JP2011513396A - Method for inhibiting tumor cell growth by use of proton pump inhibitors - Google Patents

Abstract

  Disclosed are methods for treating one or more growth deregulated cells. The growth deregulated cells outside the subject's gastric lumen are treated by administering an effective amount of a pharmaceutical composition comprising a proton pump inhibitor.

Description

  Embodiments of the invention relate in part to a method of treating tumor cells by administration of a proton pump inhibitor.

  Cytotoxic drugs remain at the heart of cancer treatment due to the very unmet need in disease. Management of these problems is an important challenge for oncologists because the oral and gastrointestinal mucosa are often severely damaged by cancer treatment. Such therapeutic complications are generally not severe or life threatening, but can result in both treatment delay and dose reduction in therapies where a therapeutic effect can be expected. A number of therapeutic approaches are being evaluated for the prevention or treatment of mucosal damage in patients undergoing cancer treatment. The results of a large placebo-controlled trial suggest that administration of proton pump inhibitors can provide both significant symptom relief and prevention for upper gastrointestinal ulcers in patients receiving cancer chemotherapy.

  In addition to addressing the side effects of chemotherapy, proton pump inhibitors have been used to reduce tumor cell resistance to cytotoxic drugs. The mechanism underlying this phenomenon is thought to utilize functions involved in the control of cell homeostasis. One mechanism of resistance may be the alteration of the tumor microenvironment via a change in pH gradient between the extracellular environment and the cytoplasm of the cell and / or a pH gradient between the cytoplasm of the cell and the lysosomal compartment. . The extracellular (ie, stromal) pH of a solid tumor is substantially more acidic than that of normal tissue, and the acidic pH of the tumor microenvironment can impair uptake of weakly basic chemotherapeutic agents.

  Cancer is a global health problem. There is a continuing need for new methods for treating and / or limiting tumor growth that enhance or replace currently used methods, compounds, and compositions.

  A method of treating tumor cells is described by administering to the tumor cells a pharmaceutically acceptable composition that can comprise a proton pump inhibitor. The proton pump inhibitor or a pharmaceutically acceptable salt thereof can be administered as a pharmaceutically acceptable composition and can reduce the amount of tumor cells. The pharmaceutically acceptable composition can include a buffer.

The pharmaceutically acceptable composition can comprise about 20 mg to about 400 mg of lansoprazole. After administration, the pharmaceutically acceptable composition can interact with tumor cells outside the cells of the gastric lumen. A proton pump inhibitor can induce apoptosis of tumor cells and / or reduce the pH of tumor cells. In one embodiment, the proton pump inhibitor can induce apoptosis in cancer cells by altering tumor cell K ⁺ levels.

In one embodiment, the proton pump inhibitor may be a substituted benzimidazole compound having an H ⁺ / K ⁺ ATPase that inhibits activity. The proton pump inhibitor is selected from the group consisting of lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole, SCH28080, and their enantiomers, isomers, free bases, salts, and mixtures Is done. In one embodiment, the composition may be administered at a dose of about 180 mg / day lansoprazole. The proton pump inhibitor may be administered in an amount of about 10 mg / kg to 100 mg / kg.

  Tumor cells are RPMI8226, NC37, MC / CAR, SUDHL4, RPMI6666, GDM-1, MOLT3, J45-01, MCF7, HL60 clone 15, Pl16, SW620, MV-4-11, SKMEL5, DAUDI, DOHH2, HUT102, It may be selected from the group consisting of CCRF-CEM, HUT78, A3, MDA-MB-435, MDA-MB-231, and RS 4.11.

  In one embodiment, the tumor cells are ES-2, IGROV1, OVCAR5, OVCAR8, J-gamma-1, KU812, NK92MI, 786-O, A498, H522, SNB19, OVCAR4, H9, HH, EKVX, OVCAR5, UACC257. , H226, UO-31, NAMALWA, SKMEL28, SKMEL2, M14, H322M, HCC2998, HL60, HT29, A549, RXF393, PC3, H460, MC116, MOLT4, JMI, HOP-62, HCT-15, SF-539, SF2 , ST486, U251, and UACC-62. Tumor cells are cell tumor, lymphoma, blastoma, myeloma, sarcoma, leukemia, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, Glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, intrauterine or uterine cancer, salivary gland cancer, renal cancer, liver cancer, prostate cancer, vulvar cancer, It may be associated with a disease selected from the group consisting of thyroid cancer and hepatocellular carcinoma.

  The second chemotherapeutic agent may be administered with a proton pump inhibitor. In one embodiment, the proton pump inhibitor, such as lansoprazole, and the second chemotherapeutic agent are administered together in the same or different dosage forms. Proton pump inhibitors such as lansoprazole and chemotherapeutic agents may be administered before, after, or simultaneously.

  Also described herein are methods of treating one or more growth deregulated cells by administering an effective amount of a pharmaceutical composition to a subject. In one embodiment, the pharmaceutical composition may comprise, for example, a dose of about 120 mg to about 400 mg per day or more of lanzoprazole. In one embodiment, lanzoprazole is administered at a dose of about 120 mg to 300 mg, and when administered to a subject, the composition interacts with a population of growth deregulated cells outside the subject's gastric lumen. Lansoprazole can induce apoptosis in deregulated cells, and the population of deregulated cells can be reduced in size approximately 3 weeks after administration.

Also described is a method of treating lymphoma comprising administering to a patient in need thereof a pharmaceutically effective amount of lansoprazole or a pharmaceutically acceptable salt thereof.
A method for treating a patient having a cancer tumor is also described. The method can include administering lansoprazole or a pharmaceutically acceptable salt thereof to a patient in need thereof in an amount sufficient to inhibit tumor growth. Growth inhibition may be measured as a delay in tumor doubling time. Tumor doubling time may be prolonged by at least two factors. Tumor burden may be reduced by at least 10%.

