JP2019537608A - Pharmaceutical compositions and methods for the treatment of cancer - Google Patents

Abstract

Pharmaceutical compositions and kits comprising a tyrosine hydroxylase inhibitor; melanin, a melanin enhancer or a combination thereof; a p450 3A4 enhancer; and a leucine aminopeptidase inhibitor are provided. 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, 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. You. [Selection diagram] None

Description

  [0001] The present invention thus relates to compositions, kits and methods for reducing cell proliferation, for example, in the treatment of cancer.

  [0002] According to the US National Cancer Institute Surveillance Epidemiology and End-Results (SEER) database for 2008, the most recent year for which incidence data is available, 11,958,000 Americans are infiltrated. Have cancer. Cancer is the second most common cause of death in the United States (above only heart disease) and accounts for one in four deaths. It is estimated that approximately 1600 Americans die from cancer every day. In addition to the medical, emotional and psychological costs of cancer, cancer imposes significant financial costs on both individuals and society. The National Institutes of Health estimates that the overall cost of cancer in 2010 was $ 263.8 billion. In addition, an additional $ 140.1 billion is estimated to be lost in productivity due to premature death.

  [0003] Today's cancer treatments include surgery, hormonal therapy, radiation, chemotherapy, immunotherapy, targeted therapy, and combinations thereof. Surgical removal of cancer has made significant progress; however, there is still a high likelihood of disease recurrence. Hormonal therapy with drugs, such as aromatase inhibitors and luteinizing hormone-releasing hormone analogs and inhibitors, has been relatively effective in treating prostate and breast cancer. Radiation and related techniques of conformal proton radiation therapy, stereotactic radiosurgery, stereotactic radiation therapy, intraoperative radiation therapy, chemomodifiers, and radiosensitizers are effective in killing cancerous cells, but not surrounding normal tissue. Can also be killed and altered. Chemotherapeutic agents alone and in combination, such as aminopterin, cisplatin, methotrexate, doxorubicin, daunorubicin, and the like, are often effective in killing cancer cells by altering the DNA replication process. Biological response modifier (BRM) therapy, biological therapy, biotherapy, or immunotherapy alters the growth of cancer cells or affects the innate immune response, resulting in biological agents, such as interferons, Includes the administration of interleukins and other cytokines, as well as antibodies, such as rituximab and trastuzumab, and even cancer vaccines, such as cyproycel-T, to patients.

  [0004] Recently, novel targeted therapies have been developed to combat cancer. These targeted therapies differ from chemotherapy because they work by killing both cancerous and normal cells and have a greater effect on cancerous cells. Targeted therapy works by affecting the processes that control the growth, division and spread of cancer cells, as well as signals that cause cancer cells to die spontaneously. Certain types of targeted therapies include growth signal inhibitors such as trastuzumab, gefitinib, imatinib, cetuximab, dasatinib and nilotinib. Another type of targeted therapy includes angiogenesis inhibitors that inhibit cancer from increasing the surrounding vasculature and blood supply, such as bevacizumab. The last type of targeted therapy involves apoptosis-inducing drugs that can induce direct cancer cell death.

  [0005] While all of these treatments have been more or less effective, they all have drawbacks and limitations. In addition to many of the treatments being expensive, they are often too inaccurate, or the cancer can adapt to them and become resistant.

  [0006] Thus, there is a great need for additional cancer treatments. In particular, there is a need for treatments for cancers that have become resistant to other forms of treatment.

  [0007] The present invention provides compositions, combination therapies, kits and methods for reducing excessive cell proliferation, including compositions, combination therapies, kits and methods related to the treatment of cancer. In certain embodiments, the present invention relates to at least one tyrosine hydroxylase inhibitor; at least one of melanin, a melanin promoter or a combination thereof; at least one p450 3A4 promoter; at least one leucine aminopeptidase inhibitor And a pharmaceutical composition comprising at least one growth hormone inhibitor. In another aspect, the invention provides a kit that includes these components together with suitable packaging. An effective amount of at least one tyrosine hydroxylase inhibitor; at least one 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 Also provided are methods of reducing cell proliferation and / or treating cancer, comprising administering one growth hormone inhibitor to a subject in need thereof.

  [0008] The present subject matter may be more readily understood by reference to the following detailed description, which forms a part of the present disclosure. The invention is not limited to the specific products, methods, conditions or parameters described and / or shown herein, and the terminology used herein is described only by way of example in particular embodiments. It is to be understood that the claimed invention is not intended to limit the claimed invention.

  [0009] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

  [0010] As used above and throughout this disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings.

  [0011] In this disclosure, the singular forms "a", "an", and "the" include plural references, and a reference to a particular numerical value, unless the context clearly indicates otherwise, at least to the order Contains a specific value. Thus, for example, reference to "a compound" is a reference to one or more of such compounds, and equivalents thereof, known to those skilled in the art. The term "plurality" as used herein means more than one. When a range of values is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. All ranges are inclusive and combinable.

