Uptake and metabolism of the new anticancer compound beta-L-(-)-dioxolane-cytidine in human prostate carcinoma DU-145 cells.

Abstract

Beta-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 t1/2 of 3.5 h and a second phase t1/2 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.

• Authors: K L Grove, Y C Cheng
• Journal: Cancer research (Cancer Res) Vol. 56 Issue 18 Pg. 4187-91 (Sep 15 1996) ISSN: 0008-5472 [Print] United States
• PMID: 8797590 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antimetabolites, Antineoplastic
• DNA, Neoplasm
• Dioxolanes
• Cytarabine
• Tritium
• troxacitabine
• Cytosine

Topics

• Antimetabolites, Antineoplastic (metabolism)
• Biological Transport
• Cell Line
• Cytarabine (metabolism)
• Cytosine (analogs & derivatives, metabolism, pharmacokinetics)
• DNA, Neoplasm (metabolism)
• Dioxolanes (metabolism, pharmacokinetics)
• Humans
• Kinetics
• Male
• Prostatic Neoplasms (metabolism)
• Tritium
• Tumor Cells, Cultured