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Potential for Selective Enhancement of the in Vivo Metabolism of 1-ß-D-Arabinofuranosylcytosine in Rats by Thymidine Pretreatment¹

Department of Experimental Therapeutics, Roswell Park Memorial Institute, Buffalo, New York 14263

In this study, the ability of deoxythymidine (dThd) to enhance selectively the metabolism of 1-ß-D-arabinofuranosylcytosine (ara-C) in rats bearing transplantable colon carcinoma was investigated. A steady-state plasma level of 375 µM dThd was achieved within 3 h after initiation of a 24-h infusion of dThd (7 g/kg/day) with a concomitant 80% reduction in circulating 2'-deoxycytidine levels. Complete recovery to control values occurred within 6 to 8 h after termination of the infusion. Under the conditions of dThd infusion, the intracellular levels of 2'-deoxycytidine 5'-triphosphate rose from 0.15 to 60 pmol/mg tumor tissue, from 2.5 to 15 pmol/mg intestinal tissue, and from 0.07 to 0.25 pmol/10⁶ bone marrow cells. During the steady-state plasma concentration of dThd, the intracellular concentration of 2'-deoxycytidine 5'-triphosphate in tumor tissue was reduced by 50% at 6 h after the initiation of dThd treatment with a complete recovery 9 h thereafter.

Differences in the apacity of tumor and host normal tissues to recover from the effects of dThd pretreatment were evaluated by measuring decreasing 1-ß-D-arabinofuranosylcytosine 5'-triphosphate formation with time following dThd infusion. The ability to accumulate 1-ß-D-arabinofuranosylcytosine 5'-triphosphate was reduced by 60 to 80% in normal tissues by 3 h after cessation of the dThd infusion but was decreased by only 15% in the tumor. These results suggested that delaying ara-C administration following dThd might result in less host toxicity while maintaining the antitumor effect. Sequential infusion of dThd (7 g/kg/day) for 24 h followed 3 h later by a 48-h infusion of ara-C (175 mg/kg/day), was as effective in reducing tumor mass as was dThd infusion immediately prior to ara-C and resulted in reduced host toxicity (less weight loss). The best schedule for the dThd-ara-C combination was two courses of alternating 24-h sequential infusions of dThd and ara-C with a 3-h delay in ara-C administration following dThd.

These data show that under the conditions used, reductions in intracellular 2'-deoxythymidine 5'-triphosphate pools by dThd in vivo do not appear to correlate with the antitumor activity of the dThd-ara-C combination. Intracellular 1-ß-D-arabinofurano-sylcytosine 5'-triphosphate accumulation, however, was prolonged in rat colon tumor compared to normal tissues, and selectivity of the dThd-ara-C combination in favor of the tumor could be achieved by schedule modification.

¹ Supported in part by USPHS Grant CA-18240 from the National Cancer Institute, Department of Health, Education, and Welfare.

² Present address: Department of Chemotherapy Research, Box 52, the University of Texas System Cancer Center, M. D. Anderson Hospital and Tumor Institute, 6723 Bertner Ave., Houston, TX 77030. This work was a portion of the dissertation submitted to the State University of New York at Buffalo in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

³ To whom requests for reprints should be addressed.

Received 9/11/84. Revised 1/ 7/85. Accepted 2/ 1/85.