  [0012] As used herein, the terms "component", "composition", "composition of compounds", "compound", "drug", "pharmacologically effective agent", "active agent" A "therapeutic agent," "therapy," "treatment," or "pharmaceutical" as used herein refers to a desired pharmacology due to local and / or systemic effects when administered to a subject (human or animal). It is used interchangeably to refer to a compound or compounds that induce a target and / or physiological effect.

  [0013] As used herein, the term "treatment" or "therapy" (as well as different forms thereof) includes preventative (eg, prophylactic), therapeutic or palliative treatment. As used herein, the term "treating" includes alleviating or reducing at least one adverse or negative effect or symptom of a disease, disorder or disorder. The disease, disorder or disorder can be cancer.

  [0014] As used above and throughout this disclosure, the term "effective amount" is effective at the dosage required to achieve the desired result and for the duration of the treatment of the associated disorder, illness or side effect. Points. The effective amount of a component of the invention will depend not only on the particular compound, component or composition selected, the route of administration, and the ability of the component to elicit the desired result in the individual, but also on the disease to be alleviated in the individual. The severity of the condition or disease, hormonal levels, age, sex, weight, physical condition of the patient, and the severity of the pathological condition being treated, concurrent drug therapy or special diet followed by that particular patient It will be appreciated that factors such as, as well as other factors which those skilled in the art will recognize will vary from patient to patient and the appropriate dosage will be at the discretion of the attending physician. . Dosage regimes can be adjusted to provide improved therapeutic response. An effective amount is also one in which any toxic or detrimental effects of the components are outweighed by the therapeutically beneficial effects.

  [0015] "Pharmaceutically acceptable" is suitable, within the scope of sound medical judgment, for contact with human and animal tissues, causing excessive toxicity, irritation, allergic reactions, or other problems, Refers to compounds, materials, compositions and / or dosage forms that are commensurate with reasonable benefit / risk ratios without complications.

  [0016] Within the scope of the present invention, the disclosed compounds can be prepared in the form of pharmaceutically acceptable salts. “Pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds, wherein the parent compound has been modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include the 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 salts 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, and the like. Glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric Includes salts prepared from acids, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like. These physiologically acceptable salts can be prepared by methods known in the art, for example, by dissolving the free amine base in an aqueous alcohol with an excess of acid, or by converting the free carboxylic acid with an alkali metal base, such as a hydroxide. Or by neutralizing with an amine.

  [0017] The compounds described herein can be prepared in alternative forms. For example, many amino-containing compounds can be used or prepared as acid addition salts. Often, such salts improve the isolation and handling properties of the compound. For example, depending on the reagents, reaction conditions, etc., the compounds described herein can be used or prepared, for example, as their hydrochloride or tosylate salt. Isomorphic crystal forms, all chiral and racemic, N-oxides, hydrates, solvates, and acid salt hydrates are also contemplated as being within the scope of this invention.

  [0018] Certain acidic or basic compounds of the present invention can exist as zwitterions. All forms of the compounds, including free acids, free bases and zwitterions, are intended to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxy groups often exist in equilibrium with their zwitterionic form. Thus, for example, all of the compounds described herein that contain both amino and carboxy groups also include a reference to their corresponding zwitterion.

  [0019] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

  [0020] The term "administering" refers to administering a compound or composition of the present invention directly, or administering a prodrug, derivative or analog that will form an equivalent amount of the active compound or substance in the body. It means both.

  [0021] The terms "subject," "individual," and "patient" are used interchangeably herein and provide an animal for which treatment is provided, including prophylactic treatment with a pharmaceutical composition according to the present invention. For example, humans. The term "subject" as used herein refers to human and non-human animals. The terms “non-human animal” and “non-human mammal” are used interchangeably herein and include all vertebrates, eg, mammals, such as non-human primates (especially higher primates), sheep, dogs, Includes rodents (eg, mice or rats), guinea pigs, goats, pigs, cats, rabbits, cows, horses and non-mammals, such as reptiles, amphibians, chickens and turkeys.

  [0022] The term "inhibitor," as used herein, includes compounds that inhibit the expression or activity of a protein, polypeptide or enzyme, and does not necessarily mean complete inhibition of expression and / or activity. Rather, inhibition includes inhibition to a sufficient extent and over time to produce the desired effect on the expression and / or activity of the protein, polypeptide or enzyme.

  [0023] The term "enhancer", as used herein, includes a compound that promotes the expression or activity of a protein, polypeptide or enzyme, and does not necessarily mean complete promotion of expression and / or activity. Rather, facilitation involves facilitation to a sufficient extent and for a time to effect the desired effect on the expression and / or activity of the protein, polypeptide or enzyme.

