ANTITUMOR THERAPY, ANTIEMETICS AND BRAIN RECEPTORS

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Nausea and vomiting are frequent and serious toxicities in patients receiving cancer chemotherapy. There is little information available on the molecular mechanisms of chemotherapy induced emesis or in the pharmacology of its treatment. Drug-induced nausea and vomiting is thought to occur primarily via interaction of emetic antitumor agents with dopaminergic receptors in the chemoreceptor trigger zone (area postrema) of the brain. The major class of antiemetic agents, phenothiazines, are known to bind to and antagonize dopamine receptors in the brain. The long-term goals of this proposal are: 1) to characterize receptor types in the human chemoreceptor trigger zone and emetic center, and the interaction of emetic agents with these receptors using dopamine radioligand binding techniques, and 2) to provide more efficacious use of phenothiazines as antiemetic agents by studying the pharmacokinetics, toxicity and efficacy of these agents in patients. The specific aims of the proposal are to characterize dopamine receptors in the chemoreceptor trigger zone using radioligand binding techniques, to determine the presence or absence of other receptor types in the human chemoreceptor trigger zone and emetic center using appropriate radioligand binding assay, to characterize the interaction of emetic antitumor agents with these receptor types, to characterize the pharmacokinetics of phenothiazines following oral administration for the treatment of nausea and vomiting and to study the toxicity, efficacy, and pharmacokinetics of phenothiazines as antiemetic agents in patients as a function of dose and schedule of administration. The major methodology in these studies will be radioligand binding assays which provide the means to characterize receptor types in brain regions, determine if emetic antitumor agents interact with these receptors, and provide a quantitative assay for the determination of low concentrations of phenothiazines in biological fluids. Results of these studies will hopefully provide a better understanding of emesis and its prevention, a rationale for design of new approaches to antiemetic chemotherapy, and more dfficacious use of phenothiazine antiemetic agents.