Synergistic effect of methotrexate and 1-beta-D-arabinofuranosylcytosine on the generation of DNA strand breaks in a human promyelocytic leukemia cell line.
We investigated the accumulation of DNA strand breaks in a human promyelocytic leukemia cell line, HL-60, treated with methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (Ara-C). The sequential treatment with MTX then Ara-C had a synergistic effect on the formation of DNA strand breaks, which was dependent on MTX and Ara-C concentrations. On the other hand, when Ara-C preceded MTX, no such synergism was observed. The addition of both thymidine and hypoxanthine to this system, but not thymidine or hypoxanthine alone, abolished the synergism. Pretreatment with MTX augmented the generation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. However, this augmentation did not necessarily correlate with the amount of strand breaks. Whatever the underlying mechanism of this synergism is, our present data provide one possible biochemical basis for sequential MTX and Ara-C therapy.
Tanizawa
A
A
Department of Pediatrics, Kyoto University, Japan.
Kubota
M
M
Takimoto
T
T
Kito
T
T
Akiyama
Y
Y
Kiriyama
Y
Y
Mikawa
H
H
D016590:Aphidicolin; D002460:Cell Line; D003561:Cytarabine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D004249:DNA Damage; D004224:Diterpenes; D004338:Drug Combinations; D004357:Drug Synergism; D006801:Humans; D019271:Hypoxanthine; D007042:Hypoxanthines; D002955:Leucovorin; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000473:pathology; D008727:Methotrexate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010766:Phosphorylation; D013936:Thymidine
D004224:Diterpenes; D004338:Drug Combinations; D007042:Hypoxanthines; D003561:Cytarabine; D019271:Hypoxanthine; D016590:Aphidicolin; D002955:Leucovorin; D013936:Thymidine; D008727:Methotrexate