Effect of alpha-difluoromethylornithine on L-phenylalanine mustard-induced cytotoxicity and DNA interstrand cross-linking in a human cell line in vitro.
We compared L-phenylalanine mustard (L-PAM)-induced cytotoxicity and DNA cross-linking with and without a 42-h preincubation with the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO, 1 mM) in a human lymphoma cell line. The combination showed increased toxicity with a Do ratio of 1.6. L-PAM-induced DNA protein cross-linking as measured by alkaline elution was not altered by a DFMO pretreatment. DNA interstrand cross-linking was increased when L-PAM-treated cells were pretreated with DFMO. The differences occurred between 12 and 24 h following the L-PAM treatment. Peak protein cross-linking occurred 6 h following L-PAM removal with or without DFMO pretreatment. While peak interstrand cross-linking occurred 6 h following L-PAM removal, the DFMO-pretreated cells maintained higher cross-link levels longer than did control cells. The increase in interstrand cross-linking seen in DFMO-pretreated cells was maintained at several different L-PAM doses. The increased cytotoxicity could not be accounted for by the increased cross-linking alone. We have postulated that DFMO pretreatment results in a delay in the appearance of a cross-link removal system. The differences seen between results using these human cells and previous reports using rodent cells are discussed.
Ducore
J M
JM
McNamara
L
L
D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D003432:Cross-Linking Reagents; D004247:DNA; D004357:Drug Synergism; D000518:Eflornithine; D006801:Humans; D008558:Melphalan / Q000494:pharmacology*; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology
D003432:Cross-Linking Reagents; D004247:DNA; D009952:Ornithine; D008558:Melphalan; D000518:Eflornithine