  [0024] In one aspect, the invention provides combination therapies that alter the protection of cancerous cells against oxidative stress. One class of such therapies increases the availability of free radicals to cancerous cells. A representative subclass of such therapy involves the administration of a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor, melanin or a melanin enhancer, a p450 3A4 enhancer, a leucine aminopeptidase inhibitor and optionally a growth hormone inhibitor. . Another subclass involves the administration of pharmaceutical compositions containing both melanin and a tyrosine hydroxylase inhibitor. Particular components of the pharmaceutical composition are described below.

[0025] While not intending to be bound by any particular mechanism of action, the tyrosine hydroxylase inhibitors according to the present invention accumulate in cancer cells and they form a coating of either lipid or hyaluronan. It works by preventing you from doing so. It is believed that preventing cancer cells from forming a coating of either lipid or hyaluron makes them more accessible to oxidative stress. Representative tyrosine hydroxylase inhibitors include tyrosine derivatives, which are typically rapidly absorbed by most cancer and inflammatory tissues. Representative tyrosine derivatives include 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 ) 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) propanoate, methyl (2R) -2-amino-3- ( 3-chloro-4-hydroxyphenyl) propanoate, H-DL-tyr-OME HCl, H-3,5-diiodo-ty r-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 (methyl (2R) -2-azanyl-3- (4-hydroxyphenyl) yl) 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, also known as Fmoc-tyr (3-NO ₂ ) -OH and α-methyl-DL-tyrosine (DL-2-methyl-3- (4-hydroxyphenyl) alanine Included).

  [0026] The present invention includes the use of at least one of melanin, a melanin promoter or a combination thereof. Thus, melanin may be used, one or more melanin promoters may be used, and both melanin and one or more melanin promoters may be used (either in separate dosage forms or in the same dosage form). either will do). A melanin enhancer 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, by suppressing TNF) and eliminate the isolated lymphatic system. Melanin is a photocatalyst and can therefore promote chemical reactions that generate free radicals, which in turn can become accessible to cancer cells. Representative melanin enhancers are methoxsalen and melanotan II.

  [0027] In some cases, the tyrosine hydroxylase inhibitor is mixed with melanin in the same dosage form. It is believed that this association of melanin with tyrosine hydroxylase inhibitors promotes uptake of melanin in cancer cells because tyrosine hydroxylase inhibitors are more easily taken up by such cells. In certain embodiments, melanin is solubilized in a solubilizing agent and then mixed with a tyrosine hydroxylase inhibitor by methods known in the art. Solubilizing agents can be removed by standard techniques, for example, evaporation, drying, and the like. The solubilizing agent can be a non-toxic solubilizing agent, such as hydrogen peroxide or other solubilizing agents commonly known in the art. The melanin and / or pharmaceutical composition can be further processed to optimize the effect of the pharmaceutical composition on cancer cells. In another aspect, the pharmaceutical composition can include additional active agents and / or pharmaceutical excipients.

  [0028] The pharmaceutical composition of the present invention also contains a p450 3A4 promoter. "Cytochrome p450 3A4" (which can be abbreviated as "p450 3A4") is a mixed function oxidase that is a member of the cytochrome p450 superfamily of enzymes and is involved in the metabolism of xenobiotics in the body. It has the broadest range of all substrates of 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. Increased p450 3A4 expression and / or activity is believed to reduce cortisone and estrogen levels in patients. In addition, increased p450 3A4 expression and / or activity also slightly lowers blood pH, which is believed to help maintain or increase melanin activity. Representative p450 3A4 promoters are 5,5-diphenylhydantoin (commercially sold as Dilantin), valproic acid and carbamazepine, which are believed to induce expression of the p450 3A4 enzyme.

  [0029] The pharmaceutical composition further comprises a leucine aminopeptidase inhibitor (also known as a leucyl aminopeptidase inhibitor). Leucine aminopeptidase is an enzyme that preferentially catalyzes the hydrolysis of leucine residues at the N-terminus of peptides and / or proteins. Inhibition of leucine aminopeptidase expression and / or activity is believed to help tumor resorption by increasing cholesterol transport to the liver. It is generally believed that aminopeptidase inhibitors, including aminopeptidase inhibitors, deplete certain amino acids from tumor cells by preventing protein recycling, thereby producing an antiproliferative effect. Representative leucine aminopeptidase inhibitors are N-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutyryl] -L-leucine and rapamycin.

  [0030] The present pharmaceutical composition optionally also contains a growth hormone inhibitor. Growth hormone (such as pancreatic growth hormone) induces cell replication. It is believed that inhibition of growth hormone expression and / or activity excludes normal cells from rapid replication while allowing cancer cells to rapidly replicate and continue to incorporate tyrosine derivatives. Representative growth hormone inhibitors are octreotide, somatostatin and seglitide.

