In vitro competition between adenosine(5')tetraphospho(5')adenosine and deoxyribonucleic acid in the reaction with diamminedichloroplatinum(II).
Competition between adenosine(5')tetraphospho(5')adenosine (Ap4A) and DNA for the synthesis of adducts with the cis or trans isomer of diamminedichloroplatinum(II) was measured in the presence and absence of magnesium and spermidinium ions. Reaction products were analysed by circular dichroism, poly(ethyleneimine) thin-layer chromatography and reversed-phase chromatography. Competition was affected by the oligovalent cations that bound specifically to the dinucleotide. Platination of DNA was favoured under all conditions. Chromatin was less competitive. The mechanism was kinetic competition, DNA reacting considerably faster than Ap4A. Platinum(II) did not exchange between adducts and free DNA and Ap4A, respectively. On that basis only low amounts of Ap4A adducts were estimated to be formed under conditions of clinical chemotherapy. The cis and trans isomers of diamminedichloroplatinum(II) were equally effective. Platinum(II) adducts of Ap4A were neither degraded by Ap4A-specific pyrophosphohydrolases nor by phosphodiesterase nor in the presence of unfractionated extract of calf thymus. Unphysiologically high concentrations of Crotalus durissus phosphodiesterase I were required for hydrolytic splitting, the amount of which was similar for both platinum(II) isomer adducts. The results suggest that Ap4A platinum(II) adducts might accumulate during chemotherapy of cancer treatment.
D000227:Adenine Nucleotides / Q000378:metabolism*; D001667:Binding, Competitive; D002942:Circular Dichroism; D002945:Cisplatin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D015226:Dinucleoside Phosphates; D007700:Kinetics
D000227:Adenine Nucleotides; D015226:Dinucleoside Phosphates; C020733:diadenosine tetraphosphate; D004247:DNA; D002945:Cisplatin