A Novel Suicide System for Human Cancer Gene Therapy

Ling Chen

《Journal of Genetics and Molecular Biology》 13卷1期 (2002/03) Pp. 50-51

https://doi.org/10.30047/JGMB.200203.0009

並列摘要

Gene therapy is emerging as a promising strategy for cancer treatment. One approach is the transfer of a ”suicide” gene encoding a prodrug activation enzyme into tumor cells so that the tumor can convert the prodrug into its toxic form for their own killing. The commonly used anticancer drug cyclophosphamide (CPA, also named Cytoxan) is an alkylating agent that requires bioactivation in liver by cytochrome P450(CYP) enzymes. The therapeutic efficacy of CPA is limited by the toxicity that associates with systemic distribution of liver-activated drug metabolites. Since tumor cells do not have the P450enzymes to activate CM, we first demonstrated that transduction of tumor cells with CYP2B 1 gene, a major catalyst of CPA activation, can dramatically sensitize tumor cells to the prodrug CPA in vitro and in vivo. CYP2B I-expressing tumor cells in the presence of CPA exert a potent “bystander killing” effect on the nearby tumor cells. This “bystander killing” effect does not require direct cell-cell contact. Subsequently, we discovered that co-transfer of P450 reductase gene with CYP2B I further enhance the prodrug activation and tumor killing. The P450/CPA-based suicide system provides a paradigm of molecular chemotherapy for cancer. The strategy of enhancing the selectivity and effectiveness of conventional anticancer agents is highly practical at the current stage of gene therapy development.