Chemotherapeutic Methods

Abstract

Disclosed herein are chemotherapeutic methods for the treatment of cancer in humans. In at least one specific embodiment, the method can include administering a therapeutic effective amount of one or more p38 inhibitor compound or salt thereof to a human. The method can also include administering a therapeutic effective of one or more IL-6 inhibitor or one or more IL-6 receptor inhibitor or salt thereof to the human. The method can also include administering a therapeutic effective amount of one or more cytotoxic compound or salt thereof to the human.

1 . A method of treatment of cancer in a human comprising:
 administering a therapeutic effective amount of one or more p38 inhibitor compound or salt thereof to a human, and administering a therapeutic effective of one or more cytotoxic compound or salt thereof to the human.   
     
     
         2 . The method of  claim 1 , wherein the p38 inhibitor is selected from the group consisting of: PH797804 (3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide); RWJ 67657 (4-[4-(4-Fluorophenyl)-1-(3-phenylpropyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-3-butyn-1-ol); SCIO 469 (6-Chloro-5-[[(2R,5S)-4-[(4-fluorophenyl)methyl]-2,5-dimethyl-1-piperazinyl]carbonyl]-N,N,1-trimethyl-α-oxo-1H-Indole-3-acetamide); EO 1428 ((2-Methylphenyl)-[4-[(2-amino-4-bromophenyl)amino]-2-chlorophenyl]methanone); Org 48762-0 ((4,6-Bis(4-fluorophenyl)-2-methyl-5-(4-pyridyl)-2H-pyrazolo[3,4-b]pyridine); SD 169 (5-Carbamoylindole); SB 203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole); SB 202190 (4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole); SB 239063 (trans-4-[4-(4-Fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazol-1-yl]cyclohexanol); SB 220025 (4-[5-(4-fluorophenyl)-3-piperidin-4-ylimidazol-4-yl]pyrimidin-2-amine); VX-745 (5-(2,6-Dichlorophenyl)-2-[2,4-difluorophenyl)thio]-6H-pyrimido[1,6-b]pyridazin-6-one); SB 242235 (N-(2,3-Dihydro-7,8-dimethoxyimidazo[1,2-c]quinazolin-5-yl)-3-pyridinecarboxamide); VX-702 (6-[(Aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridinecarboxamide); SD-282 (1H-indole-5-carboxamide); PH-797804 (3-[3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-2-oxopyridin-1-yl]-N,4-dimethylbenzamide); L-167307 (4-[3-(4-fluorophenyl)-5-(4-methylsulfinylphenyl)-1H-pyrrol-2-yl]pyridine); RPR200765A; pamapimod (6-(2,4-difluorophenoxy)-2-(1,5-dihydroxypentan-3-ylamino)-8-methylpyrido[2,3-d]pyrimidin-7-one); BIRB 796; BMS 582949; substituted 2-aza-[4.3.0]-bicyclic heteroaromatic compounds; ARRY-791; SB681323; ISIS101757; SCIO323; PS540446 (4-[5-(cyclopropylcarbamoyl)-2-methylanilino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide); SB856553 (6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide); KC706; SB230580; and SB281832 (2-[4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazol-1-yl]propane-1,3-diol) or salts thereof. 
     
     
         3 . The method of  claim 1 , wherein the cytotoxic drug is selected from the group consisting of: bendamustine, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, melphalan, procarbazine, streptozocin, temozolomide, asparaginase, capecitabine, cytarabine, 5-fluoro uracil, fludarabine, gemcitabine, methotrexate, pemetrexed, raltitrexed; actinomycin D, dactinomycin, bleomycin, daunorubicin, doxorubicin, doxorubicin (pegylated liposomal), epirubicin, idarubicin, mitomycin, mitoxantrone, etoposide, docetaxel, irinotecan, paclitaxel, topotecan, vinblastine, vincristine, vinorelbine; carboplatin, cisplatin, oxaliplatin, alemtuzamab, bacullus calmette-guerin, bevacizumab, cetuximab, denosumab, erlotinib, gefitinib, imatinib, interferon, ipilimumab, lapatinib, panitumumab, rituximab, sunitinib, sorafenib, temsirolimus, Trastuzumab, clodronate, ibandronic acid, pamidronate, zolendronic acid, anastrozole, abiraterone, amifostine, bexarotene, bicalutamide, buserelin, cyproterone, degarelix, exemestane, flutamide, and folinic acid. 
     
