The Pharmacogenomics of Vincristine-Induced Neuropathy

Thevincaalkaloidvincristinehasbeenanessential componentof the treatmentofpediatric acute lymphoblastic leukemia (ALL) since combination chemotherapy first came into widespread use in the 1960s.Becausevincristinehas robust activity against both solid tumors and other malignant conditions, and because its lack of myelosuppression makes it suitable for combining at full doses with othermyelosuppressive drugs, vincristine remains one of themost widely used anticancer agents. However, the neurotoxic effects of vincristine (andothermicrotubule-targetingagents), includingboth sensory andmotorperipheral neuropathies, continue tohaveamajor impact onour ability todeliver vincristine at fully effectivedoses and dose intensities. A pharmacogenomic explanation of susceptibility to vincristine neurotoxicity would offer the potential for individualized dosing,which in turnmight improve outcomes. A number of genes implicated in various aspects of vincristine metabolism have been evaluated for an association with neurotoxic effects. One particular gene of interest is CYP3A5. Egbelakin et al1 performed CYP3A5 JAMA