panoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-tyr-OME HCl, HD-3,5-diiodo-tyr-OME HCl, HD-tyr-OME HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HCl, methyl D-tyrosinate hydrochloride, HD-tyr -OMe HCl, D-tyrosine methyl ester HCl, HD-Tyr-OMe-HCl, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-( 4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4- hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL- m -tyrosine, DL- o -tyrosine, Boc-Tyr (3,5-I ₂ )-OSu, Fmoc-tyr( 3-NO ₂ )-OH and α-methyl-DL-tyrosine. In a suitable embodiment of the method, 60 mg of the tyrosine derivative is administered orally and 0.25 mL of a suspension of the 2 mg/mL tyrosine derivative is administered subcutaneously. The melanin promoter may be methoxsalen. In another suitable method, 10 mg of methoxsalen is administered orally and 0.25 mL of a 1 mg/mL suspension of methoxsalen is administered subcutaneously. The melanin promoter may also be melanotan II. The P450 3A4 promoter may be 5,5-diphenylhydantoin. In another suitable method, 30 mg of 5,5-diphenylhydantoin is administered orally. The P450 3A4 promoter may also be valproic acid or carbamazepine. The leucine aminopeptidase inhibitor may be N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. In another suitable method, 20 mg of N -[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine is administered orally. The leucine aminopeptidase inhibitor may also be rapamycin. The growth hormone may be pancreatic growth hormone. The growth hormone inhibitor may be octreotide. The method may further include administering an effective amount of D-leucine. The subject may be a mammal and the mammal may be a human. An exemplary method includes the cancer being non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is stage 4 non-small cell lung cancer. In other embodiments, the cancer is ovarian cancer, breast cancer, cervical cancer, cancer of the pancreas, stomach cancer, brain cancer, liver cancer, testicular cancer, leukemia, lymphoma, appendix cancer, cholangiocarcinoma, cholangiocarcinoma, colorectal cancer, colon cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, thyroid cancer, tongue cancer, tonsillar squamous cell carcinoma or urothelial cell carcinoma. In other suitable embodiments, the tyrosine hydroxylase inhibitor, melanin promoter, p450 3A4 promoter and leucine aminopeptidase inhibitor are fragments of one or more nucleic acids, proteins, antibodies or antigen-binding antibodies. Another suitable embodiment further comprises assessing progression of said cancer in said subject. The evaluation step can be performed before the administration step or the evaluation step can be performed after the administration step.

The following illustrations of specific embodiments for carrying out the invention are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

Representative pharmaceutical compositions and methods of administering the combination therapy are also provided. Various embodiments of the present invention further relate to methods of administering a pharmaceutical composition or combination therapy to a human patient for the treatment of cancer. The method may include administering the pharmaceutical composition or combination therapy by generally accepted routes of administration (eg, oral, subcutaneous, parenteral, inhalational, topical, etc.). In some instances, a pharmaceutical composition or combination therapy may be administered orally and/or subcutaneously. In some instances, a pharmaceutical composition or combination therapy may be administered between meals to a human patient.

In certain embodiments of the present invention, the pharmaceutical composition or combination therapy may be administered to a human patient 5 days per week for a period of 6 weeks to make a 30 day treatment cycle. Depending on the results after 6 weeks or 1 cycle of treatment, additional cycles of the pharmaceutical composition or combination therapy may be administered.

The present invention also

- tyrosine hydroxylase inhibitors; and melanin, a melanin promoter or a combination thereof (preferably melanin);

- a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor and a p450 3A4 promoter;

- pharmaceutical compositions comprising tyrosine hydroxylase inhibitors and leucine aminopeptidase inhibitors; and

- melanin, a melanin promoter or a combination thereof (preferably Melanotan II); p450 3A4 promoter; and a leucine aminopeptidase inhibitor.

The tyrosine hydroxylase inhibitor in these compositions is preferably α-methyl-DL-tyrosine, the p450 3A4 promoter is preferably 5,5-diphenylhydantoin and the leucine aminopeptidase inhibitor is preferably N-[ (2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine. The invention also relates to kits comprising each of these pharmaceutical compositions together with a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor; and administering each pharmaceutical composition to a patient together with a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor, preferably such that they are administered to the patient within a 24 hour period.

Example 1

Clinical trials were conducted to evaluate the efficacy, safety, acceptability and tolerability of combination therapies according to embodiments of the present invention as treatment for metastatic cancer.

Combination therapy included:

(a) capsules containing melanin (50 mcg) and α-methyl-DL-tyrosine (75 mg), administered orally;

(b) a capsule containing 5,5-diphenylhydantoin (15 mg) and α-methyl-DL-tyrosine (75 mg), administered orally;

(c) a capsule containing 5,5-diphenylhydantoin (15 mg) and α-methyl-DL-tyrosine (75 mg), administered orally;

(d) capsule containing rapamycin (0.2 mg) and α-methyl-DL-tyrosine (75 mg), administered orally;

(e) a suspension comprising rapamycin (0.15 meg), melanotan II (10 meg) and 5,5-diphenylhydantoin (2 mg), administered subcutaneously; and

(f) Suspension containing α-methyl-DL-tyrosine (5 mg) in NaCl bacteriostatic water, administered subcutaneously.

Combination therapy was administered to each patient 5 days a week for 6 weeks. More than 200 patients were screened. All patients with metastatic cancer were included in the criteria. Thirty patients who met the criteria were accepted and entered the trial.

Treatment of metastatic breast cancer

Fourteen patients in this trial had metastatic breast cancer. Patient information and results are shown in Table 1 below:

One side effect of the treatment was hyperpigmentation in all patients. Overall, all patients tolerated the combination therapy and no side effects were reported.

