We examined the O6-methylguanine-DNA methyltransferase(MGMT) protein as well as MGMT activity levels and the excisionrepair cross-complementing rodent repair deficiency gene,ERCC2 (XPD), protein levels in 14 human tumor cell lines notselected for chloroethylnitrosourea (CENU) resistance. Theseresults were compared with 1,3-bis-(2-chloroethyl)-1-nitrosourea(BCNU) cytotoxicity and UV light sensitivity. MGMTprotein correlated significantly with MGMT activity (r=0.9497,p=0.0001). There was no significant linear correlation betweenBCNU cytotoxicity and MGMT content as determined by bothWestern analysis (r=0.139, p=0.6348) and activity assay (r=0.131, p=0.6515). However, MGMT-rich cell lines were foundto be more resistant than MGMT-poor cell lines to BCNU (t=2.2375, p=0.0225) but not to UV (t=1.1734, p=0.1317).Furthermore, the most BCNU-sensitive cell lines were allMGMT-poor. UV sensitivity was significantly correlated toBCNU cytotoxicity (r=0.858, p=0.0001). Significant correlationswere found between ERCC2 protein levels and BCNUcytotoxicity (r=0.786, p=0.0009) or UV sensitivity (r=5 0.874, p=5 0.0001). Our results confirm that MGMT plays an importantrole in CENU resistance, but not in UV resistance. The correlationof UV sensitivity with BCNU cytotoxicity suggests thatnucleotide excision repair is an important modifying factor ofMGMT-mediated innate CENU resistance in human tumor celllines, especially in highly resistant cell lines. ERCC2 may beimplicated in this process.