Author(s): Shigekazu Sugino aff1 , Piotr K Janicki [*] aff1
5-HT3 receptor; antiemetics; chemotherapy-induced nausea and vomiting; cytochrome P450; genetic variants; neurokinin 1 receptor; pharmacogenetics; single nucleotide polymorphism; substance P
Chemotherapy-induced nausea and vomiting (CINV) remains one of the most uncomfortable and distressing adverse effects observed in patients during cytotoxic chemotherapy [1,2 ]. This adverse event results in expanded care and extension of hospital stay, and thus increases costs for healthcare. Despite appropriate use of antiemetic guidelines, at least 20-30% of patients experience breakthrough nausea and vomiting, secondary to chemotherapy, with highly emetogenic cytotoxic drugs. Increased risk of CINV depends on the type of chemotherapy agents; more than 90% of patients treated with high-risk agents (e.g., cisplatin) experience CINV if no antiemetic drugs are used [1 ].
When cisplatin was introduced to clinical use in the late 1970s [3 ], CINV was a major problem for the patients undergoing cancer treatment. Many physicians used dopamine D2 receptor antagonists as a first choice for antiemetic therapy. High dose (2 mg/kg) metoclopramide was one such agent tried as a treatment for CINV [ 4 ]. However, the clinical significance of D2 receptor antagonists gradually declined as a result of the development of 5-hydroxytryptamine type 3 (5-HT3 ) receptor antagonists [5,6 ]. In the 1990s, ondansetron was introduced to the clinical setting and a few additional 'setrons' were also used for CINV, but 5-HT3 receptor antagonists did not have an appreciable effect on CINV at the delayed phase of chemotherapy, 3-5 days after cisplatin [1,7 ]. Next-generation 5-HT3 (palonosetron) and neurokinin 1 (NK1 , aprepitant) receptor antagonists have recently been developed [8 ]. These drugs are efficient at acting on CINV at the delayed phase of chemotherapy, and have dramatically changed antiemetic therapy for CINV. The established guidelines for management of CINV currently recommend three types of drugs: 5-HT3 receptor antagonists, NK1 receptor antagonists and corticosteroids [2 ].
Mechanisms of CINV & antiemetic regimens
Serotonin and substance P are major neurotransmitters involved in emesis [ 9 ]. Serotonin exerts its effects via multiple serotonergic receptors, one of which, the 5-HT3 receptor, gates an ion channel permeable to monovalent and divalent cations [10 ]. The tachykinin neuropeptides, which include substance P, tachykinin A and tachykinin B, exert their biological effects via NK1 -, NK2 - and NK3 - receptors [11 ]. Although substance P can bind to all tachykinin receptors, it has the highest affinity for the NK1 receptor. Activation of the NK1 receptor can lead to diverse post-receptor signals, such as activation of PLC and adenylate cyclase cascade systems. Further downstream NK1 receptor signaling includes activation of ERK1/2 and PKA cascades [ 12 ]. Both 5-HT3 - and NK1 -receptors are key players in CINV [9 ].
Current antiemetic regimens against CINV are based upon the dogma that, during the acute phase, an emetogenic agent releases serotonin (5-HT 3 ) from the enterochromaffin cells in the gastrointestinal tract, which subsequently stimulates 5-HT3 receptors on vagal afferents to initiate the vomiting...