  [0031] The pharmaceutical composition of the present invention can further contain 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. Together with leucine aminopeptidase inhibitors, D-leucine is believed to create a physiological environment that mimics leucine deficiency. Thus, the presence of D-leucine allows for the use of lower doses of leucine aminopeptidase inhibitor in pharmaceutical compositions.

  [0032] Also provided herein are kits that include a combination therapy that produces an alteration in the protection of cancerous cells against oxidative stress. A suitable embodiment contemplated is a kit that includes a combination therapy that increases the availability of free radicals to cancerous cells. An exemplary kit comprises a tyrosine hydroxylase inhibitor of the type described above, a melanin and / or melanin enhancer, a p450 3A4 enhancer, a leucine aminopeptidase inhibitor and optionally a growth hormone inhibitor together with packaging for the same. Including. The kit can include one or more separate containers, dividers or compartments and optionally informational materials, such as instructions for administration. For example, each inhibitor or enhancer (or various combinations thereof) can be contained in a bottle, vial, or syringe, and the informational material is contained in a plastic sleeve or packet or labeled. Can be provided in In some embodiments, the kit comprises a plurality of individual containers (e.g., a pack of individual containers) each containing one or more unit dosage forms of a compound described herein. For example, a kit can include a plurality of syringes, ampules, foil packets or blister packs, each containing a single unit dose of a compound described herein, or various combinations thereof. The container of the kit can be airtight, waterproof (eg, impermeable to changes in moisture or evaporation) and / or light-tight. The kit optionally comprises a device suitable for administration of the composition, such as a syringe, inhaler, pipette, forceps, lightweight spoon, dropper (eg, eyedropper), swab (eg, swab or wooden swab) or any such delivery device. including.

  [0033] Also provided are methods of treating cancer in a subject, and methods of reducing excessive cell proliferation. Such methods can include administering an effective amount of the combination therapy that produces a change in the protection of the cancerous cells against oxidative stress. A typical method of treating cancer involves administering an effective amount of a combination therapy that increases the availability of free radicals to the cancerous cells. A suitable embodiment comprises administering an effective amount of a tyrosine hydroxylase inhibitor as described above, a melanin and / or a melanin enhancer, a p450 3A4 enhancer, a leucine aminopeptidase inhibitor and optionally a growth hormone inhibitor. It is. Other suitable methods include administering an effective amount of a melanin and tyrosine hydroxylase inhibitor.

  [0034] Suitable methods include at least two of tyrosine hydroxylase inhibitors, melanin or melanin promoters, p450 3A4 promoters and leucine aminopeptidase inhibitors, at least three of them, or each of them (in each case). , Optionally together with a growth hormone inhibitor) or at least at the same time. It is believed that it is desirable for effective concentrations of these moieties to be present simultaneously in the blood stream of the subject, and any dosage regimen that achieves this is within the scope of the invention. The desired number of inhibitors and enhancers can be provided in a single dosage form or in any number of the desired dosage forms, including in individual dosage forms. Representative dosage forms include tablets, capsules, caplets, sterile aqueous or organic solutions, reconstitutable powders, elixirs, liquids, colloidal or other types of suspensions, emulsions, beads, beadlets, Including granules, microparticles, nanoparticles and combinations thereof. The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction being treated, the manner of administration and the judgment of the prescribing physician.

  [0035] Administration of melanin, enhancers and / or inhibitors can be by a variety of routes including oral, nasal, subcutaneous, intravenous, intramuscular, transdermal, vaginal, rectal or combinations thereof. Transdermal administration can be accomplished using, for example, oleic acid, 1-methyl-2-pyrrolidone, or dodecylnonaoxyethylene glycol monoether.

  [0036] The melanin, promoter and / or inhibitor is a cycle consisting of 5 to 7 days when melanin, promoter and / or inhibitor is administered, and 1 to 2 days without melanin, promoter and / or inhibitor. Can be administered during The melanin, enhancer and / or inhibitor can be administered over the course of at least six such cycles. It may be desirable to administer these components for about 2 hours between meals to facilitate uptake.

  [0037] The subject to which the present composition is administered can be a mammal, preferably a human.

  [0038] In one exemplary method, 60 mg of a tyrosine derivative is administered orally, 0.25 mL of a 2 mg / mL suspension of the tyrosine derivative is administered subcutaneously; 10 mg of methoxsalen is administered orally, .25 mL of a 1 mg / mL suspension of methoxsalen was administered subcutaneously; 30 mg of 5,5-diphenylhydantoin was administered orally; and 20 mg of N-[(2S, 3R) -3-amino-2-hydroxy -4-phenylbutyryl] -L-leucine is administered orally.

  [0039] In certain embodiments, the combination therapy comprises the following in bacteriostatic NaCl: (i) a dosage form containing melanin (50 mcg) and α-methyl-DL-tyrosine (75 mg); (ii) Dosage form containing 5,5-diphenylhydantoin (15 mg) and α-methyl-DL-tyrosine (75 mg); (iii) 3-amino-2-hydroxy-4-phenylbutyryl] -L-leucine (50 mcg) And (iv) 3-amino-2-hydroxy-4-phenylbutyryl] -L-leucine (5 mcg), melanotan II (10 mcg), and 5 mg of α-methyl-DL-tyrosine (75 mg). A dosage form containing 2,5-diphenylhydantoin (2 mg); and (v) a dosage form containing α-methyl-DL-tyrosine (5 mg). In other embodiments, the combination therapy comprises the following in NaCl bacteriostatic water: (i) a dosage form containing melanin (50 mcg) and α-methyl-DL-tyrosine (75 mg); (ii) 5,5 A dosage form containing diphenylhydantoin (15 mg) and α-methyl-DL-tyrosine (75 mg); (iii) a dosage form containing rapamycin (0.2 mg) and α-methyl-DL-tyrosine (75 mg); iv) a dosage form containing rapamycin (0.15 mcg), melanotan II (10 mcg), and 5,5-diphenylhydantoin (2 mg); and (v) a dosage form containing α-methyl-DL-tyrosine (5 mg) . Doses twice as large, and even four times larger, are both believed to be safe and effective.

  [0040] Representative methods include those in which the cancer is non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is a stage IV non-small cell lung cancer. In yet other embodiments, the cancer is ovarian, breast, cervical, pancreatic, gastric, brain, liver, testicular, leukemia, lymphoma, appendix, biliary tract, cholangiocarcinoma, colon. Has cancer, colorectal cancer, germ cell tumor, glioma, Hodgkin lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, thyroid cancer, tongue cancer, tonsillar squamous cell carcinoma or urothelial carcinoma .

  [0041] In certain embodiments, one or more of a tyrosine hydroxylase inhibitor; a melanin promoter; a p450 3A4 promoter; and a leucine aminopeptidase inhibitor is a nucleic acid, protein, antibody or antigen-binding fragment of an antibody.

  [0042] The method can include not only the disclosed administering steps but also a step of assessing the extent of progression and / or cell proliferation of said cancer in said subject. The evaluation step can be performed before or after the administration step.

[0043] Suitable embodiments can include a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor, a melanin and / or a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor. The pharmaceutical composition can further include a growth hormone inhibitor. The growth hormone can be pancreatic growth hormone. The growth hormone inhibitor can be octreotide or somatostatin. The tyrosine hydroxylase inhibitor can be a tyrosine derivative. Tyrosine derivatives include 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) propa Noate, 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-OM 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, H- D-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 ethi Glycol ester hydrochloride, DL-m-tyrosine, _{DL-o-tyrosine, Boc-Tyr (3,5-I} 2) -OSu, Fmoc-tyr (3-NO 2) of -OH and α- methyl -DL- tyrosine It can be one or more. The melanin enhancer can be methoxsalen or melanotan II. The p450 3A4 promoter can be 5,5-diphenylhydantoin. The p450 3A4 promoter can be valproic acid or carbamazepine. The leucine aminopeptidase inhibitor can be N-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutyryl] -L-leucine or rapamycin. The pharmaceutical composition of the present invention can further contain D-leucine.

[0044] Also provided herein is a kit comprising a tyrosine hydroxylase inhibitor, a melanin and / or a melanin promoter, a p450 3A4 promoter and a leucine aminopeptidase inhibitor together with packaging for the same. The kit can further include a growth hormone inhibitor. The growth hormone can be pancreatic growth hormone. The growth hormone inhibitor can be octreotide or somatostatin. The tyrosine hydroxylase inhibitor can be a tyrosine derivative. Tyrosine derivatives include 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) propa Noate, 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-OM 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, H- D-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 Glycol 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 One or more of The melanin enhancer can be methoxsalen or melanotan II. The p450 3A4 promoter can be 5,5-diphenylhydantoin, valproic acid or carbamazepine. The leucine aminopeptidase inhibitor can be N-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutyryl] -L-leucine or rapamycin. The kit of the present invention can further include D-leucine.

