Reduced thiol content in L1210 cells treated with BSO increases DNA crosslinking by melphalan.
Endogenous thiols such as glutathione (GSH) are known to mediate the activity of bifunctional alkylating agents such as melphalan (L-PAM). GSH levels can be reduced by cell growth in the presence of an analog of gamma glutamyl, alpha-aminobutyrate, L-buthionine (S/R) sulfoximine (L-BSO). L-1210 murine lymphocytic leukemia cells grown in vitro in the presence of 10 microM less than 15% L-BSO possessed 1% of the normal GSH levels. This pretreatment regimen did not significantly alter cell viability but did enhance the cytotoxicity produced by a 15 microM-1hr L-PAM treatment. The increased cell killing correlated with enhanced DNA-DNA crosslinking immediately following L-PAM exposure. No effect of BSO pretreatments on the incomplete removal of crosslinks over 36 hr of observation was seen. These results suggest that GSH levels modulate the initial degree of L-PAM-induced DNA crosslinking, but not the long term repair of these lesions.
D000818:Animals; D019328:Buthionine Sulfoximine; D002478:Cells, Cultured; D003432:Cross-Linking Reagents; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000378:metabolism; D008558:Melphalan / Q000494:pharmacology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D013438:Sulfhydryl Compounds / Q000378:metabolism
D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan