Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis.
The involvement of 5-hydroxytryptamine (5-HT) 5-HT3 receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT3 receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT3 receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT3 receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.
Miner
W D
WD
Beecham Pharmaceuticals Research Division, Harlow, Essex, UK.
Sanger
G J
GJ
Turner
D H
DH
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001058:Apomorphine / Q000009:adverse effects / Q000037:antagonists & inhibitors; D001549:Benzamides / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002945:Cisplatin / Q000009:adverse effects / Q000037:antagonists & inhibitors; D003520:Cyclophosphamide / Q000009:adverse effects / Q000037:antagonists & inhibitors; D004294:Domperidone / Q000627:therapeutic use; D004317:Doxorubicin / Q000009:adverse effects / Q000037:antagonists & inhibitors; D005289:Ferrets; D008297:Male; D008787:Metoclopramide / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000378:metabolism*; D014839:Vomiting / Q000139:chemically induced*; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D000970:Antineoplastic Agents; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D011985:Receptors, Serotonin; D004294:Domperidone; D004317:Doxorubicin; D003520:Cyclophosphamide; C053006:renzapride; D008787:Metoclopramide; D001058:Apomorphine; D002945:Cisplatin