[0045] 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. A method is also provided. In a suitable embodiment, the method of treating cancer can further include a growth hormone inhibitor. In certain embodiments, at least two of the components (ie, melanin, enhancer and / or inhibitor) are co-administered. In other embodiments, at least three of the components are co-administered. Each of the components can be co-administered. In suitable embodiments, the components are administered orally, subcutaneously, intravenously, transdermally, vaginally, rectally, or a combination thereof. Transdermal administration can be with oleic acid, 1-methyl-2-pyrrolidone or dodecylnonaoxyethylene glycol monoether. In other embodiments, the component is administered during a cycle consisting of 5-7 days of administering the component and 1-2 days of not administering the component. The component can be administered over the course of at least six such cycles. The tyrosine hydroxylase inhibitor can be a tyrosine derivative. Tyrosine derivatives include 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) propa Noate, 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-OM 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, H- D-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 ethi Glycol 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 One or more of In a suitable embodiment of the method, 60 mg of the tyrosine derivative is administered orally, and 0.25 mL of a 2 mg / mL suspension of the tyrosine derivative is administered subcutaneously. The melanin enhancer can 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 be melanotan II. The p450 3A4 promoter can be 5,5-diphenylhydantoin. In another suitable method, 30 mg of 5,5-diphenylhydantoin is administered orally. The p450 3A4 promoter can also be valproic acid or carbamazepine. The leucine aminopeptidase inhibitor can 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 can also be rapamycin. The growth hormone can be pancreatic growth hormone. The growth hormone inhibitor can be octreotide. The method can further include administering an effective amount of D-leucine. The subject can be a mammal, and the mammal can be a human. Representative methods include those in which the cancer is non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is a stage IV non-small cell lung cancer. In other embodiments, the cancer is ovarian, breast, cervical, pancreatic, gastric, brain, liver, testicular, leukemia, lymphoma, appendix, biliary tract, cholangiocarcinoma, colon cancer. , Colorectal cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, thyroid cancer, tongue cancer, tonsil squamous cell carcinoma or urothelial carcinoma. In other suitable embodiments, the tyrosine hydroxylase inhibitor, melanin promoter, p450 3A4 promoter and leucine aminopeptidase inhibitor are one or more of a nucleic acid, protein, antibody or antigen-binding fragment of an antibody. Another suitable embodiment further comprises assessing the progression of said cancer in said subject. The evaluating step can be performed before the administering step, or the evaluating step can be performed after the administering step.

[0046] Cell proliferation in a subject comprising administering to a subject in need thereof an effective amount of a tyrosine hydroxylase inhibitor; a melanin and / or a melanin promoter; a p450 3A4 promoter; and a leucine aminopeptidase inhibitor. A method for reducing is also provided. In a suitable embodiment, the method of treating cancer can further include a growth hormone inhibitor. In certain embodiments, at least two of the components (ie, melanin, enhancer and / or inhibitor) are co-administered. In other embodiments, at least three of the components are co-administered. Each of the components can be co-administered. In suitable embodiments, the components are administered orally, subcutaneously, intravenously, transdermally, vaginally, rectally, or any combination thereof. Transdermal administration can be with oleic acid, 1-methyl-2-pyrrolidone or dodecylnonaoxyethylene glycol monoether. In other embodiments, the component is administered during a cycle consisting of 5-7 days of administering the component and 1-2 days of not administering the component. The component can be administered over the course of at least six such cycles. The tyrosine hydroxylase inhibitor can be a tyrosine derivative. Tyrosine derivatives include 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) propa Noate, 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-OM 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, H- D-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 ethi Glycol 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 One or more of In a suitable embodiment of the method, 60 mg of the tyrosine derivative is administered orally, and 0.25 mL of a 2 mg / mL suspension of the tyrosine derivative is administered subcutaneously. The melanin enhancer can 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 be melanotan II. The p450 3A4 promoter can be 5,5-diphenylhydantoin. In another suitable method, 30 mg of 5,5-diphenylhydantoin is administered orally. The p450 3A4 promoter can also be valproic acid or carbamazepine. The leucine aminopeptidase inhibitor can 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 can also be rapamycin. The growth hormone can be pancreatic growth hormone. The growth hormone inhibitor can be octreotide. The method can further include administering an effective amount of D-leucine. The subject can be a mammal, and the mammal can be a human. Representative methods include those in which the cancer is non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer is a stage IV non-small cell lung cancer. In other embodiments, the cancer is ovarian, breast, cervical, pancreatic, gastric, brain, liver, testicular, leukemia, lymphoma, appendix, biliary tract, cholangiocarcinoma, colon cancer. , Colorectal cancer, germ cell tumor, glioma, Hodgkin's lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, thyroid cancer, tongue cancer, tonsil squamous cell carcinoma or urothelial carcinoma. In other suitable embodiments, the tyrosine hydroxylase inhibitor, melanin promoter, p450 3A4 promoter and leucine aminopeptidase inhibitor are one or more of a nucleic acid, protein, antibody or antigen-binding fragment of an antibody. Another suitable embodiment further comprises assessing the progression of said cancer in said subject. The evaluating step can be performed before the administering step, or the evaluating step can be performed after the administering step.

  [0047] The following examples of specific embodiments for practicing the invention are provided for illustrative purposes only and are not intended to limit the scope of the invention in any way.

