Effects of a microtubule stabilizing agent on the response of platelets to vincristine.
The discoid shape of blood platelets is supported by a circumferential bundle of microtubules. Removal of the microtubules by an antimitotic drug, vincristine, is associated with loss of lentiform appearance, formation of tubulin paracrystals, a depressed response to aggregating agents, and impaired secretory activity. Recent studies have suggested that the action of vincristine on platelet secretion and aggregation is directly related to its action on microtubules, while other work had indicated that the antimitotic drug prevents the release reaction by inhibiting prostaglandin synthesis. The present study has examined the influence of taxol, a microtubule stabilizing agent, on the response of platelets to vincristine. Taxol completely prevented vincristine-induced shape change, microtubule disassembly, and tubulin paracrystal formation, even at concentrations one-tenth that of the antimitotic drug. Pretreatment with vincristine to dissociate microtubules and convert tubulin to crystals before exposure to taxol did not affect altered shape or tubulin paracrystals, but did cause assembly of free pools of tubulin into tubular polymers. Studies of physiology confirmed that vincristine, in amounts that remove microtubules, depresses platelet aggregation and secretion, effects that could be overcome by increasing agonist concentration. Although completely preventing microtubule dissociation, taxol had no corrective influence on vincristine-induced inhibition of platelet function. Biochemical studies revealed that vincristine concentrations that disassembled microtubules and blocked secretion did not inhibit conversion of 14C-arachidonic acid to thromboxane B2. The findings suggest that vincristine inhibits platelet function through some mechanism other than disassembling microtubules, but the other mechanism does not involve inhibition of prostaglandin synthesis.
D000470:Alkaloids / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000648:ultrastructure; D004336:Drug Antagonism; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D017239:Paclitaxel; D010974:Platelet Aggregation / Q000187:drug effects*; D013929:Thromboxane B2 / Q000096:biosynthesis; D014404:Tubulin / Q000096:biosynthesis; D014750:Vincristine / Q000494:pharmacology*
D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D001095:Arachidonic Acids; D014404:Tubulin; D013929:Thromboxane B2; D014750:Vincristine; D017239:Paclitaxel