# US 6,599,912 B1 · Methods and compositions for modulating cell proliferation and cell death > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 6,599,912 B1 - Document ID: US6599912B1 - Status: Granted - Kind: B1 - Application number: 09/587,559 - Filed: 2000-06-05 - Granted: 2003-07-29 - Earliest claimed: 1999-06-03 - Inventors: Jessie L. -S. Au; Guillaume Wientjes - Web page: https://patentgrep.com/patent/US6599912B1 ## CPC - C07K 16/22: against growth factors {; against growth regulators} - A61K 38/1825: {Fibroblast growth factor [FGF]} - A61K 39/001132: {Fibroblast growth factors [FGF]} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 17/06: Antipsoriatics - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - A61P 35/04: specific for metastasis - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K 2039/505: {comprising antibodies} - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Methods and compositions for modulating the FGF effect on the sensitivity of malignant and normal cells to anticancer agents are provided. In particular, methods and compositions for inhibiting FGF-induced resistance to a broad spectrum of anticancer agents in solid and soft-tissue tumors, metastatic lesions, leukemia and lymphoma are provided. Preferably, the compositions include at least one FGF inhibitor in combination with a cytotoxic agents, e.g., antimicrotubule agents, topoisomerase I inhibitors, topoisomerase II inhibitors, antimetabolites, mitotic inhibitors, alkylating agents, intercalating agents, agents capable of interfering with a signal transduction pathway (e.g., g., a protein kinase C inhibitor, e.g., an anti-hormone, e.g., an antibody against growth factor receptors), an agent that promotes apoptosis and/or necrosis, and interferon, an interleukin, a tumor necrosis factor, and radiation. In other embodiments, methods and composition for protecting a cell in a subject, from one or more of killing, inhibition of growth or division or other damage caused, e.g., by a cytotoxic agent, are provided. Preferably, the method includes: administering, to the subject, an effective amount of at least one FGF agonist, thereby treating the cell, e.g., protecting or reducing the damage to the dividing cell from said cytotoxic agent. ## Claims ### Claim 1 A method of improving the efficacy of a cytotoxic agent, in a subject, comprising: administering to the subject at least one cytotoxic agent; administering to the subject suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml, wherein suramin enhances the efficacy of the cytotoxic agent, relative to the effect of the cytotoxic agent in the absence of suramin. ### Claim 2 A method of inhibiting growth or proliferation of hyperproliferative cells in a subject, comprising: administering to the subject at least one cytotoxic agent and suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml which, together, is effective to inhibit growth or proliferation of the hyperproliferative cells, or is effective to induce death of the hyperproliferative cells. ### Claim 3 A method of inhibiting growth or proliferation of, or inducing killing of tumor cells in a subject, comprising: administering to the subject at least one cytotoxic agent and suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml which, together, is effective to inhibit growth or proliferation of the tumor cells. ### Claim 4 A method of inhibiting unwanted growth or proliferation of, or inducing killing of tumor cells in a human subject, comprising: administering to the human subject at least one cytotoxic agent and suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml, which together, is effective to reduce or inhibit the growth or proliferation of the established humor, induce cell death in the established tumors, or to reduce the size of the established tumors. ### Claim 5 A method of inhibiting unwanted proliferation of, or inducing killing, of, an established tumor in a subject, comprising: administering to the subject at least one cytotoxic agent and suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml, which together, is effective to reduce or inhibit the growth or proliferation of the established tumor, induce cell death in the established tumors, or to reduce the size of the established tumors, wherein the established tumor is selected from the group consisting of lung carcinoma, renal cell carcinoma, glioma, melanoma, chemotherapy resistant tumors and metastatic tumors. ### Claim 6 A method of inhibiting unwanted proliferation of, or inducing killing of, an established tumor in a subject, comprising: administering to the subject at least one cytotoxic agent and suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml, which together, is effective to reduce or Inhibit the growth or proliferation of the established lung tumor, induce cell death In the established lung tumors, or to reduce the size of the established lung tumors. ### Claim 7 (depends on 1) The method of claim 1, wherein the total suramin exposure is less than 800 micromolar-day over 96 