CELLULAR SELECTIVITY OF ANTIMETABOLITIES

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The objective is to develop more selective treatments for neoplastic diseases based on the identification of factors which are predictive for the tumor cells' sensitivity and resistance to antimetabolites. Initial studies will focus on the identification of cellular determinants of response to 1-Beta-D-arabinofuranosylcytosine (araC), and on understanding the role metabolic modulators such as dL-leucovorin (dL-CF) play in selectively alterating the therapeutic efficacy of 5-fluorouracil (FUra) and 5-fluorodeoxyuridine (FdUrd). The role of cisplatin in enhanceing the therapeutic efficacy of fluoropyrimidines + dL-CF and araC will also be evaluated. For studies involving araC, mouse leukemia L1210 transplanted intraperitoneally and subcutaneously, mouse colon carcinoma no. 26 transplanted s.c. and the lymphoid tumor P-388 transplanted i.p. will be used, based on their differential sensitivity to araC. Determinations with fluoropyrimidines will be carried out in cells with differential sensitivity and with different intracellular concentrations of thymidylate synthase and folate cofactor pools. These cell lines include leukemia L1210, P-1798 lymphosarcoma, rat colon adenocarcinoma (both with high pre-existing pools), human colon carcinoma no. 205 and B-16 melanoma containing relatively lower folate pools. Specific studies with araC include: 1) the simultaneous quantitation of araCTP pools and retention and incorporation of araC into DNA of tumors and of bone marrow and intestinal mucosa; 2) assessment of the in vivo effects of cis-DDP on araC determinants of response. These studies will compare prolonged continuous infusions of low doses vs short infusions of high doses. Studies with fluoropyrimidine will focus on the identification of optimal conditions for their potentiation by folates. The existence of a possible relationship between a defined plasma concentration of folates, intracellular folate pools and inhibition and recovery of dTMP-synthase in normal and tumor cells will be examined. The studies should provide fundamental information concerning the biochemical and pharmacological basis of drug action in vivo and the results obtained should allow the design of improved clinical protocols and the verification of response in patients with cancer.