DNA interstrand crosslinking and strand break repair in human glioma cell lines of varying [1,3-bis(2-chloroethyl)-1-nitrosourea] resistance.
The production of DNA interstrand crosslinks (ISC) by BCNU and other bifunctional alkylators and the effects of these drugs on the repair of radiation-induced DNA-single strand breaks (SSB) were studied in two human glioblastoma used to assess both DNA-ISCs and DNA-SSBs. BCNU-treated UWR2 and UWR3 cells showed a significant BCNU dose-dependent increase in radiation-induced DNA-SSBs at 6 hrs post-drug treatment, and at 100 microM BCNU DNA-ISC was completely masked in UWR2 cells. There was no enhancement of radiation-induced DNA-SSBs in both cell lines after treatment with cis-DDP, CHZ, or MNU. In the capillary clonogenic cell assay, UWR2 cells were 3.2 times more resistant than UWR3 cells; 0(6)-methylguanine-DNA methyltransferase activity was also 1.8 times higher in UWR2 than in UWR3. Our data suggest caution in the use of the standard alkaline elution technique (with 6 hrs between drug exposure and irradiation) to measure BCNU-induced DNA-ISC induction in highly BCNU-resistant cell lines. We provide evidence that the synergism between BCNU and radiation in the generation of DNA-SSBs is the result of low DNA-SSB repair capacity of the cells, and is further potentiated by the carbamoylating action of BCNU.
Ali-Osman
F
F
Department of Neurological Surgery, University of Washington Medical Center, Seattle 98195.
Srivenugopal
K
K
Berger
M S
MS
Stein
D E
DE
D000477:Alkylating Agents / Q000494:pharmacology; D002330:Carmustine / Q000494:pharmacology*; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000235:genetics / Q000528:radiation effects; D004351:Drug Resistance; D005909:Glioblastoma; D006801:Humans; D007700:Kinetics; D013311:Streptozocin / Q000031:analogs & derivatives / Q000494:pharmacology
D000477:Alkylating Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; C007028:chlorozotocin; D013311:Streptozocin; D002945:Cisplatin; D002330:Carmustine