  A method for treating cancer is also described. The method can include administering to a patient in need thereof a pharmaceutically effective amount of lansoprazole or a pharmaceutically acceptable salt thereof. Cancer is cell tumor, lymphoma, blastoma, sarcoma, leukemia, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, glioblastoma Cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, intrauterine or uterine cancer, salivary gland cancer, renal cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, and It may be selected from the group consisting of hepatocellular carcinoma.

  It also describes how to treat leukemia. The method can include administering to a patient in need thereof a pharmaceutically effective amount of lansoprazole or a pharmaceutically acceptable salt thereof.

A method for treating renal cancer is also described. The method can include administering to a patient in need thereof a pharmaceutically effective amount of lansoprazole or a pharmaceutically acceptable salt thereof.
In embodiments of the invention, lansoprazole may be administered at a dose of about 120 mg / day to about 300 mg / day. Lansoprazole may be administered at a dose of about 10 mg / kg / day to about 150 mg / kg / day. The survival rate of subjects receiving the pharmaceutical composition of the present invention can be greater than about 15% compared to patients receiving placebo.

Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: 786-O (FIG. 1A), ACHN (FIG. 1B), A498 (FIG. 1C), H226 (FIG. 1D). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: H522 (FIG. 1E), HOP92 (FIG. 1F), SNB19 (FIG. 1G), SUDHL4 (FIG. 1H) Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: OVCAR4 (FIG. 1I), IGROV1 (FIG. 1J), H9 (FIG. 1K), UO-31 (FIG. 1L). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: HH (FIG. 1M), DAUDI (FIG. 1N), LOXIMVI (FIG. 1O), NAMALWA (FIG. 1P) Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: EKVX (FIG. 1Q), DOHH2 (FIG. 1R), SNB75 (FIG. 1S), SKMEL28 (FIG. 1T). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: SKMEL5 (FIG. 1U), SKMEL2 (FIG. 1V), OVCAR5 (FIG. 1W), M14 (FIG. 1X) Shown are experimental results of tumor cells from the following cell lines treated with lansoprazole: UACC257 (FIG. 1Y), H322M (FIG. 1Z), KM12 (FIG. 1AA), H332M (FIG. 1AB). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: HUT102 (FIG. 1AC), HL60 (FIG. 1AD), CCRF-CEM (FIG. 1AE), HUT78 (FIG. 1AF). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: HT29 (FIG. 1AG), HCT116 (FIG. 1AH), CAKI-1 (FIG. 1AI), DU-145 (FIG. 1AJ). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: A549 (FIG. 1AK), H460 (FIG. 1AL), A3 (FIG. 1AM), MDA-MB-231 (FIG. 1AN). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: E-3M (FIG. 1AO), J-gamma-1 (FIG. 1AP), RXF393 (FIG. 1AQ), RS 4.11 (FIG. 1AR). ) Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: PC3 (FIG. 1AS), OVCAR3 (FIG. 1AT), and MDA-MB-435 (FIG. 1AU). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: Du-145 (FIG. 2A), J45-01 (FIG. 2B), MOLT3 (FIG. 2C), HUT78 (FIG. 2D). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: J-gamma-1 (FIG. 2E), MCF7 (FIG. 2F), Colo205 (FIG. 2G), HL60 clone 15 (FIG. 2H). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: T47D (FIG. 21), Pl16 (FIG. 2J), Ku812 (FIG. 2K), SW620 (FIG. 2L). Experimental results of tumor cells from the following cell lines treated with lansoprazole are shown: NK92MI (FIG. 2M), MV-4-11 (FIG. 2N), and HS578T (FIG. 2O). Experimental results of tumor cells from the following cell lines treated with lansoprazole, omeprazole, and SCH28080 are shown: IGROV1 (FIG. 3A), OVCAR8 (FIG. 3B), ES-2 (FIG. 3C) Shown are experimental results of tumor cells from the following cell lines treated with lansoprazole, omeprazole, and SCH28080: CAOV3 (FIG. 3D), OVCAR5 (FIG. 3E), SUGHL4 (FIG. 3F) Experimental results of tumor cells from the following cell lines treated with lansoprazole, omeprazole, and SCH28080 are shown: RPMI 8226 (FIG. 3G), RPMI 6666 (FIG. 3H), NC37 (FIG. 3I). Shown are experimental results of tumor cells from the following cell lines treated with lansoprazole, omeprazole, and SCH28080: GDM-1 (FIG. 3J), and MC / CAR (FIG. 3K). 1 shows mean tumor volume over time in a nude mouse model treated with lansoprazole. Nude mice were exposed to cell lines G401 (FIG. 4A), HEPG2 (FIG. 4B), and JR (FIG. 4C). 1 shows mean tumor volume over time in a nude mouse model treated with lansoprazole. Nude mice were exposed to cell lines G401 (FIG. 4A), HEPG2 (FIG. 4B), and JR (FIG. 4C). 1 shows mean tumor volume over time in a nude mouse model treated with lansoprazole. Nude mice were exposed to cell lines G401 (FIG. 4A), HEPG2 (FIG. 4B), and JR (FIG. 4C). 1 shows mean tumor volume over time in a nude mouse model treated with lansoprazole. (Nude mice were exposed to cell lines G401 (FIG. 5A), RS1184B (FIG. 5B), and SR (FIG. 5C).) 1 shows mean tumor volume over time in a nude mouse model treated with lansoprazole. (Nude mice were exposed to cell lines G401 (FIG. 5A), RS1184B (FIG. 5B), and SR (FIG. 5C).) 1 shows mean tumor volume over time in a nude mouse model treated with lansoprazole. (Nude mice were exposed to cell lines G401 (FIG. 5A), RS1184B (FIG. 5B), and SR (FIG. 5C).) The results of contacting various tumor cells with lansoprazole are shown: MC116 (FIG. 6A), HOP-62 (FIG. 6B). The results of contacting various tumor cells with lansoprazole are shown: JMI (FIG. 6C), RPMI 6666 (FIG. 6D). The results of contacting various tumor cells with lansoprazole are shown: MOLT4 (FIG. 6E), HCT-15 (FIG. 6F). The results of contacting various tumor cells with lansoprazole are shown: RS1184 (FIG. 6G), ST486 (FIG. 6H). The results of contacting various tumor cells with lansoprazole are shown: U251 (FIG. 6I), SF-539 (FIG. 6J). The results of contacting various tumor cells with lansoprazole are shown: SF295 (FIG. 6K), UACC-62 (FIG. 6L). Shows the results of contacting various tumor cells with lansoprazole: SR (FIG. 6M)

