Paul J. Hesketh, MD

Improved understanding of the physiologic and neuropharmacologicmechanisms underlying chemotherapy-induced nausea andvomiting (CINV) has driven significant progress in the treatment ofCINV over the past 2 decades. Recognition of the role of neurotransmittersand their receptors in the process of CINV has been central tothis progress. Initial attention focused on dopamine, then on serotonin,and most recently on substance P, which has yielded a usefulnew class of antiemetic medications known as selective neurokinin-1receptor antagonists. Preclinical studies of these neurokinin-1 receptorantagonists suggested that they would demonstrate broad antiemeticactivity in acute emesis, demonstrate activity against cisplatininduceddelayed emesis, be well tolerated, and contribute to enhancedefficacy when used in combination with other classes of antiemetics.These suggestions appear to have been largely borne out in clinicaltrials. Pharmacogenomics may offer a means to further extend andapply our understanding of CINV by enabling more selective targetingof antiemetic therapies. To date, the application of pharmacogenomicsto CINV has focused on variations in the metabolism of serotoninreceptor antagonists by CYP 450 genotype and variations in the5-HT3 receptor gene itself.