Current
therapy for
chemotherapy-induced
nausea and
vomiting includes the use of both 5-HT3 and NK1 receptor antagonists. Acute
emesis has largely been alleviated with the use of
5-HT3 receptor antagonists, while an improvement in preventing delayed
emesis has been achieved with NK1 receptor antagonists. Delayed
emesis, however, remains a problem with a significant portion of
cancer patients receiving highly emetogenic
chemotherapy. Like other drugs in its class,
palonosetron, a
5-HT3 receptor antagonist, has shown efficacy against acute
emesis. However,
palonosetron has also shown consistent improvement in the suppression of delayed
emesis. Since both 5-HT3 and NK1 receptor antagonists are often simultaneously administered to patients, the question remains if
palonosetron's effect on delayed
emesis would remain distinct when co-administered with an NK1 receptor antagonist. Recent mechanistic studies using NG108-15 cells have shown that
palonosetron and
netupitant, an NK1 receptor antagonist currently in phase 3 clinical trials, exhibited synergistic effects when inhibiting the
substance P response. The present studies showed that both
netupitant and
palonosetron-induced NK1 receptor internalization in NG108-15 cells and that when used together receptor internalization was additive.
Palonosetron-induced NK1 receptor internalization was dependent on the presence of the
5-HT3 receptor. Results provide a possible explanation for
palonosetron's enhancement of the inhibition of the SP response and suggest that the effect of
palonosetron and NK1 receptor antagonists on prevention of delayed
emesis could be additive.