The Antitumor Mechanism of 1‐(2‐Deoxy‐2‐fluoro‐4‐thio‐β‐D‐arabinofuranosyl)‐cytosine: Effects of Its Triphosphate on Mammalian DNA Polymerases

• Published in: Cancer science Vol. 92; no. 5; pp. 562 - 567
• Main Authors: Miura, Shinji, Yoshimura, Yuichi, Satoh, Hiroshi, Izuta, Shunji
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2001; Japanese Cancer Association; John Wiley & Sons, Inc
• Subjects: 4′‐Thio‐FAC; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor mechanism; Biological and medical sciences; Carcinoma, Squamous Cell - pathology; Cell Death - drug effects; Cell Division - drug effects; Cytarabine - analogs & derivatives; Cytarabine - pharmacology; Cytosine; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA polymerase; DNA Polymerase I - antagonists & inhibitors; DNA-directed DNA polymerase; Drug Interactions; Drug Synergism; Enzyme Inhibitors - pharmacology; Gemcitabine; General aspects; Kinetics; Medical sciences; Mitochondria toxicity; Mouth Neoplasms - pathology; Nucleic Acid Synthesis Inhibitors; Nucleoside analogs; Pharmacology. Drug treatments; Reductase; Ribonucleic acid; RNA; Transcription; Tumor Cells, Cultured; Antineoplastic agent; Gemcitabine; Cytotoxicity; Mitochondria; Cytarabine; Established cell line; Drug interaction; Mechanism of action; Pyrimidine nucleoside; Human; Drug combination; Squamous cell carcinoma; Enzyme; Stomatology; Transferases; Triphosphates; Malignant tumor; In vitro; Oral cavity; Nucleotidyltransferases; Antimetabolic; Analog; KB cell line; Oral cavity disease; Fluorine Organic compounds; DNA-directed DNA polymerase
• ISSN: 0910-5050; 1347-9032; 1349-7006; 1876-4673
• DOI: 10.1111/j.1349-7006.2001.tb01130.x

The mechanism of action of the antitumor nucleoside analog l‐(2‐deoxy‐2‐fluoro‐4‐thio‐β‐D‐arabinofuranosyl)cytosine (4′‐thio‐FAC) was investigated. 4′‐Thio‐FAC inhibited cellular DNA synthesis, but not RNA and protein syntheses. We observed potent inhibitory action of the triphosphate of 4′‐thio‐FAC (4′‐thio‐FACTP) against DNA polymerase α, whereas it showed moderate inhibition of DNA polymerase P and little inhibition of DNA polymerase β. The kinetic analysis showed that the inhibition mode of 4′‐thio‐FACTP towards DNA polymerase a was mixed type, implying a chain‐terminating effect of 4′‐thio‐FACTP. The triphosphate of 2′‐deoxy‐2′,2′‐difluorocytidine (gemcitabine), a known antitumor nucleoside, did not show potent inhibition of these three DNA polymerases. Thus, the effect of the diphosphate of gemcitabine on ribonucleotide reductase was suggested to be more important for the antitumor action of gemcitabine. From these findings, the main target enzymes of 4′‐thio‐FAC and gemcitabine appear to be different. We found a synergistic effect of the two drugs in an in vitro model, which supports the above idea.