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In Vitro Studies on the Mechanism of Action of Hepsulfam in Chronic Myelogenous Leukemia Patients¹

Laboratories of Pharmacology [J. R. H., N. W. G.], Experimental Hematology [C. C., C. S. J.], and Cell Biology [P. F.], AMC Cancer Research Center, Denver, Colorado 80214, and Division of Medical Oncology, Department of Medicine [A. A.], University of Colorado, Health Science Center, Denver, Colorado 80262

In the present study we have characterized the cytotoxicity and DNA damage induced by hepsulfam and busulfan in cells isolated from both chronic myelogenous leukemia (CML) patients and normal donors. Hepsulfam inhibited colony-forming units-granulocyte, macrophage to a greater extent than busulfan in peripheral blood cells (PBCs) isolated from CML patients. Normal PBCs were equally sensitive to both agents and were more sensitive than the cells isolated from CML patients. Hepsulfam induced DNA interstrand cross-links in PBCs and bone marrow from both CML and normal volunteers, whereas busulfan produced few or no DNA interstrand cross-links. In addition, hepsulfam induced higher levels of DNA interstrand cross-linking than busulfan in three samples isolated from CML patients in blast crisis. Busulfan did however cause a small number of DNA strand breaks to be formed in human cells. Both agents produced similar levels of DNA-protein cross-links in PBCs from CML patients. These results suggest that the mechanism of DNA reactivity of hepsulfam and busulfan differ and that hepsulfam may prove useful in the treatment of CML.

¹ Supported by National Institutes of Health Grant CA 505082.

² Present address: Toxicology Department, Sterling Research Group, 81 Columbia Turnpike, Rensselaer, NY 12144.

³ Present address: Department of Otolaryngology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15217.

⁴ Present address: Department of Biology, New York University, New York, NY 10003.

⁵ Present address: Division of Pharmaceutics School of Pharmacy, and Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033. To whom requests for reprints should be addressed, at School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90033.

Received 5/ 4/90. Accepted 9/ 4/90.

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