Is Monitoring of the Intracellular Active Metabolite Levels of Nucleobase and Nucleoside Analogs Ready for Precision Medicine Applications?

Nucleobase and nucleoside analogs (NAs) play important roles in cancer therapy. Although there are obvious individual differences in NA treatments, most NAs lack direct relationships between their plasma concentration and efficacy or adverse effects. Accumulating evidence suggests that the intracellular active metabolite levels of NAs predict patient outcomes. This article reviewed the relationships between NA intracellular active metabolite levels and their efficacy or adverse effects. The factors affecting the formation of intracellular active metabolites and combination regimens that elevate intracellular active metabolite levels were also reviewed. Given the mechanism of NA cytotoxicity, NA intracellular active metabolite levels may be predictive of clinical outcomes. Many clinical studies support this hypothesis. Therefore, the monitoring of intracellular active metabolite levels is beneficial for individualized NA treatment. However, to perform clinical monitoring in practice, well-designed studies are needed to explore the optimal threshold or range and the appropriate regimen adjustment strategies based on these parameters.