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 effective drug for treatment of a variety of cancers, such as carcinomas of bladder, ovarian, and testicular origin. Immunopurified DNA polymerase-alpha from rat prostate tumor PA-3 cells was inhibited (50%) in the presence of cis-DDP (165 microM) and PtCl2(en) (cis-dichloroethylenediamine platinum (II); DEDAP) (75 microM) and remained uninhibited in the presence of trans-DDP. Immunopurified DNA polymerase-alpha was preincubated with cis-DDP and separated from unreacted cis-DDP by gel filtration chromatography. The platinated DNA polymerase-alpha was unable to initiate the DNA chain extension reaction. N-ethylmaleimide (1 mM), a thiol group modifier, also inhibited (95%) the DNA polymerase-alpha catalyzed reaction in vitro. Possible disruption of a zinc-finger motif of the DNA polymerase-alpha polypeptide chain by replacement of zinc is suggested.
Kelley
T J
TJ
Department of Chemistry and Biochemistry, University of Notre Dame, IN 46556.
Moghaddas
S
S
Bose
R
R
Basu
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D051381:Rats; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D015032:Zinc / Q000032:analysis
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C002892:platinum ethylenediamine dichloride; C034697:transplatin; D006157:Guanosine Monophosphate; D004257:DNA Polymerase II; D005978:Glutathione; D015032:Zinc; D002945:Cisplatin