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Methioninase Cancer Gene Therapy with Selenomethionine as Suicide Prodrug Substrate¹

AntiCancer Incorporated, San Diego, California 92111 [K. M., M. X., A. G., Y. B., Y. T., W. A-R., R. M. H.]; Department of Surgery, University of California at San Diego, San Diego, California 92103-8220 [K. M., A. G., W. A-R., M. B., A. R. M., R. M. H.]; and Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan 113-8655 [K. M., M. M.]

In this study, we report a novel approach to gene-directed enzyme prodrug therapy for cancer. This gene therapy strategy exploits the toxic pro-oxidant property of methylselenol, which is released from selenomethionine (SeMET) by cancer cells with the adenoviral-delivered methionine ,-lyase (MET) gene cloned from Pseudomonas putida. In MET-transduced tumor cells, the cytotoxicity of SeMET is increased up to 1000-fold compared with nontransduced cells. A strong bystander effect occurred because of methylselenol release from MET gene-transduced cells and uptake by surrounding tumor cells. Methylselenol damaged the mitochondria via oxidative stress and caused cytochrome c release into the cytosol, thereby activating the caspase cascade and apoptosis. Adenoviral MET-gene/SeMET treatment also inhibited tumor growth in rodents and significantly prolonged their survival. Recombinant adenovirus-encoding MET gene-SeMET treatment thereby offers a new paradigm for cancer gene therapy.

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