Therapy of tumors and infectious agents deficient in methylthioadenosine phosphorylase

Abstract

Methods for treating diseases in humans and vertebrate animals are provided using competitive antagonists of cellular metabolites combined with a protective agent for protecting host cells from toxic effects of the drugs. Also provided are kits comprising competitive antagonists and suitable protective agents. In addition, screening methods for identifying competitive antagonists, protective agents and potentiating agents, for use according to the methods of the invention, are provided.

What is claimed is: 
     
         1 . A method for treating a subject having a disease comprising: (a) administering to the subject a competitive antagonist of a cell metabolite in an amount effective to treat the disease; and (b) administering to the subject a protective agent in an amount effective to increase the level of the cell metabolite in a population of host cells of the subject, thereby reducing the toxicity of the competitive antagonist to the subject. 
     
     
         2 . The method of  claim 1  wherein step (b) is initiated prior to step (a). 
     
     
         3 . The method of  claim 1  wherein step (a) and step (b) are carried out at least in part concurrently. 
     
     
         4 . The method of  claim 1  wherein the competitive antagonist is a structural analog of the cell metabolite. 
     
     
         5 . The method of  claim 1  wherein the cell metabolite is a product of the MTAP-pathway. 
     
     
         6 . The method of  claim 5  wherein the protective agent is a MTAP substrate. 
     
     
         7 . The method of  claim 6  wherein the protective agent is a MTA compound. 
     
     
         8 . The method of  claim 7  wherein the MTA compound is selected from the group consisting of 5′-deoxyadenosine, 2′,5′-dideoxyadenosine, 2′-deoxy-5′-deoxy-5′-methylthioadenosine, 5′-deoxy-5′-chloroadenosine, 5′-deoxy-5′-fluoroadenosine, 5′-deoxy-5′-methyloxyadenosine, 5′-deoxy-5′-methylselenoadenosine, 5′-deoxy-5′-ethylthioadenosine, 9-β-D-erythrofuranosyladenine, 5′-deoxy-5′-methylthio-2-methyladenosine, and 5′-deoxy-5′-methylthio-1-deazaadenosine. 
     
     
         9 . The method of  claim 5  wherein the protective agent is a methionine salvage pathway substrate. 
     
     
         10 . The method of  claim 5  wherein the competitive antagonist is an analog of adenine. 
     
     
         11 . The method of  claim 10  wherein the analog of adenine is selected from the group consisting of 2,6-diaminopurine, 6-methylpurine, 2-fluoroadenine, 8-azaadenine, 2-azaadenine, 4-aminopyrazolo[3,4-d]pyrimidine, 8-aza-2,6-diaminopurine, 1-methyladenine, 7-deaza-8-azaadenine, 6-methylaminopurine, 6-N-hydroxylaminopurine, 6-hydrazinopurine, 7-methyladenine, 8-methyladenine, 8-hydroxyadenine, and the 2-methyl-, 2-chloro-, 2-iodo-, 2-hydroxy, 2-methylthio, and 2-mercapto-derivatives of adenine. 
     
     
         12 . The method of  claim 5  wherein the competitive antagonist is an analog of methionine. 
     
     
         13 . The method of  claim 12  wherein the analog of methionine is selected from the group consisting of ethionine, selenomethionine, methoxinine, selenoethionine, α-methylmethionine, and trifluoromethionine. 
     
     
         14 . The method of  claim 5  wherein the cell metabolite is adenine and the competitive antagonist of adenine is a substrate for a phosphoribosyltransferase which utilizes 5-phosphoribosyl-1-pyrophosphate (PRPP) as the phosphoribosyl donor. 
     
     
         15 . The method of  claim 14  wherein the phosphoribosyltransferase is selected from the group consisting of APRT, HGPRT, OPRT, QPRT, NAPRT, NAMPRT. 
     
     
         16 . The method of  claim 1  wherein the subject has cancer. 
     
     
         17 . The method of  claim 1  wherein the subject has an infectious disease. 
     
     
         18 . The method of  claim 1  wherein the subject has a target cell and wherein the target cell is MTAP negative. 
     
     
         19 . The method of  claim 1  wherein the subject has a target cell and wherein the target cell is MTAP positive. 
     
