title: Formation and repair of 1,3-bis-(2-chloroethyl)-1-nitrosourea and cisplatin induced total genomic DNA interstrand crosslinks in human glioma cells.
abstract: The kinetics of formation and repair of total genomic DNA interstrand crosslinks (ISCs) induced by BCNU and cis-DDP were studied in cells of 6 human malignant gliomas and related with their degree of drug resistance. DNA ISCs were formed rapidly (peak 6-12 h) following a 2 h exposure to 50 microM BCNU or 25 uM cis-DDP, and on an equimolar basis higher levels of crosslinking were observed with cis-DDP than with BCNU. Repair of cis-DDP induced crosslinks was characteristically bi-phasic and the rate was significantly higher than that for BCNU induced crosslinks. Overall, a low crosslink index and a high crosslink repair rate correlated with cis-DDP and BCNU resistance. The data demonstrate, conclusively, the ability of human glioma cells to repair cis-DDP and, for the first time, BCNU induced DNA ISCs and that DNA crosslink repair is a significant contributing factor to the resistance of these tumors to the two agents.
authors.affiliation: Department of Experimental Pediatrics, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: F
authors.initials: F
authors.lastname: Ali-Osman
authors.forename: A
authors.initials: A
authors.lastname: Rairkar
authors.forename: P
authors.initials: P
authors.lastname: Young
mesh_terms: D002330:Carmustine / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004351:Drug Resistance; D004996:Ethidium / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D013050:Spectrometry, Fluorescence; D014407:Tumor Cells, Cultured
chemical_list: D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; C052890:ethidium-DNA complex; D004247:DNA; D004996:Ethidium; D002945:Cisplatin; D002330:Carmustine