SEROTONIN MECHANISMS IN CHEMOTHERAPY-INDUCED EMESIS IN CANCER-PATIENTS

Emesis is a common side effect of chemotherapeutic drugs. Cisplatin, n itrogen mustard and dacarbazine induce increases in urinary 5-hydroxyi ndoleacetic acid (5-HIAA) in parallel with the development of the peri od of emesis which is sensitive to 5-HT3 receptor antagonists ('acute emesis'). It is suggested that these cytotoxics release serotonin from enterochromaffin cells, which then acts on 5-HT3 receptors to trigger the emetic response. Cyclophosphamide, on the other hand, induces a m odest emetic response, partly sensitive to 5-HT3 receptor antagonists, but not associated with increases in urinary 5-HIAA. It is suggested that cyclophosphamide-induced emesis is not mediated by the release of serotonin from enterochromaffin cells. Although after high-dose cispl atin most emesis is sensitive to 5-HT3 receptor antagonists, patients often present a milder, although more prolonged form of emesis which i s mostly resistant to 5-HT3 receptor antagonists (also known as 'delay ed emesis'). This form of emesis is not associated with increases in u rinary 5-HIAA (not due to serotonin released from the enterochromaffin cells). Treatment with p-chlorophenylalanine (a serotonin synthesis i nhibitor) inhibited cisplatin-induced emesis and cisplatin-induced inc reases in urinary 5-HIAA excretion. In summary, these results indicate that in human patients, serotonin plays a fundamental role in chemoth erapy-induced emesis. Serotonin released from enterochromaffin cells s eems to mediate emesis sensitive to 5-HT3 receptor antagonists induced by cisplatin, dacarbazine and nitrogen mustard. Emesis sensitive to 5 -HT3 receptor antagonists associated with cyclophosphamide treatment, is not mediated by the release of serotonin from enterochromaffin cell s by the cytotoxic. Therefore, cyclophosphamide could induce serotonin release either from enteric serotonin nerves or from the CNS. Cisplat in-induced emesis resistant to 5-HT3 receptor antagonists ('delayed em esis') is not mediated by serotonin released from enterochromaffin cel ls.