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Mechanism of Action of the Antileukemic Xanthone Psorospermin: DNA Strand Breaks, Abasic Sites, and Protein-DNA Cross-Links¹

Departments of Radiology and Medical Microbiology and Immunology [P. A. P., R. M. S.] and College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy [D. K. H., J. M. C.], The Ohio State University, Columbus, Ohio 43210

Psorospermin, a cytotoxic dihydrofuranoxanthone isolated from Psorospermum febrifugum, produced aberrant simian virus 40 DNA replication intermediates when added to lytically infected CV-1 monkey kidney cells. The aberrant viral intermediates showed dose-dependent DNA strand breaks and protein-DNA cross-links, as well as decreased electrophoretic mobility. Simian virus 40 DNA from psorospermin-treated cells was shown to contain numerous abasic (apyrimidinic/apurinic) sites. The density of abasic sites was a function of the psorospermin dose. We conclude that psorospermin causes extensive loss of DNA bases in vivo. Primary amine groups of cellular proteins are known to react with abasic sites to form covalent protein-DNA cross-links and DNA strand breaks. Cytochrome c cross-linked spontaneously to viral DNA prepared from psorospermin-treated cells but not to DNA from untreated cells. This suggests that the protein-DNA cross-links and many of the DNA strand breaks observed in vivo result from reactions between abasic sites and chromosomal proteins. It is likely that the protein-DNA cross-links and DNA strand breaks contribute to the cytotoxicity and antineoplastic activity of psorospermin.

¹ This work supported by USPHS grants CA-45208 to R. S., CA33326 to J. M. C., and P30-CA16058-6A1 to the Ohio State University Comprehensive Cancer Center.

² Present address: Division of Pediatrics, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010.

³ Present address: National Cancer Institute-Frederick Cancer Research and Development Center, P.O. Box B, Frederick, MD 21702-1201.

⁴ To whom requests for reprints should be addressed, at Ohio State University, Dept. of Radiology, 103 Wiseman Hall, 400 West 12th Avenue, Columbus, OH 43210-1214.

Received 9/16/93. Accepted 4/19/94.

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