Mechanisms of the Emetic Response to Chemotherapy and of the Antiemetic Action of 5-HT₃Receptor Antagonists: Clinical Studies

Abstract

In this work, we evaluated the role of 5-HT and 5-HT₃receptors on the emetic response to antineoplastic drugs, in human patients with cancer. 1) 5HT₃antagonists prevented vomiting induced by cisplatinum or cyclophosphamidebased chemotherapies. Emesis ensuing after high doses of ondansetron would be mediated by a non-5-HT₃receptor mechanism (delayed emesis?). 2) Increases in plasma and on the urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) were produced by highly emetogenic treatments (high-dose cisplatinum or dacarbazinebased chemotherapies). For both drugs, the time courses for emesis were superimposed with those for the increases in 5-HIAA. With high-dose cisplatinum, the increases in 5-HIAA lasted 12 to 14 hours and no increases in 5-HIAA were observed during the period of delayed emesis. Platelet or plasma 5-HT were not modified by cisplatinum or cyclophosphamide. A direct relationship was observed between emetogenecity and serotonin-releasing properties of the drugs. The antiemetics, ondansetron, metoclopramide, and dexamethasone failed to modify the increases in 5-HIAA induced by high-dose cisplatinum. The emetic response and the increases in 5-HT metabolism induced by cisplatinum were not affected by the somatostatin analog (octreotide). These results suggest that 5-HT and 5-HT₃receptors mediate the early, intense emetic response to chemotherapy. 5-HT appears to be released from the gut, since urinary 5-HIAA is a marker of gastrointestinal content and turnover of 5-HT and since platelet 5-HT does not contribute to the increases in 5-HIAA. Damage of the gut mucosa may be responsible for the release of serotonin induced by high-dose cisplatinum.