     
         20 . The method of  claim 19  wherein the subject is treated with a target cell inhibitory agent. 
     
     
         21 . A method for the selective protection of a host cell exposed to a competitive antagonist of a cell metabolite, comprising contacting the host cell with a protective agent in an amount effective to increase the level of the cell metabolite in the host cell thereby reducing the toxicity of the competitive antagonist to the host cell. 
     
     
         22 . The method of  claim 21  wherein a subject having the host cell is treated with the competitive antagonist to inhibit a target cell. 
     
     
         23 . The method of  claim 22  wherein the cell metabolite is a product of the MTAP-pathway. 
     
     
         24 . The method of  claim 23  wherein the protective agent is a MTAP substrate. 
     
     
         25 . The method of  claim 24  wherein the protective agent is a MTA compound. 
     
     
         26 . The method of  claim 25  wherein the MTA compound is selected from the group consisting of 5′-deoxyadenosine, 2′,5′-dideoxyadenosine, 2′-deoxy-5′-deoxy-5′-methylthioadenosine, 5′-deoxy-5′-chloroadenosine, 5′-deoxy-5′-fluoroadenosine, 5′-deoxy-5′-methyloxyadenosine, 5′-deoxy-5′-methylselenoadenosine, 5′-deoxy-5′-ethylthioadenosine, 9-β-D-erythrofuranosyladenine, 5′-deoxy-5′-methylthio-2-methyladenosine, and 5′-deoxy-5′-methylthio-1-deazaadenosine. 
     
     
         27 . The method of  claim 23  wherein the protective agent is a methionine salvage pathway substrate. 
     
     
         28 . The method of  claim 23  wherein the competitive antagonist is an analog of adenine. 
     
     
         29 . The method of  claim 28  wherein the analog of adenine is selected from the group consisting of 2,6-diaminopurine, 6-methylpurine, 2-fluoroadenine, 8-azaadenine, 2-azaadenine, 4-aminopyrazolo[3,4-d]pyrimidine, 8-aza-2,6-diaminopurine, 1-methyladenine, 7-deaza-8-azaadenine, 6-methylaminopurine, 6-N-hydroxylaminopurine, 6-hydrazinopurine, 7-methyladenine, 8-methyladenine, 8-hydroxyadenine, and the 2-methyl-, 2-chloro-, 2-iodo-, 2-hydroxy, 2-methylthio, and 2-mercapto-derivatives of adenine. 
     
     
         30 . The method of  claim 23  wherein the competitive antagonist is an analog of methionine. 
     
     
         31 . The method of  claim 30  wherein the analog of methionine is selected from the group consisting of ethionine, selenomethionine, methoxinine, selenoethionine, α-methylmethionine, and trifluoromethionine. 
     
     
         32 . The method of  claim 30  wherein the analog of methionine is ethionine. 
     
     
         33 . The method of  claim 23  wherein the cell metabolite is adenine and the competitive antagonist of adenine is a substrate for a phosphoribosyltransferase which utilizes 5-phosphoribosyl-1-pyrophosphate (PRPP) as the phosphoribosyl donor. 
     
     
         34 . The method of  claim 33  wherein the phosphoribosyltransferase is selected from the group consisting of APRT, HGPRT, OPRT, QPRT, NAPRT, NAMPRT. 
     
     
         35 . The method of  claim 22  wherein the target cell is a tumor cell. 
     
     
         36 . The method of  claim 22  wherein the target cell is an infectious agent. 
     
     
         37 . A method of treating a subject having a MTAP negative target cell comprising: a) administering to the subject a competitive antagonist of adenine or methionine in an amount sufficient to inhibit the MTAP negative target cell; and b) administering to the subject a protective agent that increases the production of adenine or methionine by the MTAP-pathway in a host cell in the subject, thereby decreasing the toxic mechanism of action on the subject. 
     
     
         38 . The method of  claim 37  wherein the MTAP negative target cell is a tumor cell. 
     
     
         39 . A method of treating a subject having a MTAP positive target cell comprising: a) contacting the MTAP positive target cell with an agent that inhibits the production or activity of MTAP in the target cell; b) administering to the subject a competitive antagonist of adenine or methionine in an amount sufficient to inhibit the MTAP positive target cell; and c) administering to the subject a protective agent that increases the production of adenine or methionine by the MTAP-pathway in a host cell in the subject, thereby decreasing the toxic mechanism of action on the subject. 
     
