The objective of this proposal is two-fold: (1) to understand the biochemical and pharmacological basis for the tissue selectivity of 5-fluorouracil prodrug, 5'-deoxy-fluorouridine (5'- dFUrd) and to evaluate the role of metabolic modulators in the selective modulation of the therapeutic efficacy of this agent in sensitive and relatively resistant tumors. This includes transplantable colon carcinoma in mice (No. 26), ward colon tumor in rats, and human Hep-2 cells in nude mice. Modulators such as Leucovorin (CF) and deoxyinosine (dIno) will be studied, (2) since studies from this laboratory revealed a direct relationship between Ara-C metabolism, Ara-CTP retention, and response, studies in vivo aimed at the selective alteration of these parameters in tumor cells with differ- ential sitivity to Ara-C will be carried out. This includes L1210 and P288 tumors. The use of high dose Ara-C as compared to continuous infusion will be studied to identify determinants of response.
The specific aims are: (1) to correlate in vivo activation and metabolism of 5'-dFUrd with the anti- tumor activity and tissue toxicity to this drug, (2) to determine whether CF and dIno can selectively modify the metabolism and consequently the therapeutic efficacy of 5'-dFUrd. Free FdUMP, inhibition and recovery of dTMP-synthetase; and incorporation of the drug into RNA will be quantitated. The ultimate aim is to understand the biochemical and pharmacological basis for the therapeutic efficacy of 5'-dFurd. (3) to investigate means by which the intracellular retention of Ara-CTP can be selectively manipulated in tumor vs normal tissues. High dose Ara-C schedule will be evaluated and the results will be compared with these obtained when continuous infusion of Ara-C under optimal therapeutic conditions is employed. In P288 cells were the retention of Ara-CTP is is low, high dose Ara-C will be investigated to determine the feasibility of this approach in the alteration of this para- meter and to evaluate the therapeutic consequences of such alterations, and (4) to utilize cell separation methodologies for quantitation of drug met- abolism in different cell subtypes in an attempt to understand heterogeneity of biochemical sensitivity. The results of drug metabolism studies in relevant fractions will be correlated with their growth rate and with the in vivo drug sensitivity.
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