  [0048] Also provided are exemplary methods of administering the pharmaceutical compositions and combination therapies. Various aspects of the invention further relate to methods of administering a pharmaceutical composition or combination therapy to a human patient for the treatment of cancer. The method can include administering the pharmaceutical composition or combination therapy by a generally accepted route of administration (eg, oral, subcutaneous, parenteral, inhalation, topical, etc.). In some cases, a pharmaceutical composition or combination therapy can be administered orally and / or subcutaneously. In some cases, the pharmaceutical composition or combination therapy can be administered to a human patient between meals.

  [0049] In certain embodiments of the invention, the pharmaceutical composition or combination therapy may be administered to a human patient for a period of 6 weeks, 5 days per week to create one cycle of treatment for 30 days. Depending on the outcome after six weeks or one cycle of treatment, additional cycles of the pharmaceutical composition or combination therapy can be administered.

[0050] The present invention also provides the following:
-A pharmaceutical composition comprising a tyrosine hydroxylase inhibitor; and melanin, a melanin promoter or a combination thereof (preferably melanin);
-A pharmaceutical composition comprising a tyrosine hydroxylase inhibitor and a p450 3A4 promoter;
-A pharmaceutical composition comprising a tyrosine hydroxylase inhibitor and a leucine aminopeptidase inhibitor; and-a pharmaceutical composition comprising melanin, a melanin promoter or a combination thereof (preferably melanotan II); a p450 3A4 promoter; and a leucine aminopeptidase. A pharmaceutical composition comprising an inhibitor.

  The tyrosine hydroxylase inhibitor in such a composition is preferably α-methyl-DL-tyrosine, the p450 3A4 promoter is preferably 5,5-diphenylhydantoin, and the leucine aminopeptidase inhibitor is Preferred is N-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutyryl] -L-leucine. The present invention provides a kit comprising each of these pharmaceutical compositions together with a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor; and each of the pharmaceutical compositions together with a pharmaceutical composition comprising a tyrosine hydroxylase inhibitor in a patient, preferably Also provided such that is administered to the patient within 24 hours.

Example 1
[0051] Clinical trials have been performed to evaluate the efficacy, safety, tolerability and tolerability of the combination therapy according to aspects of the present invention as a treatment for metastatic cancer.
Combination therapy included the following:
(A) capsules containing melanin (50 mcg) and α-methyl-DL-tyrosine (75 mg), administered orally;
(B) capsules 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) Capsules containing rapamycin (0.2 mg) and α-methyl-DL-tyrosine (75 mg), administered orally;
(E) a suspension containing rapamycin (0.15 mcg), melanotan II (10 mcg), and 5,5-diphenylhydantoin (2 mg), administered subcutaneously; and (f) α-methyl-DL-tyrosine ( 5 mg) in NaCl bacteriostatic water, administered subcutaneously.

  [0052] Each patient received the combination therapy for a period of 6 weeks, 5 days per week. More than 200 patients were screened. Criteria included patients with any metastatic cancer. Thirty patients who met the criteria were accepted and participated in the study.

Treatment of metastatic breast cancer
[0053] Fourteen patients in the study had metastatic breast cancer. Patient information and results are as in Table 1 below:

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

  [0054] More than 200 cancer patients have been screened in clinical trials. Thirty (30) subjects meeting the test criteria agreed. The average age of the patients was 56 years, ranging from 30 to 70 years. Patients in the study included tyrosine hydroxylase inhibitors (ie, α-methyl-DL-tyrosine), melanin enhancers (ie, melanotan II), p450 3A4 enhancers (ie, 5,5-diphenylhydantoin) and leucine aminopeptidase inhibitors (ie, (Rapamycin). The compounds were administered for a period of 6 weeks, each of 5 days per week, and not administered 1 or 2 days during the weekly cycle.

  [0055] After 6 weeks of treatment, 12 of the 30 patients (40%) received the US East Coast Cancer Clinical Trials Group (ECOG) 0-5 scale (Oken, et al., Toxicity And Response Criteria). Of the Eastern Cooperative Oncology Group, Am. J. Clin. Oncol., 5: 649-655, 1982). Fourteen (14) (46%) of the 30 had a 1-3 point improvement in their ECOG rating.

  [0056] Fourteen (14) (46%) of the thirty patients had the European Organization for Research and Treatment Quality of Life Questionnaire (EORTC) 1-7 scale (eg, 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. (See 635-42). Sixteen (16) (54%) of the 30 had an improvement of 1-5 points in their EORTC rating.

  [0057] Eleven (11) of the 30 patients gained 1-9 pounds of weight, 17 of the 30 remained the same weight, and 2 of the 30 Lost 1-2 pounds.

