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Uptake and Metabolism of the New Anticancer Compound ß-L-(-)-Dioxolane-Cytidine in Human Prostate Carcinoma DU-145 Cells¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066

ß-L-(-)-dioxolane cytidine [(-)-OddC] is the first nucleoside analogue with the unnatural L configuration shown to have anticancer activity. The transport and metabolism of this unique compound were studied in human prostate carcinoma DU-145 cells. (-)-OddC was translocated rapidly into the cells by both equilibrative-sensitive and -insensitive nucleoside transport systems. Accumulation of (-)-OddCMP, (-)-OddCDP, and (-)-OddCTP occurred in a time- and concentration-dependent manner, with (-)-OddCDP being the major metabolite. Elimination of (-)-OddCTP was biphasic, with an initial t of 3.5 h and a second phase t of >20 h. The incorporation of (-)-OddCTP into DNA was concentration dependent, and toxicity was directly correlated with the amount of (-)-OddCMP present in the DNA. Treatment with (-)-OddC led to the degradation of DNA into large fragments at high concentrations, but internucleosomal laddering was not observed. The rapid membrane permeation of (-)-OddC and prolonged retention of its metabolites may contribute to the potent activity of this compound against DU-145 xenografts.

¹ This work was supported by United States Public Health Service Grant and CA44358 and CA63477.

² To whom requests for reprints should be addressed, at Department of Pharmacology, Yale University, Sterling Hall of Medicine, 333 Cedar Street, New Haven, CT 06520-8066.

Received 4/16/96. Accepted 7/17/96.

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