A novel in vitro model system for studying the action of ara-C.
The antimetabolite 1-beta-D-arabinofuranosyl-cytosine (ara-C) has proven to be one of the most effective agents available for the treatment of acute leukemia. While ara-C has been implicated as a potent inhibitor of mammalian cell DNA replication, the specific mechanism by which ara-C kills cells is not known. In this report we describe the development of an in vitro model system to study the molecular mechanism of ara-CMP incorporation into DNA. This model system makes use of a recently described human cell multiprotein DNA replication complex (MRC) that is competent to replicate DNA in vitro. The MRC can successfully incorporate ara-CMP into replicating DNA at internucleotide positions. These results are similar to those described for studies using intact cells. This MRC-driven in vitro replication system may therefore serve as a powerful model for the study of anticancer agents that directly affect human cell DNA synthesis.
Wills
P
P
University of Maryland School of Medicine, Department of Pharmacology and Experimental Therapeutics, Baltimore, MD 21201, USA.
Hickey
R
R
Ross
D
D
Cuddy
D
D
Malkas
L
L
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003561:Cytarabine / Q000378:metabolism / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004279:DNA, Viral / Q000096:biosynthesis; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D013539:Simian virus 40 / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D004279:DNA, Viral; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate