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

• Published in: Cancer research (Chicago, Ill.) Vol. 56; no. 18; pp. 4187 - 4191
• Main Authors: GROVE, K. L, CHENG, Y.-C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.1996
• Subjects: Antimetabolites, Antineoplastic - metabolism; Antineoplastic agents; Biological and medical sciences; Biological Transport; Cell Line; Chemotherapy; Cytarabine - metabolism; Cytosine - analogs & derivatives; Cytosine - metabolism; Cytosine - pharmacokinetics; Dioxolanes - metabolism; Dioxolanes - pharmacokinetics; DNA, Neoplasm - metabolism; Humans; Kinetics; Male; Medical sciences; Pharmacology. Drug treatments; Prostatic Neoplasms - metabolism; Tritium; Tumor Cells, Cultured; Antineoplastic agent; Human; Intracellular transport; Urinary system disease; Carcinoma; Prostate disease; Cytotoxicity; Malignant tumor; Metabolism; In vitro; Dioxolane derivatives; Membrane transport; Established cell line; L stereoisomer; Intracellular; Mechanism of action; Male genital diseases; Prostate; Pyrimidine nucleoside; Tumor cell; Enantiomer(-)
• ISSN: 0008-5472; 1538-7445

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.