PARTICIPATION OF SEROTONIN ON EARLY AND DELAYED EMESIS INDUCED BY INITIAL AND SUBSEQUENT CYCLES OF CISPLATINUM-BASED CHEMOTHERAPY - EFFECTS OF ANTIEMETICS

The role of serotonin as the possible trigger mechanism of vomiting associated with chemotherapeutic drugs was further investigated in cancer patients (n = 86). Increases in 5-hydroxyindoleacetic acid (5-HIAA) excretion rates (2.5-2.9 times baseline values) were observed 4 to 8 hours after high-dose cisplatinum (greater-than-or-equal-to 50 mg/m2). The daily excretion of 5-HIAA from 24-48, 48-72, and 72-96 hours after cisplatinum was not different from pre-cisplatinum levels. These results, together with the efficacy data for 5-HT3 antagonists, suggests that serotonin may trigger the early, intense period of emesis, but not the period of delayed emesis, following high-dose cisplatinum. Compared with the first cycle of chemotherapy, higher peak levels and more sustained elevations of 5-HIAA excretion were found after subsequent cycles, with high-dose cisplatinum. Further, no evidence of serotonin depletion was found after a single or after repeated cycles of treatment with high-dose cisplatinum. These data suggest that the more intense emetic response associated to repeated cycles of treatment may be triggered by greater changes in serotonin release. No significant differences in the rate and amount of 5-HIAA excreted induced by low-dose (30 +/- 2 mg/m2) and high-dose (84 +/- 3 mg/m2) cisplatinum were found between those patients who received dexamethasone (D) (20 mg IV) and those who received metoclopramide (M) (2 mg/kg, IV), irrespectively of the cycle of treatment. Interestingly, for M but not for D, best antiemetic protection was observed when lower amounts of serotonin were released (i.e., low-dose cisplatinum and initial cycles of treatment). This suggests, that contrary to D, the effects of M, a purported antagonist of 5-HT3 receptors, are highly dependent on the quantity of serotonin release induced by a chemotherapeutic drug. Finally, our data suggest that D does not interfere with cisplatinum-induced serotonin release.