Cisplatin-induced changes in biological activity of blood platelets: thiol-related mechanisms.
The effects of cisplatin (cis-diamminedichloroplatinum (II), CDDP) and transplatin (trans-diamminedichloroplatinum(II), TDDP), and their complexes with glutathione (GS-Pt) in vitro on oxygen free radical generation O2-.), lipid peroxidation and ADP-induced aggregation in pig blood platelets were studied. Incubation of pig blood platelets with cisplatin or transplatin caused a loss of both protein -SH and the thiol groups of GSH. In pig blood platelets exposed to cisplatin or transplatin (20 microM) the GS-Pt complex was formed as a major metabolite. The formation of GS-Pt complexes in platelet cytosol was time dependent and the intracellular content of this complex reached a maximal level after 24 h. GS-Pt complexes were found to induce platelet lipid peroxidation, measured as thiobarbituric acid reactive substance level, and O2-. generation, and it was more active than cisplatin or transplatin alone. Cisplatin and its GS-Pt complex had an inhibitory effect on ADP-induced platelet aggregation. These results showed that GS-Pt complexes affect platelet metabolism and function. It seems that glutathione-associated metabolism of platinum compounds plays an important role in the cytotoxicity and biological activity of these drugs.
Olas
B
B
Department of General Biochemistry, University of Banacha, Lódź, Poland.
Wachowicz
B
B
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002945:Cisplatin / Q000097:blood / Q000494:pharmacology*; D005978:Glutathione / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000097:blood*; D013552:Swine
D000970:Antineoplastic Agents; D013438:Sulfhydryl Compounds; C034697:transplatin; D016718:Arachidonic Acid; D005978:Glutathione; D002945:Cisplatin