Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate

In this study, we report a novel approach to gene-directed enzyme prodrug t herapy for cancer. This gene therapy strategy exploits the toxic pro-oxidan t property of methylselenol, which is released from selenomethionine (SeMET ) by cancer cells with the adenoviral-delivered methionine alpha,gamma -lya se (METE) gene cloned from Pseudomonas putida. In MET-transduced tumor cell s, the cytotoxicity of SeMET is increased up to 1000-fold compared with non transduced cells. A strong bystander effect occurred because of methylselen ol release from MET gene-transduced cells and uptake by surrounding tumor c ells. Methylselenol damaged the mitochondria via oxidative stress and cause d cytochrome c release into the cytosol, thereby activating the caspase cas cade and apoptosis. Adenoviral MET-gene/SeMET treatment also inhibited tumo r growth in rodents and significantly prolonged their survival. Recombinant adenovirus-encoding MET gene-SeMET treatment thereby offers a new paradigm for cancer gene therapy.