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Designing cytochrome P450 enzymes for use in cancer gene therapy
Saskya E Carrera-Pacheco1, Alexander Mueller1, Juan A Puente-Pineda1
1Centro de Investigación Biomédica (CENBIO), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador.
Abstract:
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.
Insights
Engineered Cytochrome P450 (CYP) enzymes offer a promising approach in cancer gene therapy. Gene-directed enzyme prodrug therapy (GDEPT) utilizes these modified enzymes to activate chemotherapy drugs specifically within cancer cells, enhancing treatment efficacy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Cancer poses a significant global health and economic challenge, with millions of deaths annually.
- Gene therapy advancements are transforming cancer treatment strategies.
- Gene-directed enzyme prodrug therapy (GDEPT) is an emerging approach for targeted cancer treatment.
Purpose of the Study:
- To compile genetic modifications of Cytochrome P450 (CYP) enzymes for enhanced cancer gene therapy.
- To review the potential of engineered CYP enzymes in GDEPT.
- To discuss challenges and future directions in CYP-based GDEPT.
Main Methods:
- Genetic engineering of CYP enzymes using rational design, directed evolution, and phylogenetic methods.
- Review of preclinical and clinical trials involving engineered CYP enzymes for GDEPT.
- Compilation of genetic modifications aimed at improving therapeutic gene efficiency.
Main Results:
- Engineered CYP enzymes can be tailored to efficiently bio-activate various chemotherapeutic prodrugs.
- GDEPT utilizing engineered CYP enzymes shows promise in preclinical and clinical settings.
- Genetic modifications enhance CYP enzyme activity for targeted cancer cell elimination.
Conclusions:
- Engineered CYP enzymes represent a powerful tool for advancing GDEPT in cancer gene therapy.
- Optimized CYP enzymes can improve prodrug conversion, increase therapeutic efficacy, and minimize chemotherapy side effects.
- Further research into challenges and limitations will guide the future development of CYP-based GDEPT.
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