Uptake and metabolism of the new anticancer compound beta-L-(-)-dioxolane-cytidine in human prostate carcinoma DU-145 cells.
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.
Grove
K L
KL
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Cheng
Y C
YC
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism*; D001692:Biological Transport; D002460:Cell Line; D003561:Cytarabine / Q000378:metabolism; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D004273:DNA, Neoplasm / Q000378:metabolism*; D004148:Dioxolanes / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D014316:Tritium; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004148:Dioxolanes; D003561:Cytarabine; D014316:Tritium; C074908:troxacitabine; D003596:Cytosine