Mode for carrying out the present invention

  In general, the present disclosure relates to a method of treating a tumor by administering a pharmaceutical composition comprising a proton pump inhibitor. In addition, the present disclosure relates to a method of treating a tumor by contacting or administering to a tumor cell a pharmaceutical composition comprising a proton pump inhibitor in the presence or absence of a cytotoxic or chemotherapeutic agent. Although the present disclosure is illustrated in many different forms, some specific embodiments are considered as merely illustrative of the principles of the invention and limit the invention to the illustrated embodiments. It is described herein with the understanding that it is not.

  As used herein, “treating” or “treatment” does not require a complete cure. Symptoms of the underlying disease or condition are at least reduced and / or one or more of the underlying cellular, physiological, or biochemical causes or mechanisms that cause symptoms are reduced, and / or Or mean to be eliminated. As used in this context, reduction is understood to mean relative to the state of the disease or condition, including not only the physiological state of the disease or condition, but also the molecular state of the disease or condition.

  As used herein, the term “tumor” refers to a single cell or multiple cells. As used herein, “tumor” refers to any growth deregulated cell that may be part of a tissue population.

  As used herein, the term “growth deregulated cell” refers to a single or multiple cancer cells characterized by unregulated cell growth. Growth deregulated cells may form a tissue population that causes excessive cell growth or proliferation, either benign (non-cancerous) or malignant (cancerous), including all cancerous lesions.

  As used herein, the terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals in which a population of cells is characterized by deregulated cell growth. Examples of such include, but are not limited to, cytomas, lymphomas, blastomas, sarcomas, and leukemias. More specific examples of such cancers are squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma Tumor, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, intrauterine or uterine cancer, salivary gland cancer, renal cancer, liver cancer, prostate cancer, vulvar cancer, thyroid cancer, Including, but not limited to, hepatocellular carcinoma and various types of head and neck cancer.

As used herein, the term “proton pump inhibitor” (PPI) includes, but is not limited to, neutral forms or salt forms of omeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, perprazole ( H ⁺ , K ⁺ -ATPase, including s-omeprazole magnesium), habeprazole, lansoprazole, pariprazole, and leminoprazole, single enantiomers or isomers, or other derivatives or alkali salts of the enantiomers Any substituted benzimidazole possessing pharmaceutical activity as an inhibitor of Proton pump inhibitors also act by irreversibly blocking the gastric wall cell hydrogen / potassium adenosine triphosphatase enzyme system (H ⁺ / K ⁺ ATPase, or more commonly simply a gastric proton pump). As a compound that is functionally defined. The proton pump is at the end of gastric acid secretion and is directly involved in secreting H ⁺ ions into the gastric lumen, making it an ideal target for inhibition of acid secretion. Proton pump inhibitors also include the compound SCH28080.

  “Derivatives and analogs of lansoprazole” include compounds having the following general formula and stereoisomers and pharmaceutically acceptable salts thereof, as described in US Pat. No. 4,628,098. .

  “Pharmaceutically acceptable salts of lansoprazole” refers to those salts of lansoprazole derivatives that retain the biological effects and properties of the free acid or free base and are not unacceptable for pharmaceutical use. A pharmaceutically acceptable salt of a lansoprazole derivative includes a salt of an acidic or basic group that may be present in the lansoprazole derivative. Derivatives of lansoprazole, which are basic in nature, can form a wide variety of salts with a variety of inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are non-toxic acid addition salts, i.e. chloride, bromide, iodide, nitrate, sulfate, Bisulfate, phosphate, acid phosphate, isonicotinic acid, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, hydrogen tartrate, ascorbate, Succinate, maleate, gentate, fumarate, gluconate, glucaronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfone Acid salts, p-toluenesulfonic acid salts, and pamoic acid (ie, l, l′-methylene-bis- (2-hydroxy-3-naphthoic acid)) salts. Derivatives of lansoprazole containing an amino moiety can also form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above. Derived from lansoprazole, which is acidic in nature, can form a wide variety of salts with various inorganic and organic bases. Suitable base salts are formed from bases that donate cations to form non-toxic salts, and suitable cations include sodium, aluminum, calcium, lithium, magnesium, potassium, zinc, and diethanolamine salts, It is not limited to this. For a review on pharmaceutically acceptable salts, see Berge et al. , J .; Pharm. Sci, 66, 1-19 (1977), and REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Ed. (1990, Mack Publishing Co., Easton, Pa.).

  The phrase “pharmaceutically effective” refers to the ability of an active ingredient such as lansoprazole to elicit a biological or medical response sought by a researcher, veterinarian, physician or other clinician. Non-limiting examples include, but are not limited to, reducing the size of a patient's tumor, extending survival time, and the like.

The phrase “therapeutically effective amount” includes the amount of an active ingredient such as lansoprazole that elicits a biological or medical response sought by a researcher, veterinarian, physician or other clinician. The compounds of the present invention may be administered in an amount sufficient to reduce tumor size and / or prolong survival. Alternatively, a therapeutically effective amount of an active ingredient is to achieve a desired therapeutic and / or prophylactic effect, such as the amount of active ingredient that results in prevention or reduction of symptoms associated with the condition (eg, meets an endpoint). The amount of compound required. Effective amounts include, but are not limited to, increased gastric pH, reduced gastrointestinal bleeding, reduced need for blood transfusion, improved survival, faster recovery, mural cell activation and H ⁺ , K ⁺ − May include an amount with or without transient adverse side effects, including ATPase inhibition, or improvement or elimination of symptoms, and other indicators as selected as appropriate criteria by one of ordinary skill in the art .

