The goal of this project is to develop chemotherapeutic strategies to exploit the finding that there are subsets of human leukemias, malignant gliomas, and non-small cell lung carcinomas that lack activity of the enzyme 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAPase). MTAPase phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA), generated as a byproduct of polyamine biosynthesis, to free adenine and 5- methylthioribose-1-phosphate (MTR-1-P); the former product is salvaged back to adenine nucleotide pools, while MTR-1-P is converted to methionine and formate. MTAPase deficiency in malignant cells most likely occurs as a result of deletions within the p21-22 region of chromosome 9; importantly, the normal cellular counterparts of these tumor cells and all known normal tissues contain MTAPase. This proposal will explore several chemotherapeutic approaches that may be selectively cytotoxic to MTAPase-deficient malignant cells: 1) MTAPase-deficient cells, unable to salvage adenine from MTA, may have a higher dependency on purine de novo synthesis, and may be more susceptible to agents that inhibit this pathway, e.g. methotrexate, 20 certain MTA analogs e.g. 5'- deoxy-5'-S-isobutyladenosine, act as irreversible inhibitors of the key enzyme S-adenosylhomocysteine hydrolase (SAH hydrolase), and also serve as substrates for MTAPase. MTAPase-containing normal cells would cleave these MTA analogs, preventing them from inactivating SAH hydrolase; MTAPase-deficient cells would not be able to protect SAH hydrolase, whose inhibition may lead to decreased transmethylations and a trapping of folates as 5-methyltetrahydrofolate. Combinations of methotrexate and these MTA analog/SAH inactivators may be selectively cytotoxic to MTAPase-deficient malignancies. 3) N2O inactivation of vitamin B12 leads to a loss of methionine synthetase activity and a depletion of folate pools, e.g. formyltetrahydrofolates. MTA is, via MTR-1-P, a source of methionine and formate in MTAPase-containing cells, and is known to reverse some of the metabolic perturbations of N2O-induced B12 deficiency; MTAPase-deficient cells, however, would not be rescued by MTA. In addition, MTAPase deficiency may be closely linked to the deletion of genes encoding interferon-alpha (IFNA) and -beta1 (IFNB1); thus MTAPase deficiency may be a marker for IFN deficiency, and vice versa. Techniques to improve the detection of both IFN deficiency and MTAPase deficiency will be developed. IFN deficiency may be responsive to either treatment with one or more IFN, or gene replacement with one of the IFNA genes, or IFNB1.
| Chen, Z H; Olopade, O I; Savarese, T M (1997) Expression of methylthioadenosine phosphorylase cDNA in p16-, MTAP- malignant cells: restoration of methylthioadenosine phosphorylase-dependent salvage pathways and alterations of sensitivity to inhibitors of purine de novo synthesis. Mol Pharmacol 52:903-11 |
| Zhang, H; Chen, Z H; Savarese, T M (1996) Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-alpha1, interferon-beta1, and other 9p21 markers in human malignant cell lines. Cancer Genet Cytogenet 86:22-8 |
| Chen, Z H; Zhang, H; Savarese, T M (1996) Gene deletion chemoselectivity: codeletion of the genes for p16(INK4), methylthioadenosine phosphorylase, and the alpha- and beta-interferons in human pancreatic cell carcinoma lines and its implications for chemotherapy. Cancer Res 56:1083-90 |
