The MTAP gene, at chromosomal locus 9p21, is frequently co-deleted with p16, especially in T-cell acute lymphocytic leukemias, mesotheliomas, gliomas, lung and pancreatic carcinomas, and sarcomas. In normal cells, MTAP cleaves MTA to adenine and 5-methylthioribose-1-phosphate, which are converted to adenine nucleotides and methionine. We previously showed that mice are protected from 6TG toxicity by preadministration of MTA, generating adenine and blocking conversion of 6TG to its nucleotide. (Lubin M, Lubin A. 2009: Proceedings of the American Association for Cancer Research. Abstract LB-29; Selective Killing of Tumors Deficient in Methylthioadenosine Phosphorylase: A Novel Strategy: PLoS One, ePub May 29, 2009). We now demonstrate that MTA completely protects mice bearing MTAP-negative CEM-CCRF human T-cell leukemia from 6TG toxicity while the tumor remains responsive. Following two small pilot studies, 24 NOD-SCID mice were inoculated subcutaneously with 5 million CEM cells; when tumor size reached 500 cubic mm, mice were randomized to 4 groups of 6 animals. All mice treated with vehicle or MTA alone were sacrificed on day 14 because of tumor size; MTA showed no toxicity. Animals treated with 6TG (75 mg/kg), on days 1, 4, 7, had marked tumor regression but died of toxicity by day 12. However, animals treated with MTA (100 mg/kg) followed one hour later by 6TG (75 mg/kg) had complete tumor regression by day 14, and no weight loss; but tumor recurred in all animals by day 24. While further optimization of dose and schedule is needed, these studies clearly show that marked tumor regression can be obtained without toxicity in tumors lacking MTAP, by competitively inhibiting 6TG conversion to nucleotides. As MTA has been given safely to humans, we are planning clinical trials using this strategy in patients with tumors lacking MTAP.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5393.