     
         40 . The method of  claim 39  wherein the MTAP positive target cell is a tumor cell. 
     
     
         41 . A composition, comprising
 a sterile protective agent capable of increasing a level of a cell metabolite in a host cell, formulated in a carrier for delivery to a cancer patient in an effective amount for reducing the toxicity of a competitive antagonist of the cell metabolite in the subject.   
     
     
         42 . A kit comprising
 a container housing a protective agent capable of increasing a level of a cell metabolite in a host cell in a sterile formulation and instructions for administering the protective agent to a subject in an effective amount for reducing the toxicity of a competitive antagonist of a cell metabolite in the subject.   
     
     
         43 . The kit of  claims 42  wherein the container houses a single dose for administration to a human subject. 
     
     
         44 . The kit of  claim 43  wherein the human subject has cancer. 
     
     
         45 . The kit of  claim 44  wherein the cancer is a MTAP negative cancer. 
     
     
         46 . The kit of  claim 42  further comprising a container housing a competitive antagonist of a cell metabolite 
     
     
         47 . The kit of  claim 46  wherein the competitive antagonist is a structural analog of the cell metabolite. 
     
     
         48 . The kit of  claim 42  wherein the cell metabolite is a product of the MTAP-pathway. 
     
     
         49 . The kit of  claim 48  wherein the protective agent is a MTAP substrate. 
     
     
         50 . The kit of  claim 49  wherein the protective agent is a MTA compound. 
     
     
         51 . The kit of  claim 50  wherein the MTA compound is selected from the group consisting of 5′-deoxyadenosine, 2′,5′-dideoxyadenosine, 2′-deoxy-5′-deoxy-5′-methylthioadenosine, 5′-deoxy-5′-chloroadenosine, 5′-deoxy-5′-fluoroadenosine, 5′-deoxy-5′-methyloxyadenosine, 5′-deoxy-5′-methylselenoadenosine, 5′-deoxy-5′-ethylthioadenosine, 9-β-D-erythrofuranosyladenine, 5′-deoxy-5′-methylthio-2-methyladenosine, and 5′-deoxy-5′-methylthio-1-deazaadenosine. 
     
     
         52 . The kit of  claim 48  wherein the protective agent is a methionine salvage pathway substrate. 
     
     
         53 . The kit of  claim 48  wherein the competitive antagonist is an analog of adenine. 
     
     
         54 . The kit of  claim 53  wherein the analog of adenine is selected from the group consisting of 2,6-diaminopurine, 6-methylpurine, 2-fluoroadenine, 8-azaadenine, 2-azaadenine, 4-aminopyrazolo[3,4-d]pyrimidine, 8-aza-2,6-diaminopurine, 1-methyladenine, 7-deaza-8-azaadenine, 6-methylaminopurine, 6-N-hydroxylaminopurine, 6-hydrazinopurine, 7-methyladenine, 8-methyladenine, 8-hydroxyadenine, and the 2-methyl-, 2-chloro-, 2-iodo-, 2-hydroxy, 2-methylthio, and 2-mercapto-derivatives of adenine. 
     
     
         55 . The kit of  claim 48  wherein the competitive antagonist is an analog of methionine. 
     
     
         56 . The kit of  claim 55  wherein the analog of methionine is selected from the group consisting of ethionine, selenomethionine, methoxinine, selenoethionine, α-methylmethionine, and trifluoromethionine. 
     
     
         57 . The kit of  claim 48  wherein the cell metabolite is adenine and the competitive antagonist of adenine is a substrate for a phosphoribosyltransferase which utilizes 5-phosphoribosyl-1-pyrophosphate (PRPP) as the phosphoribosyl donor. 
     
     
         58 . The kit of  claim 57  wherein the phosphoribosyltransferase is selected from the group consisting of APRT, HGPRT, OPRT, QPRT, NAPRT, NAMPRT. 
     
     
         59 . The kit of  claim 42  wherein the subject has cancer. 
     
     
         60 . The kit of  claim 42  wherein the subject has an infectious disease.