RESUMEN
Cancer is a significant global socioeconomic burden, as millions of new cases and deaths occur annually. In 2020, almost 10 million cancer deaths were recorded worldwide. Advancements in cancer gene therapy have revolutionized the landscape of cancer treatment. An approach with promising potential for cancer gene therapy is introducing genes to cancer cells that encode for chemotherapy prodrug metabolizing enzymes, such as Cytochrome P450 (CYP) enzymes, which can contribute to the effective elimination of cancer cells. This can be achieved through gene-directed enzyme prodrug therapy (GDEPT). CYP enzymes can be genetically engineered to improve anticancer prodrug conversion to its active metabolites and to minimize chemotherapy side effects by reducing the prodrug dosage. Rational design, directed evolution, and phylogenetic methods are some approaches to developing tailored CYP enzymes for cancer therapy. Here, we provide a compilation of genetic modifications performed on CYP enzymes aiming to build highly efficient therapeutic genes capable of bio-activating different chemotherapeutic prodrugs. Additionally, this review summarizes promising preclinical and clinical trials highlighting engineered CYP enzymes' potential in GDEPT. Finally, the challenges, limitations, and future directions of using CYP enzymes for GDEPT in cancer gene therapy are discussed.
RESUMEN
Evidence validating the influence of the cytochrome P450 (CYP) 2D6 and 2C19 enzymes genetic polymorphisms in the response to antipsychotics is scarce. We examined the hypothesis that a higher prevalence of CYP2D6 and/or CYP2C19 ultra rapid metabolizers might be found among refractory schizophrenia patients. Three groups were studied: refractory and non-refractory schizophrenia patients, and healthy controls. Participants were genotyped for CYP2D6 and CYP2C19 polymorphisms and classified in metabolic phenotypes. No between-group differences in the distribution of the phenotypes were found. Therefore, our findings do not support the CYPs 2D6 and 2C19 genotyping in the prediction of therapeutic response in schizophrenia.