Inhibition of immunopurified DNA polymerase-alpha from PA-3 prostate tumor cells by platinum (II) antitumor drugs

Cancer Biochem Biophys. 1993 Jun;13(3):135-46.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Binding, Competitive
  • Cisplatin / metabolism
  • Cisplatin / pharmacology
  • DNA Polymerase II / antagonists & inhibitors*
  • DNA Polymerase II / chemistry
  • Glutathione / metabolism
  • Guanosine Monophosphate / metabolism
  • In Vitro Techniques
  • Male
  • Organoplatinum Compounds / pharmacology*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / enzymology*
  • Rats
  • Stereoisomerism
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / enzymology
  • Zinc / analysis

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • platinum ethylenediamine dichloride
  • transplatin
  • Guanosine Monophosphate
  • DNA Polymerase II
  • Glutathione
  • Zinc
  • Cisplatin