Inhibitory effects of cisplatin and its conjugate with glutathione on blood platelet activity.

Cisplatin (cis -diamminedichloroplatinum II, CDDP) is a widely used chemotherapeutic agent; however, its haematological toxicity may become an important dose-limiting factor. The aim of the present study was to evaluate the effects of cisplatin and its metabolite with glutathione (GS-Pt conjugate) on thrombin-induced platelet aggregation, the secretory process and the arachidonate pathway in vitro. Pre-treatment of platelets with GS-Pt conjugate (60 min, 20 microM) but not with cisplatin alone, caused inhibition of thrombin-induced platelet aggregation. GS-Pt conjugate had also a strong inhibitory effect on the release of proteins and adenine nucleotides from platelet granules. After pre-incubation of platelets with cisplatin and its conjugate, we observed in thrombin-activated platelets, a decreased amount of malonyldialdehyde (a marker of thromboxane A(2) synthesis). We suggest that arachidonate metabolism plays an important role in determining the cytotoxicity of cisplatin.