Effect of thymidine on the toxicity, antitumor activity, and metabolism of 1-beta-D-arabinofuranosylcytosine in rats bearing a chemically induced colon carcinoma.

Abstract

Abstract The effect of thymidine (dThd) on the toxicity, antitumor activity against colon carcinoma, and metabolism of 1-β-d-arabinofuranosylcytosine (ara-C) in female Fischer rats was evaluated utilizing continuous i.v. infusion of these agents into the tail vein of unrestrained rats. Treatment of normal rats with a 24-hr infusion of dThd (7.0 g/kg/day) followed by coadministration of dThd with ara-C for 48 hr resulted in a 35-fold augmentation of the toxicity of ara-C. In rats bearing s.c. implanted colon carcinoma, a slightly superior inhibition of tumor growth occurred when ara-C was administered at the maximally tolerated dose following a 24-hr infusion with dThd than when ara-C was given with no prior dThd. However, no significant increase in life span over control was observed using ara-C alone or in combination with dThd, with or without dThd pretreatment. Analysis of rat plasma by high-pressure liquid chromatography revealed that treatment with dThd by continuous infusion and not by i.v. bolus injection produced a dramatic reduction in the circulating level of deoxycytidine from 21.8 ± 4.6 (S.D.) to 4.4 ± 0.6 µm within 24 hr following the initiation of infusion. The in vivo metabolism of ara-C following i.v. bolus administration of [5- 3 H]ara-C to 0.9% NaCl solution- or dThd-infused rats was also studied. High-pressure liquid chromatography analysis of the acid-soluble fractions of tumor and of various host tissues from these rats showed that the intracellular levels of 1-β-d-arabinofuranosylcytosine 5′-triphosphate were greater in the rats infused with dThd than were those in 0.9% NaCl solution controls and varied from 7- to 1830-fold over controls in the order of bone marrow > tumor > intestines > spleen > liver. The increase in ara-C incorporation into nucleic acid fractions was also in the same direction and was greater when dThd treatment preceded ara-C. These data suggest that modulation of the plasma levels of deoxycytidine by dThd as well as the enhanced intracellular activation of ara-C to 1-β-d-arabinofuranosylcytosine 5′-triphosphate following infusion of dThd may account in part for enhanced tumor and host sensitivities to ara-C.