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Interactions of Mitomycin C with Mammalian DNA Detected by Alkaline Elution¹

Departments of Medicine [R. T. D., D. S. A., J. D. L.] and Radiology [G. T. B.], Cancer Center Division, The University of Arizona, Tucson, Arizona 85724

The antitumor antibiotic mitomycin C (MMC) was studied in vitro using L1210 leukemia and 8226 human myeloma cells. Cytotoxicity was evaluated by colony formation in soft agar, and DNA damage was analyzed using alkaline elution filter assays. The purposes of these studies were: (a) to characterize the time course of MMC-DNA damage; (b) to characterize the type of DNA damage [DNA-DNA interstrand cross-links (ISC), DNA-protein cross-links (DPC), single and double strand breaks (SSBs, DSBs)]; and (c) to correlate this damage with cytotoxicity in vitro. Colony-forming assays showed the D₀ value for 1 h MMC to be 15.0 µM for L1210 cells and 17 µM for 8226 cells. Alkaline elution studies showed that dose-dependent ISCs and DPCs formed rapidly following MMC exposure. Removal of cross-links was delayed, with only 50% repaired 32 h after exposure. There was a good correlation between ISCs and cytotoxicity in dose-response studies in each cell line. ISCs appeared to comprise most of the MMC-DNA lesions in both cell lines. No DNA SSBs or DSBs were observed following MMC exposure. Nuclei isolated from both cell lines and exposed to MMC produced less MMC alkylation than whole cells but, again, no strand breaks were evident. These results demonstrate that MMC is principally an alkylating agent when used at pharmacological (cytotoxic) concentrations in vitro. The lack of evidence for DNA strand breaks discounts a significant role for putative quinone-generated oxygen free radicals in the production of MMC cytotoxicity.

¹ Supported in part by Grants CA 23074, CA 17094, CA 26972, and CA 17343 from the National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, MD 20205.

Presented in part at the Seventy-fifth Annual Meeting of the American Association for Cancer Research, May 10, 1984, Toronto, Canada (14).

² To whom requests for reprints should be addressed, at Cancer Center, Arizona Health Sciences Center, 1501 N. Campbell Avenue, Tucson, AZ 85724.

Received 12/14/84. Revised 4/24/85. Accepted 4/26/85.

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