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    • These results from the present study are summarized in Table

    2022-11-18

    These results from the present study are summarized in Table 1. Eight drugs (doxorubicin, epirubicin, daunorubicin, idarubicin, irinotecan, imatinib, sunitinib and gefitinib) inhibited 5-HT-induced 5-HT3A and 5-HT3AB currents; three (irinotecan, topotecan and mitoxantrone) showed different responses depending on the 5-HT3B subunit, and one (mitoxantrone) showed a bell-shaped dose-response curve. Surprisingly, 28% of the drugs examined in the present study modified the 5-HT current, acting mainly as 5-HT3 receptor antagonists. To predict the activity of the antagonist, we focused on molecular weight as a predictor of the affinity of a molecule to fit the binding pocket of a receptor (Kim and Skolnick, 2008). The mean molecular weight of the drugs that modified the 5-HT current was 493.87 ± 20.66, whereas the molecular weights of most remaining drugs were higher or lower than this (Fig. 4).
    Discussion We have reported here that 28% of the 35 anticancer drugs we tested modulated 5-HT-induced 5-HT3 receptor currents, and that none acted as a 5-HT3 receptor agonist. Sunitinib, irinotecan, idarubicin, imatinib, doxorubicin, epirubicin, daunorubicin and gefitinib were 5-HT3A and 5-HT3AB receptor antagonists. Topotecan inhibited the 5-HT3A receptor current, and potentiated that of the 5-HT3AB receptor. Mitoxantrone potentiated the 5-HT3AB receptor current at low doses and inhibited 5-HT3A and 5-HT3AB at high doses. Importantly, irinotecan, imatinib, doxorubicin, epirubicin and mitoxantrone, which all inhibited the 5-HT-induced current through the 5-HT3A receptor with IC50s of 6.76, 9.76, 11.93, 12.98, and 11.50µM, respectively, in the presence of 2µM 5-HT (Table 3), are known to have comparatively high rotenone concentrations in cancer patients (Buitenkamp et al., 2010, Tjuljandin et al., 1990). Intravenous infusion of 100–750mg/m2 irinotecan to cancer patients results in a plasma Cmax of 3–27µM (Abigerges et al., 1995). Oral imatinib at doses of 260–570mg/m2 results in a plasma Cmax of 6–14µM (Champagne et al., 2004). After intravenous infusion of 30mg/m2 doxorubicin in patients with peripheral T-cell lymphomas, the Cmax in plasma is approximately 17µM (Fan et al., 2011). While plasma concentrations for various anticancer agents may indeed be sufficient to modulate the 5-HT3 receptor current (Table 3) (Buitenkamp et al., 2010, Champagne et al., 2004, Fan et al., 2011, Sparreboom et al., 2004), the concentration in tissues may not be. Several paper reported that some anticancer drugs tend to accumulate in tissues, including in the intestinal wall (Chen et al., 2015, Fujiwara, 2011, Looby et al., 1997). All of these studies used rats or mice. Although the accumulation of anticancer drugs in rodent experiment can not apply to human cancer patients, local concentrations of these drugs could affect 5-HT3 receptor. Among anticancer drugs categorized as ‘high emetic risk’, cisplatin is the most studied with regard to the mechanism of nausea and vomiting via the 5-HT3 receptor. Anticancer drugs such as cisplatin form free radicals that are associated with anticancer action (Torii et al., 1993). These free radicals stimulate enterochromaffin cells in the intestine, followed by release of an enormous amount of 5-HT, which stimulates 5-HT3 receptors on vagal afferent nerves to cause emesis (Andrews et al., 1988). In the present study, anticancer drugs categorized as high emetic risk did not inhibit 5-HT3 receptor current. However, anticancer drugs that modified 5-HT3 receptor current did not fall in the minimal emetic risk category alone. Importantly, 5-HT3 receptor antagonists mainly control the severity of acute chemotherapy-induced nausea and vomiting, not delayed effects (Kris et al., 2006, Kris et al., 1994, Rudd et al., 1994). Current standard of care for highly emetic chemotherapy associated with delayed nausea and vomiting is triple/quadruple (5-HT3 receptor agonist + neurokinin 1 receptor agonist + dexamethasone ± olanzapine) by MASCC and ESMO guideline and ASCO guideline for antiemetics in oncology (Hesketh et al., 2017, Roila et al., 2016), indicating that anticancer drugs having the properties of a 5-HT3 receptor antagonist cannot inhibit delayed emesis. Emetic risk (Table 1) is calculated according to criteria established by the MASCC and ESMO guideline (Roila et al., 2010), which focus on both acute and delayed nausea and vomiting. This may partly explain the present results showing that the drugs acting as 5-HT3 receptor antagonists are not only classified as minimal emetic risk. However, we question whether these drugs would have been highly emetic if it had not been for their inhibition of 5-HT3 receptor current. Several studies have shown that the frequency or severity of nausea and vomiting due to irinotecan (one of the anticancer drugs having the effects of a 5-HT3 antagonist) does not increase proportionally with the concentration, unlike that observed with most other anticancer drugs (Reardon et al., 2011, Rowinsky et al., 1994). This effect might be because high concentrations of irinotecan also inhibit the actions of 5-HT3 receptors.