MECHANISM OF ACTION OF THE ANTILEUKEMIC XANTHONE PSOROSPERMIN - DNA STRAND BREAKS, ABASIC SITES, AND PROTEIN-DNA CROSS-LINKS

Psorospermin, a cytotoxic dihydrofuranoxanthone isolated from Psorospe rmum febrifugum, produced aberrant simian virus 40 DNA replication int ermediates when added to lytically infected CV-1 monkey kidney cells. The aberrant viral intermediates showed dose-dependent DNA strand brea ks and protein-DNA cross-links, as well as decreased electrophoretic m obility. 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. Cytoc hrome c cross-linked spontaneously to viral DNA prepared from psorospe rmin-treated cells but not to DNA from untreated cells. This suggests that the protein-DNA cross-links and many of the DNA strand breaks obs erved in vivo result from reactions between abasic sites and chromosom al proteins. It is likely that the protein-DNA cross-links and DNA str and breaks contribute to the cytotoxicity and antineoplastic activity of psorospermin.