  The term “pharmaceutically acceptable” or “pharmacologically acceptable” refers to a molecular entity that does not produce an adverse, allergic, or other undesirable response when administered to an animal or, where appropriate, a human. And refers to the composition. The term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is known in the art. Unless any conventional vehicle or agent is incompatible with the active ingredient, its use in a therapeutic composition is envisioned. Supplementary active ingredients can also be incorporated into the compositions.

  Any suitable route of administration may be employed to provide a subject with an effective amount of lansoprazole. Rectal, parenteral (non-limiting examples include subcutaneous, intramuscular, intravenous), transdermal, topical, oral administration, eyeball, ear, nostril administration, and the like are possible. Oral dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules and the like.

  The composition may comprise a dry formulation, solution and / or suspension of a proton pump inhibitor. As used herein, the terms “suspension” and “solution” are interchangeable and mean a solution and / or suspension of a substituted benzimidazole.

In certain embodiments, after administration of PPI, the drug is absorbed through the gastric lumen and delivered via the bloodstream to various tissues and cells of the subject, including various tumor cells. Without being bound by any theory, it is believed that PPI prevents tumor cell H ⁺ destruction by contacting the tumor cells and inhibiting the H / K ATPase proton pump. Inhibition of the proton pump may increase the intracellular pH of tumor cells and ultimately lead to cell apoptosis.

  A pharmaceutical composition comprising a proton pump inhibitor, such as lansoprazole, omeprazole, or other proton pump inhibitors and derivatives thereof may be used for the treatment or prevention of cancer. For example, pharmaceutical compositions containing a proton pump inhibitor such as lansoprazole are ovarian cancer, lymphoma, B lymphocyte myeloma, Hodgkin lymphoma, breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone It may be used for the treatment or prevention of cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer, or cervical cancer. Treatment of these conditions may be achieved by administering to the subject an effective amount of a pharmaceutical composition according to an embodiment of the invention.

  The dose range of other proton pump inhibitors, such as lansoprazole, or substituted benzimidazoles and derivatives thereof, may range from about <20 mg / day to about 400 mg / day, or more. Approximate daily oral doses are about 20 mg esomeprazole, about 360 mg omeprazole, about 240 mg pantoprazole, about 120 mg rabeprazole and, but not limited to, habeprazole, pariprazole, dontoprazole, lansoprazole, per Other PPI pharmaceutically equivalent doses may be included, including prazole (s-omeprazole magnesium), and leminoprazole. Alternatively, the dose range of other proton pump inhibitors, such as lansoprazole, or substituted benzimidazoles and derivatives thereof, may range from about <10 mg / kg to about 100 mg / kg, or more.

  The pharmaceutical composition of the proton pump inhibitor employed in the embodiments of the present invention may be administered to the subject in any form. This may be accomplished, for example, by administering the solution via the nasogastric (ng) tube or other indwelling tube placed in the gastrointestinal tract.

  The terms “individual”, “patient” or “subject” are used interchangeably herein, eg, animals such as humans, eg primates, and eg dogs, cats, pigs, cattle Any mammal, including other animals such as sheep, and horses. The compounds of the present invention can be administered to mammals such as humans, but also include, for example, livestock (eg, dogs, cats, etc.), farm animals (eg, cows, sheep, pigs, horses, etc.), and laboratory animals (eg, Rat, mouse, guinea pig, etc.), for example, and other mammals such as animals in need of veterinary treatment. As used herein, the term “subject” includes cells of cultured or tumor tissue cells.

  In one embodiment, a liquid oral pharmaceutical composition may be prepared by mixing lansoprazole (PREV ACID®) and / or other proton pump inhibitors or derivatives thereof with a solution containing a buffer. . For example, lansoprazole and / or another proton pump inhibitor may be mixed with a sodium bicarbonate solution to achieve the desired final lansoprazole (or other PPI) concentration. As an example, the concentration of lansoprazole in solution may range from about <180 mg / ml to about 300.0 mg / ml, or more.

  In one embodiment, the liquid oral pharmaceutical composition may be prepared by mixing lansoprazole (PREV ACED®) and / or other proton pump inhibitors or derivatives thereof with a solution containing a buffer. . For example, lansoprazole and / or another proton pump inhibitor may be mixed with a sodium bicarbonate solution to achieve the desired final lansoprazole (or other PPI) concentration. As an example, the concentration of lansoprazole in solution may range from about <180 mg / ml to about 300.0 mg / ml, or more.

  Sodium bicarbonate is one of the buffers employed in certain embodiments of the invention to protect the PPI against acid degradation, but many other weak and strong bases (and mixtures thereof) May be adopted. For purposes of this application, a “buffer” is sufficient to preserve the bioavailability of the administered PPI when formulated or delivered with the PPI (eg, before, during, and / or after). By stomach acid is meant any pharmaceutically suitable weak base or strong base (and mixtures thereof) that functions to substantially prevent or inhibit acid degradation of PPI. When used, the buffer may be administered in an amount sufficient to substantially achieve the functionality described above. Furthermore, the buffer of the present invention is only necessary to raise the pH of the stomach so that adequate bioavailability is fully achieved so as to produce a therapeutic effect when in the presence of gastric acid.

  Thus, examples of buffering agents include sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, magnesium hydroxide / sodium bicarbonate coprecipitate, a mixture of amino acid and buffer, Examples include, but are not limited to, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffers include sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, triphosphate phosphate. Sodium, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate , And other calcium salts.

