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Effect of -Difluoromethylornithine on L-Phenylalanine Mustard-induced Cytotoxicity and DNA Interstrand Cross-Linking in a Human Cell Line in Vitro¹

Department of Pediatrics, The University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texas 75235

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 -difluoromethylornithine (DFMO, 1 mM) in a human lymphoma cell line. The combination showed increased toxicity with a D₀ 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.

¹ This investigation was supported by USPHS Grant 1-R23-CA35156-01 awarded by the National Cancer Institute, Department of Health and Human Services.

² Junior Faculty Clinical Fellow of the American Cancer Society. To whom requests for reprints should be addressed, at University of Texas Health Science Center, 5323 Harry Hines Boulevard, Dallas, TX 75235.

Received 4/22/85. Revised 7/17/85. Revised 11/ 6/85. Accepted 11/ 7/85.