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Influence of WR2721 on DNA Cross-Linking by Nitrogen Mustard in Normal Mouse Bone Marrow and Leukemia Cells in Vivo¹

Division of Hematology and Oncology, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201

In previous studies we showed that WR2721 enhanced nitrogen mustard (HN2) cytotoxicity to AKR mouse leukemia. Simultaneously, it protected normal bone marrow from drug cytotoxicity. In this study, the method of alkaline elution was used to measure the modifications of HN2 induced DNA damage in the same animal model.

In leukemia cells, no significant differences in DNA-DNA interstrand cross-links were observed between mice treated with WR2721 and HN2 and mice treated with HN2 alone. In normal bone marrow, DNA-DNA cross-linking was decreased by about 50% in mice treated by WR2721 and HN2. The difference was significant (P = 0.01). In leukemia, half-time of repair was 73 min for HN2 and 83 for WR2721 and HN2 treated mice, while in normal bone marrow, respectively, 73 and 64 min were calculated.

WR2721 modulation significantly decreases DNA-protein cross-links in leukemia cells (P < 0.05). This decrease was observed for early as well as for late DNA-protein cross-links. In normal bone marrow cells, only early DNA-protein cross-links were decreased. The meaning of this observation is unclear.

¹ This investigation was supported by USPHS Grants CA-34133 and CA-42186 from the National Cancer Institute, Department of Health and Human Services, and by the Wayne State University Ben Kasle Trust for Cancer Research.

² Supported partially by an award from the Belgian Work against Cancer.

³ To whom requests for reprints should be addressed, at Division of Hematology and Oncology, Wayne State University, P. O. Box 02188, Detroit, MI 48201.

Received 3/28/88. Revised 6/20/88. Accepted 7/28/88.