  The pharmaceutically acceptable buffer may comprise a Group IA metal bicarbonate as a buffer, and may be prepared by mixing a Group IA metal bicarbonate, preferably sodium bicarbonate with water. Good. The concentration of the Group IA metal bicarbonate in the composition may be any concentration. In a non-limiting example, the bicarbonate concentration may range from about 5.0% to about 60.0%. The concentration of the Group IA metal bicarbonate may range from about 7.5% to about 10.0%. In one embodiment of the invention, sodium bicarbonate is a salt and is present at a concentration of about 8.4%.

  In one embodiment, the amount of 8.4% sodium bicarbonate used in the solution of the present invention is about 1 mEq per 2 mg lansoprazole, ranging from about 0.2 mEq (mmol) to 5 mEq (mmol) per 2 mg lansoprazole. (Or mmol) sodium bicarbonate.

In certain embodiments, enterally coated lansoprazole particles may be used. Alternatively, lansoprazole powder may be used. Enterally coated lansoprazole particles may be mixed with a sodium bicarbonate (NaHCO ₃ ) solution (8.4%) that dissolves the enteric coating and forms a lansoprazole solution. Lansoprazole solution (a) 1-3 hours after administration of enteric coated pellets, faster drug absorption time after administration of lansoprazole solution (approximately 10-60 minutes) (b) NaHCO ₃ solution is absorbed Protect lansoprazole from previous acid degradation, (c) NaHCO ₃ acts as an antacid while lansoprazole is absorbed, and (d) solution does not clog, eg, small diameter needle catheter feeding tube Has pharmacokinetic advantages over standard sustained release lansoprazole capsules, including that may be administered through existing indwelling tubes, such as nasogastric or other feeding tubes (jejunum or duodenum) obtain.

  In addition, various additives may be incorporated into the solutions of the present invention to enhance their stability, sterility, and isotonicity. Furthermore, bactericidal preservatives such as AMBICIN (registered trademark), antioxidants, chelating agents, and additional buffering agents may be added. However, microbiological evidence indicates that the formulation inherently possesses antibacterial and antifungal activity. Various antibacterial and antifungal agents such as, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. can enhance prevention of microbial activity.

In certain embodiments, for example, saccharides, sodium chloride sugar isotonic agents may be included in the composition. In addition, the use of thickeners such as methylcellulose may be desirable to reduce the precipitation of lansoprazole, or other PPI or its derivatives, from the suspension.
The solution further includes a flavoring agent (eg, chocolate, root beer, or watermelon), or other flavoring agent that is stable at pH 7-9, and an antifoam (eg, Simethicone 80 mg, Mylicon®).

  Embodiments of the present invention further comprise a pharmaceutical composition comprising lansoprazole, or other proton pump inhibitors and derivatives thereof, and one or more buffers in a form that is convenient for storage, wherein the composition is an aqueous solution. The composition dissolves to produce a suspension suitable for enteral administration to a subject. The pharmaceutical composition may be in solid form prior to dissolution or may be a suspension in an aqueous solution. Lansoprazole, or other PPI, and buffer may be formed into tablets, capsules, pellets, or granules by methods known to those skilled in the art.

  The resulting lansoprazole solution can be stabilized at room temperature for several weeks and can inhibit bacterial or fungal growth. The solution can retain a potency of greater than 90% for 12 months. Of a pharmaceutical composition comprising lansoprazole or other PPI with a buffer in a solid form that can be later dissolved or suspended in a prescribed amount of an aqueous solution to produce the desired concentration of lansoprazole and buffer. By providing, production, transportation, and storage costs can be greatly reduced because no liquid is transported (reducing weight and cost), and the solid form of the composition or solution need not be refrigerated. Once mixed, the resulting solution may then be used to provide doses to one patient or to several patients over time.

  As noted above, the formulations of the present invention may also be manufactured in concentrated forms such as tablets, suspension tablets, and effervescent tablets, or powders, so that when reacted with water or other diluents, Aqueous forms of are produced for oral, enteral, or parenteral administration.

  In addition to suspension tablets, the solid formulations of the present disclosure may be powdered, tablets, capsules, or other suitable solid dosage forms (e.g., when ingested in the presence of a diluent or when taken orally) It may be in the form of pellets or effervescent tablets, troches or powders. For example, water in gastric secretion or water used to swallow solid dosage forms may act as an aqueous diluent.

  The pharmaceutical composition of the present disclosure includes, as an active ingredient, for example, a PPI such as lansoprazole, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients. May be included.

  According to embodiments of the present invention, the sodium, lithium, potassium, magnesium, calcium, or barium salt of lansoprazole may be used. The salt may be a crystal. For example, the salts of the present invention can be obtained from (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H-benzimidazole. Sodium salt (specifically, crystal), (R) -2-[[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl] methyl] sulfinyl] -1H- It may be a potassium salt of benzimidazole (specifically, a crystal). In addition, the salt may be solvated.

In one embodiment of the invention, the PPI may be administered in combination with PEG300. For example, an active ingredient such as lansoprazole is mixed with PEG300 and administered to the subject.
In one embodiment of the invention, for example, a PPI such as lansoprazole may be administered to a subject along with another chemotherapeutic agent. Other possible chemotherapeutic agents include: alkylating agents such as carboplatin and cisplatin; nitrogen mustard alkylating agents; nitrosourea alkylating agents such as carmustine (BCNU); antimetabolites such as methotrexate; purine analog antimetabolites Pyrimidine analog antimetabolites such as fluorouracil (5-FU) and gemcitabine; hormonal antineoplastic agents such as goserelin, leuprolide and tamoxifen; aldesleukin, interleukin-2, docetaxel, etoposide (VP-16), Natural antineoplastic agents such as interferon, paclitaxel, and tretinoin (ATRA); antibacterial natural antineoplastic agents such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin; binblast And including vinca alkaloids natural antineoplastics, such as vincristine, but is not limited thereto. In addition, the following additional drugs are not considered as antineoplastic agents, but may be used in combination with PPI and / or another chemotherapeutic agent: dactinomycin; daunorubicin HCl; dodetaxel; doxorubicin HCl; epoetin alfa Etoposide (VP-16); ganciclovir sodium; gentamicin sulfate; interferon leuprolide acetate; meperidine HCl; methadone HCl; ranitidine HCl; vinblastine sulfate; and zidovudine (AZT).

