INHIBITION OF IMMUNOPURIFIED DNA POLYMERASE-ALPHA FROM PA-3 PROSTATE TUMOR-CELLS BY PLATINUM (II) ANTITUMOR DRUGS

Cisplatin (cis-diamminedichloroplatinum(II); cis-DDP) is used as an ef fective drug for treatment of a variety of cancers, such as carcinomas of bladder, ovarian, and testicular origin. Immunopurified DNA polyme rase-alpha from rat prostate tumor PA-3 cells was inhibited (50%) in t he presence of cis-DDP (165 muM) and PtCl2(en) (cis-dichloroethylenedi amine platinum (II); DEDAP) (75 muM) and remained uninhibited in the p resence of trans-DDP. Immunopurified DNA polymerase-alpha was preincub ated with cis-DDP and separated from unreacted cis-DDP by gel filtrati on chromatography. The platinated DNA polymerase-alpha was unable to i nitiate the DNA chain extension reaction. N-ethylmaleimide (1 mM), a t hiol group modifier, also inhibited (95%) the DNA polymerase-alpha cat alyzed reaction in vitro. Possible disruption of a zinc-finger motif o f the DNA polymerase-alpha polypeptide chain by replacement of zinc is suggested.