hours. ### Claim 8 (depends on 1) The method of claim 1, wherein the total suramin exposure is less than 252 micromolar-day over 96 hours. ### Claim 9 (depends on 1) The method of claim 1, wherein suramin is administered in an amount that results in a concentration ranging from 0.1 to 90 μg/ml over 96 hours. ### Claim 10 (depends on 1) The method of claim 1, wherein suramin is administered in an amount that results in a concentration ranging from abut 15 to 45 μg/ml over 96 hours. ### Claim 11 (depends on 1) The method of claim 1, wherein suramin is administered over a time period which ends less then 180 days after the last day on which the cytotoxic agent is administered. ### Claim 12 (depends on 1) The method of claim 1, wherein suramin is administered over a time period which ends less than 30 days after the last day on which the cytotoxic agent is administered. ### Claim 13 (depends on 1) The method of claim 1, wherein suramin is administered over a time period which begins less then 180 days before the first day on which the cytotoxic agent is administered. ### Claim 14 (depends on 1) The method of claim 1, wherein suramin is administered over a time period which begins lose then 30 days before the first day on which the cytotoxic agent is administered. ### Claim 15 (depends on 2, 3) The method of any of claims 2, 3, or 4, wherein the tumor is selected from the group consisting of a fibrosarcoma, myosarcoma, liposarcoma chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcome, lymphangioandotheliosarcoma, synoviome, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, gastric cancer, esophageal cancer, colon carcinoma, rectal cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, uterine cancer, cancer of the head and neck, skin cancer, brain cancer, squamous cell carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinome, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepetoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular cancer, lung carcinoma, small call lung carcinoma, non-small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astracytoma, medulloblastoma, craniopharyngloma, ependymoma, pinealoma, hemangloblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma and Kaposl's sarcoma. ### Claim 16 (depends on 4) The method of claim 4, wherein the established tumor comprises a cancer forming from a tissue or cell selected from the group consisting of a tissue or cell where an FGF molecule is expressed, a tissue or cell that is in contact or exposed to aFGF, bFGF or nd an FGF-producing tissue or cells. ### Claim 17 (depends on 2) The method of claim 2, wherein the hyperproliferative disorder comprises unwanted growth forming from a tissue or cell selected from the group consisting of a tissue or cell where an FGF molecule is expressed, a tissue or cell that is in contact or exposed to aFGF, bFGF or both, and an FGF-producing tissue or cells. ### Claim 18 (depends on 1, 2, 3) The method of any of claims 1, 2, 3, or 4, wherein the subject is a mammal. ### Claim 19 (depends on 18) The method of claim 18, wherein the subject is a human. ### Claim 20 (depends on 1, 2, 3) The method of any of claims 1, 2, 3, or 4, wherein the cytotoxic agent is selected from the group consisting of an antimicrotubule agent, a topoisomerase I inhibitor, a topoisomerase II inhibitor, an antimetabolite, a mitotic inhibitor, an alkylating agent, an intercalating agent, an agent capable of interfering with a signal transduction pathway, an agent that promotes apoptosis and/or necrosis, an interferon, an interleukin, a tumor necrosis factor, and radiation. ### Claim 21 (depends on 20) The method of claim 20, wherein the cytotoxic agent is one or more of paclitaxel, interferon alpha, gemcitabine, fludarabine, irinotecan, carboplatin, cisplatin, taxotere, doxorubicin, epirubicin, 5-fluorouracil, UFT, tamoxifen, goserelin, ketoconazole, an anti-Her2/heu antibody, anti-CD20, leuprolide (Lupron) or flutamide. ### Claim 22 (depends on 1, 2, 3) The method of any of claims 1, 2, 3, or 4, wherein the cytoxic agent and suramin are administered simultaneously. ### Claim 23 (depends on 1, 2, 3) The method of any of claims 1, 2, 3, or 4, wherein repeated dosages of the same, or a different cytotoxic agent are administered. ### Claim 24 (depends on 1, 2, 3, 4) The method of any of claims 1, 2, 3 or 4, wherein repeated dosages of suramin are administered. ### Claim 25 (depends on 1, 2, 3) The method of any of claims 1, 2, 3, or 4, wherein the cytotoxic agent is administered parenterally, orally, locoregionally, nasally, rectally, topically, or transdermally. ### Claim 26 (depends on 1, 2, 3) The method of any of claims 1, 2, 3, or 4, wherein suramin is administered parenterally, orally, locoregionally, nasally, rectally, topically, or transdermally. ### Claim 27 (depends on 1, 2, 3) The method of any of claims 1, 2, 3, or 4, further comprising monitoring the FGF levels of the subject prior to administering suramin to the subject. ### Claim 28 (depends on 27) The method of claim 27, wherein