  As used herein, the phrase “combination therapy” is intended as part of a specific treatment plan intended to provide a beneficial effect from the simultaneous action of these therapeutic agents, such as lansoprazole, etc. Of a PPI inhibitor and another chemotherapeutic agent. The beneficial effects of the combination include, but are not limited to, the simultaneous effects of chemotherapy or pharmacodynamics resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination is typically performed over a predetermined time period (usually week, month, or year, depending on the combination selected). Combination therapy is intended to encompass the administration of multiple therapeutic agents in turn, that is, each therapeutic agent is not only administered at a different time, but also these therapeutic agents, or at least two therapeutic agents. Are administered substantially simultaneously. Substantial simultaneous administration is achieved, for example, by administering to a subject a single tablet or capsule in which each therapeutic agent has a fixed ratio, or each of the therapeutic agents in multiple single capsules. Sequential or substantially simultaneous administration of each therapeutic agent is affected by any suitable route, including but not limited to oral route, intravenous route, intramuscular route, and direct absorption through mucosal tissue. obtain. The therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination may be administered by intravenous injection, while the other therapeutic agent of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.

  Combination therapy may also include administration of therapeutic agents as described above in combination with further biologically active ingredients and non-drug therapies. If the combination therapy further includes non-drug treatment, the non-drug treatment may be performed at any suitable time, so long as a beneficial effect is achieved from the simultaneous action of the combined therapeutic agent and non-drug treatment. . For example, where appropriate, beneficial effects are achieved even when non-drug treatment is temporarily removed from administration of a therapeutic agent, perhaps days or even weeks.

  The components of the combination may be administered to the patient simultaneously or sequentially. It should be understood that the components may be present in the same pharmaceutically acceptable carrier and are therefore administered simultaneously. Alternatively, the active ingredients may be present in a separate pharmaceutical carrier, such as a conventional oral dosage form, which can be administered simultaneously or sequentially.

  According to one embodiment of the invention, PPI may be used in the manufacture of a medicament for the treatment of tumors. For example, the use of lansoprazole in the manufacture of a drug for the treatment of tumors represents an embodiment of the present invention.

The invention is further described in the following examples, which are provided by way of illustration and are not intended to limit the invention in any way.
Example I
In one trial, adherent cells were placed in 180 μl growth medium for approximately 16-24 hours prior to the experimental day. On the day of the experiment, the adherent cells that were placed were analyzed and counted, and the suspended cells were placed in 180 μl growth medium. A 10 × lansoprazole compound and vehicle were prepared. Lanxoprazole compounds were prepared by diluting lansoprazole to final concentrations of 100 μM, 30 μM, 10 μM, 3 μM, and 1 μM. The vehicle was prepared by preparing a PBS solution equivalent to the amount used for 10 μM lansoprazole, wherein the 1 × solution constitutes about 0.06% PBS. 10 μl of various 10 × lansoprazole solutions and vehicle were added to the cells. Cells were incubated for 48 hours at 37 ° C., 5% CO ₂ . The medium was then aspirated. The cell suspension was then spun at 1500 RPM for 10 minutes. The medium was slowly removed. 200 μl of MTT solution was added to each well at a concentration of 0.863 mg / ml MTT in growth medium. Cells were incubated for 4 hours at 37 ° C., 5% CO ₂ and then the medium was aspirated. The plate containing the cell suspension was then spun at 1500 RPM for 10 minutes. The media was slowly removed using a multichannel dispenser. 100 μl DMSO was added to each well. Cells were incubated for 5 minutes at 37 ° C., 5% CO ₂ and absorbance was obtained at 560 nm using a Dynax Opsys MR plate reader. The cells used for this procedure were the following cell lines: IGROV1 (ovarian cancer); OVCAR8 (ovarian cancer); ES-2 (ovarian cancer); CAOV3 (ovarian cancer); OVCAR5 (ovarian cancer); SUDHL4 ( Lymphoma); RPMI 8226 (myeloma); RPMI 6666 (Hodgkin lymphoma); NC37 (lymphoma); GDM-I (leukemia); MC / CAR (prostate cancer); DU-145 (prostate cancer), J45-01 (leukemia), MOLT3 (leukemia), HUT78, J-gamma-1 (leukemia), MCF7, (leukemia), COLO205 (colon cancer), HL60 clone 15 (leukemia), T47D (breast cancer), Pl16 (intestinal cancer), KU812 (leukemia) , SW620 (colon cancer), MK92-M1 (lymphoma), MV-4-11 (leukemia), HS578T (breast cancer) , HT29 (colon cancer), HCT116 (colon cancer), CAKI-1 (kidney cancer), A549 (lung cancer), H460 (lung cancer), A3 (colon cancer), MDA-MB231 (melanoma), MALME3M (melanoma) RXF393, (kidney cancer), RS4.11 (leukemia), PC3 (prostate cancer), OVCAR3 (ovarian cancer), MDA-MB435 (melanoma), HUT102 (lymphoma), HL60 (leukemia), CCRF-CEM (leukemia) ), HUT78 (lymphoma), 786-O (renal cancer), ACHN (renal cancer), A498 (renal cancer), H226 (lung cancer), H522 (lung cancer), HOP92 (lung cancer), SNB19 (brain cancer), OVCAR4 ( (Ovarian cancer), H9 (lymphoma), UO-31 (kidney cancer), HH (lymphoma), DAUDI (leukemia), LOXIMVI (melanoma), NAMAL A (lymphoma), EKVX (lung cancer), DOHH2 (lymphoma), SNB75 (brain cancer), SKMEL28 (melanoma), SKMEL5 (melanoma), SKMEL2 (melanoma), M14 (melanoma), UACC257 (melanoma) , H332M (lung cancer), KM12 (colon cancer), HCC2998 (colon cancer), G401 (renal cancer), RS1184 (lymphoma), MC116 (leukemia) MOLT4 (leukemia) JM1 (liver cancer), HOP-62 (lung cancer), HCT -15 (colon cancer), SF-539 (brain cancer), SF295 (brain cancer), ST486 (lymphoma), U251 (brain cancer) and UACC-62 (melanoma). As shown in FIGS. 1A-AU, 2A-2O, 6A-6M, the following cell lines showed a marked reduction in tumor cell growth: ES-2, IGROV1, OVCAR5, OVCAR8, J-gamma-1, KU812. , NK92MI, 786-O, A498, H522, SNB19, OVCAR4, H9, HH, EKVX, OVCAR5, UACC257, H226, UO-31, NAMALWA, SKMEL28, SKMEL2, M14, H322M, HCC2998, HL60H, TCC2998, HL60H , PC3, H460, RPMI8226, NC37, MC / CAR, SUDHL4, RPMI6666, GDM-1, MOLT3, J45-01, MCF7, HL60 clone 15, Pl16, SW620, MV-4-11, SKMEL5 ( Melanoma), DAUDI, DOHH2, HUT102, CCRF-CEM, HUT78, A3, MDA-MB-435, MDA-MB-231, RS4.11, MC116, MOLT4, JMI, HOP-62, HCT-15, SF- 539, SF295, ST486, U251, and UACC-62.

Example II
Prior to the experimental day, adherent cells were placed in 180 μl growth medium for approximately 16-24 hours. On the day of the experiment, the adherent cells that were placed were analyzed and counted, and the suspended cells were placed in 180 μl growth medium. A 10 × lansoprazole compound, vehicle, and chemotherapeutic cocktail were prepared. Lanxoprazole compounds were prepared by diluting lansoprazole to final concentrations of 100 μM, 30 μM, 10 μM, 3 μM, and 1 μM. The vehicle was prepared by preparing a PBS solution equivalent to the amount used for 10 μM lansoprazole, wherein the 1 × solution constitutes about 0.06% PBS. A chemotherapeutic cocktail was prepared by diluting the velcade solution to 10 μM, 100 μM, the etoposide solution to 1 mM and 20 μM, and the taxol solution to 200 μM to obtain a 10 × solution. 10 μl of various 10 × lansoprazole solutions, chemotherapy cocktail, and vehicle were added to the cells. Cells were incubated for 48 hours at 37 ° C., 5% CO ₂ . The medium was then aspirated. The plate containing the cell suspension was then spun at 1500 RPM for 10 minutes. The media was slowly removed using a multichannel dispenser. 200 μl of MTT solution was added to each well at a concentration of 0.863 mg / ml MTT in growth medium. Cells were incubated for 4 hours at 37 ° C., 5% CO ₂ and then the medium was aspirated. The plate containing the cell suspension was then spun at 1500 RPM for 10 minutes. The media was slowly removed using a multichannel dispenser. 100 μl DMSO was added to each well. Cells were incubated for 5 minutes at 37 ° C., 5% CO ₂ and absorbance was obtained at 560 nm using a Dynax Opsys MR plate reader. The cells used for this procedure may include the following cell lines: IGROV1, OVCAR8, ES-2, CAOV3, OVCAR5 SUDHL4, RPMI8226, RPMI6666, NC37, GDM-1, MC / CAR, DU-145, J45. -01, MOLT3, HUT78, J-gamma1, MCF7, COLO205, HL60 clone 15, T47D, P116, KU812, SW620, MK92-M1, MV-4-11, HS578T, HT29, HCT116, CAKI-1, A549, H460, A3, MDA-MB231, MALME 3M, RXF393, RS4.11, PC3, OVCAR3, MDA-MB435, HUT102, HL60, CCRF-CEM, HUT78, 786-O, ACHN, A498, H 26, H522, HO P92, SNB19, OVCAR4, H9, UO-31, HH, DAUDI, LOXIMVI, NAMALWA, EKVX, D0HH2, SNB75, SKMEL28, SKMEL5, SKMEL2, M14, UACC257, G12H, M12 RS1184.

Example III
JR (Rhabdomyosarcoma), HepG2 (hepatocytoma), SR fluid leukemia (leukemia), RS1184B lymphoma (lymphoma), and G401 labroid (kidney) cell carcinoma for use in a xenograft mouse model SR liquid leukemia, RS1184B lymphoma, and G401 labroid tumor cell lines were collected and injected subcutaneously at a volume of 100 μl, 5 × 10 ⁶ cells per nude mouse. Animals were examined three times a week to determine tumor progression and body weight. Administration began when the tumors reached a size of about 75-150 mm ³ . The animals were randomized and divided into groups so that the average tumor weight for all groups was within 15% of the average tumor weight for Group 1 (control-vehicle group). When a target size of approximately 75-150 mm ³ was reached, an effective amount of lansoprazole was administered to the mice in a suspension of PEG300 at a concentration of 100 mg / kg. As shown in FIGS. 4A-4C and 5A-5C, lansoprazole effectively reduced tumor growth and prolonged population life in mice. Lansoprazole was particularly effective in treating tumor cells from HepG2, G401, and SR liquid leukemia tumor cell lines.

Example IV
As described in Example II and Example III, experiments were performed such as omeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, perprazole (s-omeprazole magnesium), habeprazole, lansoprazole, paliprazole, and leminoprazole. This was done using an ATPase inhibitor.

