The DNA methylation inhibitor 5-azacytidine modulates 6-thioguanine toxicity in mammalian cells.
In order to assess the effects of combining two antimetabolites used separately to treat human leukemias, we carried out an experimental study by exposing V79 Chinese hamster cells, a 6-thioguanine (6-tG)-sensitive cell line, to sequential and concurrent treatments with 5-azacytidine (5-azaC) and 6-tG. In this paper, we demonstrate that there is a clear dependency for the way in which this combination was tested. Pre-treatment with 5-azaC made V79 cells more resistant to 6-tG by a substantial reduction in 6-tG incorporation into DNA; this effect could still be detected for several cell divisions after the removal of 5-azaC, and was achieved neither by reduced cell growth nor by the induction of hypoxanthine-guanine-phosphoribosyltransferase (HGPRT-) mutants. The reverse order of treatment produced a higher toxic effect than exposure to each prodrug alone.
Sciandrello
Giulia
G
Dipartimento di Biologia Cellulare e dello Sviluppo A. Monroy, Università di Palermo, Viale delle Scienze Parco d'Orleans, Palermo 90128, Italy. giscian@mbox.unipa.it
Caradonna
Fabio
F
Barbata
Giusi
G
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001374:Azacitidine / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D004357:Drug Synergism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013866:Thioguanine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D004247:DNA; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine; D001374:Azacitidine