the amount of suramin administered to the subject is determined, at least in part, based upon the levels of FGF present in the subject as determined by said monitoring step prior to administering suramin. ### Claim 29 (depends on 1) The method of claim 1, wherein, suramin improves the efficacy of the cytotoxic agent against an established tumor. ### Claim 30 A method for inhibiting chemoresistance of a tumor cell to a cytotoxic agent, comprising: administering to the tumor cell suramin In an amount that results in a plasma concentration of between 0.1 end 90 μg/ml such that chemoresistance of the tumor cell to the cytotoxic agent is inhibited. ### Claim 31 (depends on 30) The method of claim 30, wherein the tumor cell is in a subject. ### Claim 32 (depends on 31) The method of claim 31, wherein the tumor cell is in an established tumor in a subject. ### Claim 33 A method for treating or preventing a disorder involving aberrant growth or proliferation of benign proliferative tissue, comprising: contacting the tissue with at least one cytotoxic agent and suramin in an amount that results In a plasma concentration of between 0.1 and 90 μg/ml, which, together, is effective to Inhibit growth or proliferation of the tissue or to induce death of hyperproliferative cells. ### Claim 34 (depends on 33) The method of claim 33, wherein the disorder is selected from the group consisting of psoriasis, cysts, benign prostatic hyperplasia, and endometriosis. ### Claim 35 (depends on 33) The method of claim 33, wherein the disorder is selected from the group consisting of oral papillomas, central giant cell granulomas of the mouth or pharynx, benign cementoblastomas of the oral cavity, oral plakia, gastric polyps, gastric adenomas, small intestinal adenomas, small intestinal granulomas, small intestinal papillomas, small intestinal oncocytomas, small intestinal Schwannomas, colonic polyps, colonic adenomas, Crohn's disease, hepatic adenoma, hepatic cirrhosis, biliary papillomatosis, pancreatic adenomas, pancreatic ductal hyperplasia, renal oncocytomas, renal papillomas, adenomas of the bladder, malakoplakia of the bladder, pseudosarcomas of the bladder, endometriosis, benign prostatic hyperplasia, erythroplasia of the penis, polyps and papillomas of the vulva, vagina, or cervix, endometrial polyps, adenomas, papillomas, or leimyomas, ovarian cysts, fibrocystic disease of the breast, lipoma of the breast, sclerosing adenosis, hemangioma, ductal hyperplasia of the breast, fibroadenomas, adenomyoepitheliomas, hamartoma, nevus of the skin, genodermatoses, fibrosis of the bone, fibrous dysplasia, chondrodysplasisa, sclerosing bone dysplasia, axial osteomalacia, fibrogenesis imperfecta, osteomas, osteoid osteomas, osteoblastomas, osteochondomas, enchondromas, chondromyxoid fibromas, chondroblastomas, synovial lipomas, adenomas of endocrine organs, goiter, Graves' disease, adrenal hyperplasia, adrenal adenomas, adrenal MEN I syndrome, and adrenal myelolipomas. ### Claim 36 A method of improving the efficacy of a cytotoxic agent, in a human subject, comprising: administering to the subject at least one cytotoxic agent; administering to the subject suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml, wherein the suramin enhances the efficacy of the cytotoxic agent, relative to the effect of the cytotoxic agent in the absence of the suramin. ### Claim 37 A method of inhibiting growth or proliferation of hyperproliferative cells in a human subject, comprising: administering to the subject at least one cytoxic agent and suramin In an amount that results in a plasma concentration of between 0.1 and 90 μg/ml, which, together, is effective to inhibit growth or proliferation of the hyperproliferative cells, or is effective to induce death of the hyperproliferative cells. ### Claim 38 A method of inhibiting growth or proliferation of, or inducing killing of tumor cells in a human subject, comprising: administering to the subject at least one cytotoxic agent and suramin in an amount that results in a plasma concentration of between 0.1 and 90 μg/ml, which, together, is effective to inhibit growth or proliferation of the tumor cells or Induce death of tumor cells. ### Claim 39 A method of improving the efficacy of a cytotoxic agent in a subject, comprising: administering to the subject at least one cytotoxic agent; and administering to the subject suramin in an amount that results in a total exposure of less than about 800 μm-day over 96 hours, wherein the suramin enhances the efficacy of the cytotoxic agent, relative to the effect of the cytotoxic agent in the absence of the suramin. ### Claim 40 A method of improving the efficacy of a cytotoxic agent, in a subject, comprising: administering to the subject at least one cytotoxic agent end administering to the subject suramin in an amount that results in a total exposure of not more than about 2,000 μm-day over 20 days, wherein the suramin enhances the efficacy of the cytotoxic agent, relative to the effect of the cytotoxic agent In the absence of the suramin.