Over 200 patients were screened in clinical trials. Thirty subjects who met the test criteria consented. The mean patient age was 56 years and ranged from 30 to 70 years. A tyrosine hydroxylase inhibitor (i.e., α-methyl-DL tyrosine), a melanin promoter (i.e., melanotan II), a p450 3A4 promoter (i.e., 5,5-diphenylhydantoin), and leucine aminopeptone were administered to patients in this study. A treatment regimen comprising a tidase inhibitor (i.e., rapamycin) was administered. These compounds were administered each 5 days per week for a period of 6 weeks, with 1 or 2 days off between weekly cycles.

After 6 weeks of treatment, 12 of 30 patients (40%) were grade 0–5 by the Eastern Cooperative Oncology Group (ECOG) (Oken, et al., Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group , Am. J. Clin. Oncol., 5:649-655, 1982). Fourteen out of 30 (46%) had a 1-3 point improvement in their ECOG score.

Fourteen out of 30 patients (46%) scored on the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC) grades 1-7 ( For example, Bergman, et al., The EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life Questionnaire (QLQ-C30) for use in lung cancer clinical trials, EORTC Study Group on Quality of Life, Eur. J. Cancer, 1994. 30A(5): p. 635-42). Sixteen of 30 (54%) had a 1–5 point improvement in their EORTC score.

Eleven of 30 patients gained 1 to 9 pounds, 17 of 30 stayed at the same weight, and 2 of 30 lost 1 to 2 pounds.

Pain levels were reduced in 13 of 30 (43%) patients. Seventeen out of 30 (57%) participated with minimal pain and remained the same. Nine out of 30 (30%) took pain medication to participate in the trial and 8 out of these nine (89%) no longer needed pain medication at the end of the cycle.

In 4 of 30 (13%) patients, no disease was observed on routine physical examination, whole body review, and imaging. Eight out of 30 (27%) had a significant reduction in tumor quantity and/or largest tumor size. Eight out of 30 (27%) showed a decrease in the number of tumors and/or the size of the largest tumor. Ten of 30 patients (33%) showed no disease progression.

Twenty-nine of 30 patients survived with a median survival of 22 weeks. Thirteen out of 30 (43%) were rescued and returned home. Seventeen out of 30 (57%) continue treatment. Hyperpigmentation developed in all subjects.

Overall, the above-described treatment was well tolerated by the subjects, there were no treatment-related side effects and a response to treatment was recorded as 100%.

Example 2

In one aspect, the present invention provides a method of inducing melanin production in vivo with one or both of methoxsalen and melanotan and/or via administration of melanin. Without wishing to be bound by any particular theory of operation, it is believed that melanin enables beneficial and therefore desirable reactions or potentials because of its photocatalytic nature and its ability to convert a variety of ambient wavelengths or evoked electromagnetic radiation into electrical energy. . It has been determined that in some patients, because of genetic variability, infirmity, urgent need for use or to realize maximum efficacy, melanin is preferably mechanically or chemically combined with α-methyl-DL-tyrosine prior to administration.

As a photocatalyst, melanin is believed to be polar at some point in its physical mass. It has been determined that small melanin particles can produce less electrical energy than larger particles and that a plurality of melanin particles tend not to accumulate in a polarity-specific formation. An effective way to obtain a high yield of electrical energy from melanin is to form it into large, polarized particles. Implicitly, it is believed that nanoparticles in any quantity are not as desirable as larger particles in cancer treatment, with larger particles having a better ability to be accommodated by cancer cell membranes.

According to certain embodiments, melanin is associated with α-methyl-DL-tyrosine in at least three ways.

1) Mechanically mixing α-methyl-DL-tyrosine with a compressive force to attach naturally occurring or synthetic melanin to the water-insoluble and somewhat malleable melanin. Following the initial incorporation of these components, it is preferred to add additional α-methyl-DL-tyrosine until substantial coverage of melanin is achieved.

2) Melanin is a U.S. It can be solubilized by a number of methods, as described in Patent No. 5,225,435, the contents of which are incorporated herein by reference. One preferred method involves mixing melanin with distilled water and hydrogen peroxide to achieve a melanin concentration of at least 5 weight percent and then placing the resulting composition in a microwave oven until it reaches boiling point. The dissolved, produced melanin is used to inject or saturate through the mass of α-methyl-DL-tyrosine. The composition is then dried and a dry powder is used.

3) α-methyl-DL-tyrosine is put in 5-benzyloxy-6-methoxy-indole and distilled water and sealed for up to one month. It is believed that the L portion of racemic α-methyl-DL-tyrosine is converted to (DOPA) melanin. The size of the melanin particles can be controlled by controlling the time of the growth period. The resulting powder is then washed and dried. Although the ratio of the racemic mix is no longer 50/50, the availability of chemically bound components seems to promote melanin penetration and potentially provide sufficient benefits even with the reduction of the L component.

Claims (1)

a) α-methyl-DL-tyrosine;
b) a melanin promoter that is melanin, methoxsalen or melanotan II, or a combination of melanin, methoxsalen and melanotan II;
c) 5,5-diphenylhydantoin; and
d) rapamycin
A pharmaceutical composition for use in a method for treating cancer in a patient in need thereof, comprising:
Here, the cancers include appendix cancer, cholangiocarcinoma, cholangiocarcinoma, colon cancer, colon cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, thyroid cancer, tongue cancer, tonsillar squamous cell carcinoma, and urinary tract. selected from epithelial cell carcinoma;
A pharmaceutical composition, wherein the pharmaceutical composition is administered to a patient within a period of 24 hours, at least 5 days per week for at least 6 weeks.