Role of 5-hydroxytryptamine3 (5-HT3) antagonists in the prevention of emesis caused by anticancer therapy

Most anticancer drugs are cytotoxic and produce various side-effects, among which nausea and vomiting are almost ubiquitous and usually extremely distressing to the patient. Cancer chemotherapy elicits two main phases of vomiting: an intense, acute phase of vomiting that occurs almost immediately following anti-cancer therapy and a milder, delayed phase of nausea and vomiting of longer duration. The mechanisms underlying the induction of nausea and vomiting after cancer chemotherapy are poorly understood but may be mediated by serotonin (5-hydroxytryptamine or 5-HT), particularly in the acute phase. Serotonin activates 5-HT3 receptors, which function as ligand-gated ion channels located either in the periphery and/or in the central nervous system to produce emesis, among other effects. The peripheral 5-HT3 receptors may be pharmacologically distinct from the central 5-HT3 receptors and may exhibit some association with GTP-binding proteins. In addition, different populations may exist as distinct subtypes of the same receptor. The 5-HT3 receptor antagonist ondansetron (GR 38032F) is effective in preventing the emesis induced by cytotoxic agents currently used in the treatment of many forms of cancer. Ondansetron has, comparatively, a much higher efficacy in the treatment of acute emesis following cancer chemotherapy than it does in the delayed phase, suggesting that the late phase of emesis may be mediated by other distinct mechanisms.