Abstract
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 alpha,gamma-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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenoviridae / genetics
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Carbon-Sulfur Lyases / genetics*
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Carbon-Sulfur Lyases / metabolism
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Cytochrome c Group / metabolism
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Female
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Genetic Therapy / methods*
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Humans
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Liver Neoplasms, Experimental / pathology
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Liver Neoplasms, Experimental / therapy
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Methanol / analogs & derivatives
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Methanol / pharmacokinetics
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Methanol / pharmacology
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Mice
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Mice, Nude
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Mitochondria / drug effects
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Mitochondria / metabolism
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Organoselenium Compounds / pharmacokinetics
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Organoselenium Compounds / pharmacology
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Oxidative Stress / drug effects
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Prodrugs / pharmacokinetics*
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Prodrugs / pharmacology
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Rats
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Selenomethionine / pharmacokinetics*
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Selenomethionine / pharmacology
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Cytochrome c Group
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Organoselenium Compounds
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Prodrugs
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methaneselenol
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Selenomethionine
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Carbon-Sulfur Lyases
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L-methionine gamma-lyase
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Methanol