Abstract: The present invention provides methods of treating cancer using inhibitors of protein kinases. The inhibitors of protein kinases are combined with agents that inhibit a cellular ATP synthetic pathway. Inhibitors of ATP synthesis include inhibitors of de novo purine biosynthesis, inhibitors of the salvage pathway of ATP biosynthesis, and inhibitors of the enzyme inosine monophosphate dehydrogenase.

Abstract: The invention provides a method for diagnosis of, and determining a prognosis for, cancer causatively associated with derangements of chromosome 9p21. Underlying the invention is the discovery that such derangements have their genesis in deletions occurring centromeric to STS 3.21, most often including breakpoints in exon 8 and/or between exons 4 and 5 of the gene which codes for methylthioadenosine phosphorylase. As the cancer and tumor development advance, deletions in 9p21 progress centromerically from the genesis point toward the gene encoding p16. Thus, the method of the invention is performed by determining whether (a) portions of the 9p21 region including and telomeric to STS 3.21 are deleted; and (b) portions of the 9p21 region centromeric to STS 3.

Abstract: The invention provides a method for diagnosis of, and determining a prognosis for, cancer causatively associated with derangements of chromosome 9p21. Underlying the invention is the discovery that such derangements have their genesis in deletions occurring centromeric to STS 3.21, most often including breakpoints in exon 8 and/or between exons 4 and 5 of the gene which codes for methylthioadenosine phosphorylase. As the cancer and tumor development advance, deletions in 9p21 progress centromerically from the genesis point toward the gene encoding p16. Thus, the method of the invention is performed by determining whether (a) portions of the 9p21 region including and telomeric to STS 3.21 are deleted; and (b) portions of the 9p21 region centromeric to STS 3.

Abstract: An in vivo method for depleting mammalian cells of adenosine 5′-monophosphate (AMP) useful in the treatment of certain cancers is provided. According to the method, a population of cells is obtained from a host and assayed for loss of methylthioadenosine phosphorylase (MTAse) activity. MTAse catabolizes methylthioadenosine to adenine for endogenous salvage incorporation into the intracellular AMP pool. The preferred method for assaying loss of MTAse activity is a hybridization technique for detection of a homozygous loss of the gene which encodes MTAse. Hosts having MTAse deficient tumors are treated with a therapeutically effective amount of an agent which inhibits the activity of adenylsuccinate synthetase, which converts inosine 5-monophosphate to AMP, thus depleting the tumor cells of substrates for de novo AMP production. L-alanosine is the preferred ASS inhibitory agent for use in the method of the invention.

Abstract: Methods for treating and preventing the onset and maintainance of multiple drug resistance (MDR) in animals undergoing chemotherapy for cancer are provided. According to the methods, target cells are depleted of adenosine 5′-monophosphate (AMP) and adenosine 5′-triphosphate (ATP) such that the cells are unable to support P-glycoprotein activity. According to one method, a population of target cells is obtained from a host and assayed for loss of methylthioadenosine phosphorylase (MTAse) activity. MTAse catabolizes methylthioadenosine to adenine for endogenous salvage incorporation into the intracellular AMP pool. MTAse deficient cells are treated with a purine synthesis inhibitor, such as L-alanosine, which starves the cells of adenine and suppresses P-glycoprotein activity. MTAse competent cells are also treated for MDR with purine synthesis inhibitors.

Abstract: An in vivo method for depleting mammalian cells of adenosine 5'-monophosphate (AMP) useful in the treatment of certain cancers is provided. According to the method, a population of cells is obtained from a host and assayed for loss of methylthioadenosine phosphorylase (MTAse) activity. MTAse catabolizes methylthioadenosine to adenine for endogenous salvage incorporation into the intracellular AMP pool. The preferred method for assaying loss of MTAse activity is a hybridization technique for detection of a homozygous loss of the gene which encodes MTAse. Hosts having MTAse deficient tumors are treated with a therapeutically effective amount of an agent which inhibits the activity of adenylsuccinate synthetase, which converts inosine 5'-monophosphate to AMP, thus depleting the tumor cells of substrates for de novo AMP production. L-alanosine is the preferred ASS inhibitory agent for use in the method of the invention.

Abstract: Novel adenine derivatives whose structures are represented by Formula I, are disclosed, as are methods of using those compounds and others of Formula II to treat monocyte-mediated disorders such as rheumatoid arthritis and multiple sclerosis.

Abstract: Novel adenine derivatives whose structures are represented by Formula I, are disclosed, as are methods of using those compounds and others of Formula II to treat monocyte-mediated disorders such as rheumatoid arthritis and multiple sclerosis.

Abstract: Novel adenine derivatives whose structures are represented by Formula I, are disclosed, as are methods of using those compounds and others of Formula II to treat monocyte-mediated disorders such as rheumatoid arthritis and multiple sclerosis.

Abstract: Novel adenine derivatives whose structures are represented by Formula I, are disclosed, as are methods of using those compounds and others of Formula II to treat monocyte-mediated disorders and autoimmune diseases.