     
         4 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: breast cancer, pancreas cancer, skin cancer, bone cancer, prostate cancer, liver cancer, lung cancer, brain cancer, cancer of the larynx, gallbladder, pancreas, rectum, parathyroid, thyroid, adrenal, neural tissue, head and neck, colon, stomach, bronchi, kidneys, basal cell carcinoma, squamous cell carcinoma, metastatic skin carcinoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, malignant fibrous histiocytoma, fibrosarcoma, multiple myeloma, reticulum cell sarcoma, myeloma, giant cell tumor, small-cell lung tumor, gallstones, islet cell tumor, primary brain tumor, acute and chronic lymphocytic and granulocytic tumors, hairy-cell tumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor, leiomyomater tumor, cervical dysplasia and in situ carcinoma, neuroblastoma, glioblastoma, retinoblastoma, soft tissue sarcoma, malignant carcinoid, topical skin lesion, mycosis fungoide, rhabdomyosarcoma, Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia, renal cell tumor, polycythemia vera, adenocarcinoma, glioblastoma multiforma, leukemias, lymphomas, malignant melanomas, and epidermoid carcinomas. 
     
     
         5 . The method of  claim 1 , wherein a therapeutic effective amount of the p38 inhibitor is from about 50 mg/day to about 2,000 mg/day. 
     
     
         6 . The method of  claim 1 , wherein the therapeutic effective amount of the cytotoxic drug is from about 50 mg/day to about 2,000 mg/day. 
     
     
         7 . The method of  claim 1 , wherein the treatment results in apoptosis of at least one cancer cell. 
     
     
         8 . The method of  claim 1 , wherein a time between administering the p38 inhibitor and administering the cytotoxic drug is about 1 hour to about 1 week. 
     
     
         9 . The method of  claim 1 , wherein the p38 inhibitor is an inhibitor of the IL-6 pathway. 
     
     
         10 . The method of  claim 9 , wherein the inhibitor of the IL-6 pathway is an IL-6 inhibitor or an IL-6 receptor (IL-6R) inhibitor. 
     
     
         11 . The method of  claim 10 , wherein the IL-6 inhibitor or the IL-6R inhibitor inhibits the activity and/or the expression of IL-6 or IL-6R. 
     
     
         12 . The method of  claim 10 , wherein the IL-6 inhibitor is an anti-IL6 aptamer. 
     
     
         13 . The method of  claim 10 , wherein the IL-6 inhibitor is (4S)-3-[(2S,3S)-3-Hydroxy-2-methyl-4-methylene-1-oxononyl]-4-(1-methylethyl)-2-oxazolidinone (LMT-28) or curcumin. 
     
     
         14 . The method of  claim 10 , wherein the IL-6 inhibitor is an anti-IL-6 antibody or an IL-6 binding fragment of an anti-IL-6 antibody. 
     
     
         15 . The method of  claim 14 , wherein the anti-IL-6 antibody is a polyclonal or a monoclonal antibody. 
     
     
         16 . The method of  claim 15 , wherein the monoclonal antibody is a chimeric or humanized antibody. 
     
     
         17 . The method of  claim 14 , wherein the anti-IL-6 antibody or the IL-6 binding fragment thereof is Siltuximab, Olokizumab, ALD518 (BMS-945429), C326, Sirukumab, Elsilimomab or Clazakizumab. 
     
     
         18 . The method of  claim 10 , wherein the IL-6R inhibitor is an anti-IL-6R antibody or an IL-6R binding fragment of an anti-IL-6R antibody. 
     
     
         19 . The method of  claim 18 , wherein the anti-IL-6R antibody is a polyclonal or a monoclonal antibody. 
     
     
         20 . The method of  claim 19 , wherein the monoclonal antibody is a chimeric or humanized antibody. 
     
     
         21 . The method of  claim 20 , wherein the anti-IL-6R antibody or the IL-6R binding fragment thereof is tocilizumab, sarilumab, REGN88 (SAR153191) or ALX-0061. 
     
     
         22 . The method of  claim 10 , wherein the IL-6R inhibitor is a fusion protein of IL-6R with an Fc fragment of IgG or a soluble gp130-Fc fusion protein.