Reduction in cis-diamminedichloroplatinum(II)-induced cytotoxicity, sister chromatid exchange, and DNA interstrand cross-links in 9L cells treated with the polyamine biosynthesis inhibitor (2R,5R)-6-heptyne-2,5-diamine.
The effects of depletion of intracellular levels of the polyamines putrescine and spermidine on cis-diamminedichloroplatinum(II)-induced cytotoxicity, sister chromatid exchanges, DNA interstrand cross-linking, and intracellular glutathione levels were studied in 9L rat brain tumor cells pretreated with the ornithine decarboxylase inhibitor (2R,5R)-6-heptyne-2,5-diamine (R,R-MAP). Pretreatment of 9L cells with R,R-MAP for 48 h decreased cis-diamminedichloroplatinum(II) cytotoxicity with an average dose reduction ratio of 0.55 at both the 5 and 10% survival levels; addition of putrescine partially prevented this effect. The number of sister chromatid exchanges and DNA interstrand cross-links was also reduced (31 and 38%, respectively). Within 24 h of treatment with R,R-MAP, intracellular glutathione levels began to increase relative to untreated control cells and were significantly elevated in R,R-MAP-treated cells 48-72 h after addition of drug. We discuss several mechanisms by which polyamine depletion could reduce cis-diamminedichloroplatinum(II) toxicity.
Milam
K M
KM
Department of Neurological Surgery, School of Medicine, University of California, San Francisco 94143.
Hunter
K J
KJ
Deen
D F
DF
Marton
L J
LJ
D000480:Alkynes; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects*; D002945:Cisplatin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D003432:Cross-Linking Reagents; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D003959:Diamines / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D011073:Polyamines / Q000037:antagonists & inhibitors*; D051381:Rats; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D000480:Alkynes; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D003959:Diamines; D011073:Polyamines; C039613:6-heptyne-2,5-diamine; D005978:Glutathione; D002945:Cisplatin