EFFECT OF DNA CONFORMATION ON CISPLATIN ADDUCT FORMATION

The anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) has b een shown previously to form adducts preferentially within internucleo somal or linker DNA rather than to DNA within the nucleosome. To deter mine whether other ''open'' regions of chromatin have an increased aff inity for cisplatin, adduct formation within specific chromatin domain s was analyzed. There was a significant increase in cisplatin-DNA addu ct formation for DNA associated with the nuclear matrix (NM) compared with other chromatin domains and total unfractionated DNA. In contrast , treatment of the same cells with trans-diamminedichloroplatinum(II) (transplatin) did not result in preferential adduct formation. These f indings led to the hypothesis that it might be possible to alter DNA t o make it a more favorable target for cisplatin. The effect of arginin e butyrate on cisplatin-DNA adduct formation was analyzed in human can cer cells. The combination of arginine butyrate and cisplatin resulted in a concentration-responsive increase in cisplatin-DNA adduct format ion in PC-3 cells and an overall increase in cisplatin-DNA adduct form ation in three other human cancer cell lines. The same combination als o resulted in a significant increase in drug-induced cytotoxicity at a low concentration of cisplatin. These results suggest that chromatin configuration can affect cisplatin adduct formation.