Inhibition of RNA polymerase as a possible anti-leukaemic action of cytosine arabinoside

• Published in: Nature (London) 1976-04, Vol.260 (5551), p.549-550
• Main Authors: CHUANG, RONALD Y, CHUANG, LINDA F
• Format: Article
• Language: English
• Subjects: Arabinofuranosyluracil - pharmacology; Cell-Free System; Cells, Cultured; Cytarabine - pharmacology; DNA-Directed RNA Polymerases - antagonists & inhibitors; Humanities and Social Sciences; Kinetics; letter; Leukemia - enzymology; multidisciplinary; Science; Science (multidisciplinary); Structure-Activity Relationship
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/260549a0

CYTOSINE arabinoside (ara-C, 1-β- D -arabinosylcytosine) has marked anti-tumour and anti-viral activities 1,2 , and is currently one of the most successful drugs used to induce remissions in acute granulocytic leukaemia 3 . Its cytotoxic activity is ascribed to its effect of inhibiting DNA polymerase after being phos-phorylated intracellularly to its triphosphate derivative (ara-CTP) 4 . Studies with murine leukaemic cells 5 and mouse L cell line have indicated 6 , however, that acute cell death induced by ara-C does not completely correlate with the inhibition of DNA synthesis: (1) DNA polymerase activity was rapidly restored after ara-C was removed, whereas cells were still non-viable; (2) the amount of ara-C incorporation into DNA did not correlate with the degree of cell lethality. We have shown previously 7 that ara-CTP could inhibit RNA polymerase II activity from chicken leukaemic cells when the enzyme was purified. This report describes results of our kinetic studies characterising the nature of this inhibition.