  [0058] Thirteen (13) (43%) of the 30 patients had a reduction in pain levels. Seventeen (17) (57%) of the thirty participated with minimal pain and maintained the same level. Nine (9) (30%) of the 30 patients participated in the study while receiving pain medication, and 8 (89%) of them no longer had pain at the end of the cycle. No drug therapy was required.

  [0059] In 4 (4) (13%) of the 30 patients, no disease was detected and had normal physical examination, general appearance and imaging. Eight (8) (27%) of the 30 had a significant reduction in tumor mass and / or maximal tumor size. Eight of the thirty (8) (27%) showed a reduction in tumor mass and / or maximal tumor size. Ten (10) (33%) of the 30 did not show disease progression.

  [0060] Twenty-nine (29) of the thirty survived and had a median survival of 22 weeks. Thirteen (13) of the thirty were released and returned home. Seventeen (17) of the thirty continue to be treated. All of the subjects developed hyperpigmentation.

  [0061] Overall, the treatment noted above is well tolerated by the subject without treatment-related adverse events, and the response is 100% documented for the treatment.

Example 2
[0062] In one aspect, the present invention provides a method for inducing melanin production in vivo using one or both of methoxsalen and melanotan and / or a method by administering melanin. While not intending to be bound by any particular theory of operation, melanin converts its photocatalytic properties and various wavelengths of ambient or induced electromagnetic radiation into electrical energy and thus the desired reaction Or is believed to be beneficial for its ability to enhance dislocations. In some patients, melanin is preferably administered mechanically or chemically prior to administration, either because of genetic variation, weakness, the need for enhanced availability, or to achieve maximum efficacy. Has been determined to be combined with α-methyl-DL-tyrosine.

  [0063] Melanin as a photocatalyst is believed to be polar at several points in its physical mass. It has been determined that small melanin particles can produce less electrical energy than larger particles, and that multiple melanin particles do not tend to accumulate in a polarity-specific form. An effective way to obtain high electrical energy yields from melanin is to form melanin in large, polarized particles. Implicitly, it is believed that nanoparticles, regardless of quantity, are less desirable than larger particles for cancer treatment, and that larger particles have a greater ability to be accepted by cancer cell membranes.

  [0064] According to certain embodiments, melanin is combined with α-methyl-DL-tyrosine in at least three ways.

  [0065] 1) Melanin (either naturally occurring or synthetic) is mechanically utilizing the compressive force to adhere water-insoluble and somewhat malleable melanin to α-methyl-DL-tyrosine. Mixed. After the initial combination of these components, it is desirable to add additional α-methyl-DL-tyrosine until substantial coverage of melanin is achieved.

  [0066] 2) Melanin can be solubilized by a number of methods as described in US Patent No. 5,225,435, the contents of which are incorporated herein by reference. One preferred method mixes melanin with distilled water and hydrogen peroxide to achieve a melanin concentration of at least 5 weight percent, and then places the resulting composition in a microwave oven until it reaches boiling point Including. The dissolved melanin produced is used to soak 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 placed in distilled water with 5-benzyloxy-6-methoxy-indole 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 duration of the growth period. The resulting powder is then cleaned and dried. Although the ratio of the racemic mixture is no longer 50/50, the usefulness of the chemically combined components promotes melanin penetration even though the L component is reduced, potentially providing significant benefits. It seems to give.

Claims (3)

A method for treating cancer in a patient, wherein the patient in need thereof:
a) 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) propanoate, Tyl (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, H -D-3,5-diiodo-tyr-OMe HCl, HD-tyr-OMe HCl, D-tyrosine methyl ester hydrochloride, D-tyrosine-OMe HCl, methyl D-tyrosinate hydrochloride, 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 Salt, 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-I2 ) -OSu, Fmoc-tyr (3-NO 2) -OH or tyrosine hydroxylase inhibitor is α- methyl -DL- tyrosine;
b) a melanin enhancer that is methoxsalen or melanotan II, melanin, or a combination of melanin, methoxsalen and melanotan II;
c) a p450 3A4 promoter which is 5,5-diphenylhydantoin, valproic acid or carbamazepine; and d) N-[(2S, 3R) -3-amino-2-hydroxy-4-phenylbutyryl] -L-leucine. Or a leucine aminopeptidase inhibitor that is rapamycin;
Administering a pharmaceutical composition comprising:
The cancer may be appendix cancer, biliary tract cancer, cholangiocarcinoma, colon cancer, colorectal cancer, germ cell tumor, glioma, Hodgkin lymphoma, lung cancer, neuroblastoma, prostate cancer, kidney cancer, sarcoma, The above method, wherein the method is thyroid cancer, tongue cancer, tonsil squamous cell carcinoma or urothelial carcinoma.   2. The method of claim 1, wherein said pharmaceutical composition is administered to said patient within 24 hours.   2. The method of claim 1, wherein said pharmaceutical composition is administered to said patient for a period of 6 weeks, 5 days per week.