[Effect of pretreatment with N-methyl-N-nitrosourea or streptozotocin on the cytotoxicity and the induction of sister chromatid exchanges in human and rodent brain tumor cells treated with chloroethylnitrosourea].
Effects of pretreatment with N-methyl-N-nitrosourea (MNU) or streptozotocin (STZ) on cytotoxicity and induction of sister chromatid exchanges (SCE) in human and rodent brain tumor cells treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-chloroethyl)-1-nitrosourea (CNU) were investigated. 9L-2 and SF-188 cells were more resistant to the cytotoxic effects of chloroethylnitrosourea than 9L and SF-126 cells. SF-295 cells were more resistant to the cytotoxic effects than SF-126, but more sensitive than SF-188 cells. Pretreatment of 9L-2 cells with MNU or STZ resulted in a dose-dependent increase in cytotoxicity and SCE induction by BCNU. Treatment with 1mM MNU or 1.5mM STZ completely reversed the cellular resistance of 9L-2 cells to BCNU but did not potentiate either cytotoxicity or SCE induction in 9L cells. Pretreatment of SF-188 and SF-295 cells with MNU or STZ resulted in a dose-dependent increase in cytotoxicity and SCE induction by CNU. Treatment with 500 microM MNU or 1.5mM STZ for SF-188 cells, and with 250 microM MNU or 1.5mM STZ for SF-295 cells completely reversed the cellular resistance to CNU. These results are consistent with the hypothesis that pretreatment with MNU or STZ inhibits O6-alkylguanine-DNA-alkyltransferase (O6-AT) and inhibition of the enzyme allows the formation of DNA interstrand cross-links resulting in increase in cytotoxicity and induction of SCE in resistant cells treated with chloroethylnitrosourea. In this regard, O6-AT plays an important role in determining the cytotoxicity and induction of SCE by chloroethylnitrosourea in both rodent and human brain tumor cells.
Tokuda
K
K
Department of Neurosurgery, Hokkaido University School of Medicine, Sapporo, Japan.
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002330:Carmustine / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D004357:Drug Synergism; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D008770:Methylnitrosourea / Q000494:pharmacology*; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D011916:Rats, Inbred F344; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013311:Streptozocin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C017139:1-(2-chloroethyl)-1-nitrosourea; D013311:Streptozocin; D008770:Methylnitrosourea; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005038:Ethylnitrosourea; D002330:Carmustine