Example V
As described in Example I, experiments were performed with lansoprazole, omeprazole, and SCH28080 at concentrations of 1 μM, 10 μM, and 100 μM. FIGS. 3A-3K show the experimental results when tumor cells from the following cell lines were treated with lansoprazole, omeprazole and SCH28080: IGROV1 (FIG. 3A), OVCAR8 (FIG. 3B), ES-2 ( 3C), CAOV3 (FIG. 3D), OVCAR5 (FIG. 3E), SUDHL4 (FIG. 3F), RPMI8226 (FIG. 3G), RPMI6666 (FIG. 3H), NC37 (FIG. 3I), GDM-1 (FIG. 3J), and MC / CAR (FIG. 3K). As seen in FIGS. 3E-I and 3K, 100 μM lansoprazole was effective in reducing tumor cell growth (omeprazole reduced tumor cell growth in the MC / CAR cell line, as shown in FIG. 3K. Was effective). In addition, 10 μM concentrations of lansoprazole, omeprazole, and SCH28080 were effective in reducing tumor cell growth in the GDM-I cell line, as shown in FIG. 3J.

Example VI
To reduce the size of a subject's tumor, the subject is first examined and a tumor diagnosed. Tumor diagnosis is accomplished by means well known to those skilled in the art. Once the tumor has been diagnosed, a pharmaceutically acceptable composition is administered to the subject. Pharmaceutically acceptable compositions include lansoprazole, excipients, and instructions for administering the pharmaceutically acceptable composition to a subject suffering from a tumor. Determine that the subject is not suffering from transient gastric acid production. The pharmaceutically acceptable composition is administered according to the instructions provided. The instructions indicate how much pharmaceutically acceptable composition will be administered to the subject to reduce the size of the diagnosed tumor. When properly administered, the pharmaceutically acceptable composition reduces the amount of tumor diagnosed, further tumor growth is inhibited through cytostatic effects, and tumor cells have a cytocidal effect. Dies through.

  While this invention is described in specific embodiments, the present invention may be further modified without departing from the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses, or adaptations of the invention using its general principles. Furthermore, this application is intended to cover such deviations from this disclosure that are within the known or routine practice of the art to which this invention belongs and that fall within the scope of the appended claims. .

Equivalents It is to be understood that the disclosed invention is not limited to the particular methodologies, protocols, and dosages described so as to vary. Also, the terminology used herein is for the purpose of describing particular embodiments only and is intended to limit the scope of the invention which is limited only by the appended claims. It should also be understood that it is not intended.

Claims (17)

A method of killing tumor cells,
Administering a pharmaceutically acceptable composition comprising an effective amount of a proton pump inhibitor or a pharmaceutically acceptable salt thereof to said tumor cells to reduce tumor burden. A method of reducing the size of a subject's tumor, comprising:
Diagnosing the tumor of the subject;
Administering to the subject a pharmaceutically acceptable composition comprising a proton pump inhibitor in an amount sufficient to reduce the size of the tumor;
Including a method.   3. The method of any one of claims 1 and 2, wherein upon administration, the pharmaceutically acceptable composition interacts with tumor cells outside the gastric lumen.   Said proton from lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole, SCH28080, and any of these enantiomers, isomers, free bases, salts, and mixtures 4. The method of any one of claims 1 and 3, further comprising selecting a pump inhibitor.   5. The method of any one of claims 1-4, wherein administering the pharmaceutically acceptable composition comprises inducing apoptosis of the tumor cell.   6. The method of any one of claims 1-5, further comprising administering the pharmaceutically acceptable composition at a dose of about 180 mg / day lansoprazole.   The tumor cells are RPMI8226, NC37, MC / CAR, SUDHL4, RPMI6666, GDM-1, MOLT3, J45-01, MCF7, HL60 clone 15, Pl16, SW620, MV-4-11, SKMEL5, DAUDI, D0HH2, HUT102. , CCRF-CEM, HUT78, A3, MDA-MB-435, MDA-MB-231, RS4.11, ES-2, IGROV1, OVCAR5, OVCAR8, J-gamma-1, KU812, NK92MI, 786-O, A498 , H522, SNB19, OVCAR4, H9, HH, EKVX, OVCAR5, UACC257, H226, UO-31, NAMALWA, SKMEL28, SKMEL2, M14, H322M, HCC2998, HL60, H 29, A549, RXF393, PC3, H460, MCl16, MOLT4, JMI, HOP-62, HCT-15, SF-539, SF295, ST486, U251, and UACC-62. 6. The method according to any one of 6.   The tumor cells are cell tumor, lymphoma, blastoma, myeloma, sarcoma, leukemia, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma Glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, colorectal cancer, in utero or uterine cancer, salivary gland cancer, renal cancer, liver cancer, prostate cancer, vulvar cancer 8. The method of any one of claims 1-7, associated with a disease selected from the group consisting of: thyroid cancer, and hepatocellular carcinoma.   8. The administering of the pharmaceutically acceptable composition comprises administering the proton pump inhibitor in an amount of about 10 mg / kg to about 100 mg / kg. The method of any one of -8.   10. The method of any one of claims 1-9, further comprising administering a second agent, wherein the second agent is a chemotherapeutic agent.   11. The method of any one of claims 1-10, further comprising administering a buffer.   12. The method of any one of claims 1-11, wherein the growth deregulated cell population decreases in size about 3 weeks after the administration.   13. The method of any one of claims 1-12, wherein administering the pharmaceutically acceptable composition results in the subject's survival being greater than about 15% compared to a subject receiving a placebo. Method.   14. The method of any one of claims 2-13, further comprising determining that the subject is not suffering from increased gastric acid secretion.   Use of a proton pump inhibitor in the manufacture of a drug for the treatment of tumor cells.   16. Use according to claim 15, wherein the proton pump inhibitor comprises lansoprazole. A pharmaceutical composition for use in reducing the size of a subject's tumor, comprising:
An amount of a proton pump inhibitor or a pharmaceutically acceptable salt thereof for treating the tumor of the subject;
A pharmaceutically acceptable excipient;
Instructions for administering the proton pump inhibitor to the subject suffering from the tumor to treat the tumor.