Anticancer activity of β-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L configuration

• Published in: Cancer research (Chicago, Ill.) Vol. 55; no. 14; pp. 3008 - 3011
• Main Authors: GROVE, K. L, XIN GUO, SHWU-HUEY LIU, ZHILING GAO, CHU, C. K, YUNG-CHI CHENG
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.07.1995
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biological and medical sciences; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Cell Division - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - metabolism; Cytarabine - pharmacology; Cytosine - analogs & derivatives; Cytosine - chemistry; Cytosine - pharmacology; Dioxolanes - chemistry; Dioxolanes - pharmacology; Drug Screening Assays, Antitumor; General aspects; Humans; KB Cells; Leukemia P388 - drug therapy; Leukemia P388 - metabolism; Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Male; Medical sciences; Mice; Molecular Structure; Pharmacology. Drug treatments; Phosphorylation; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Stereoisomerism; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Prostate disease; Hepatic disease; Cytotoxicity; Deoxycytidine deaminase; Deoxycytidine kinase; Liver cell carcinoma; Established cell line; Mechanism of action; Male genital diseases; Pyrimidine nucleoside; Tumor cell; Human; Urinary system disease; Enzyme; Transferases; Malignant tumor; Metabolism; In vitro; Dideoxynucleoside; L stereoisomer; Digestive diseases; Hydrolases; Stereospecificity; Prostate
• ISSN: 0008-5472; 1538-7445

Naturally occurring nucleosides and all anticancer nucleoside analogue drugs are in the beta-D configuration. L-(-)-dioxolane-cytidine [(-)-OddC] is the first L-nucleoside analogue ever shown to have anticancer activity. This compound was converted within cells to its mono-, di-, and triphosphate metabolites and was incorporated into DNA. As with cytosine arabinoside, conversion to the monophosphate was catalyzed by cellular deoxycytidine kinase, which was essential for cytotoxicity. However, unlike cytosine arabinoside, (-)-OddC was not susceptible to degradation by deoxycytidine deaminase. Because (-)-OddC inhibited the growth of hepatocellular and prostate tumors that are generally difficult to treat, it is a promising candidate for additional testing. Our results indicate that there is a great deal of variability in the chiral specificities of cellular enzymes and demonstrate how these differences can be exploited in the design of better anti-viral and anticancer drugs.