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Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis
W D Miner1, G J Sanger, D H Turner
1Beecham Pharmaceuticals Research Division, Harlow, Essex, UK.
Abstract:
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.
Insights
Severe emesis from cancer therapies is mediated by 5-HT3 receptors. Drugs targeting these receptors, like metoclopramide and BRL 24924, effectively reduced chemotherapy-induced vomiting in ferrets.
Area of Science:
- Pharmacology
- Neuroscience
- Gastroenterology
Background:
- Severe emesis is a common side effect of cytotoxic cancer therapies and total body irradiation.
- The 5-hydroxytryptamine (5-HT) 5-HT3 receptor is implicated in the emetic response.
- Understanding the role of 5-HT3 receptors is crucial for developing effective anti-emetic strategies.
Purpose of the Study:
- To investigate the role of 5-HT3 receptors in mediating severe emesis induced by cytotoxic drugs and total body irradiation.
- To evaluate the efficacy of different anti-emetic compounds targeting dopamine and/or 5-HT3 receptors.
Main Methods:
- Experiments were conducted in ferrets to study emesis evoked by various stimuli.
- Anti-emetic compounds including domperidone, metoclopramide, and BRL 24924 were administered.
- The ability of these compounds to prevent emesis induced by apomorphine, cis-platin, total body irradiation, and a combination of doxorubicin and cyclophosphamide was assessed.
Main Results:
- Domperidone and metoclopramide prevented apomorphine-evoked emesis, but domperidone did not prevent emesis from cis-platin or irradiation.
- Metoclopramide and BRL 24924, both 5-HT3 receptor antagonists, significantly reduced or prevented emesis induced by cis-platin and total body irradiation.
- Metoclopramide and BRL 24924 also effectively prevented emesis caused by a combination of doxorubicin and cyclophosphamide.
Conclusions:
- 5-HT3 receptors play a fundamental role in mediating severe emesis associated with cancer treatment therapies.
- Targeting 5-HT3 receptors with agents like metoclopramide and BRL 24924 offers a promising strategy for managing chemotherapy- and irradiation-induced emesis.