Nausea and
vomiting are major side effects of
chemotherapy and one key reason for non-compliance with
cancer treatment. The introduction of
5-HT3 receptor antagonists in the 1990s was a major advance in the prevention of acute
emesis, and highlighted the critical role of
serotonin in the
emetic response. The next major advance in the treatment of
chemotherapy induced
nausea and
vomiting (CINV) occurred in 2003 with the introduction of
aprepitant, a
tachykinin 1 (NK1) receptor antagonist.
Aprepitant not only reduced acute
emesis but also helped in the reduction of delayed
emesis. Also in 2003,
palonosetron, a second generation
5-HT3 receptor antagonist became available. Unlike the first generation
5-HT3 receptor antagonists,
palonosetron demonstrated efficacy in preventing both acute and delayed
emesis. This review focuses on the mechanism of action of 5-HT3 and NK1 receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the
emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between
palonosetron and other
5-HT3 receptor antagonists in the clinic. In vitro and in vivo experiments have shown that
palonosetron can inhibit
substance P-mediated responses, presumably through its unique interactions with the
5-HT3 receptor. The crossroads of acute and delayed
emesis seem to include interactions among the 5-HT3 and NK1 receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV.