Methioninase cancer gene therapy with selenomethionine as suicide prodrug substrate.
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.
Miki
K
K
AntiCancer Incorporated, San Diego, California 92111, USA.
Xu
M
M
Gupta
A
A
Ba
Y
Y
Tan
Y
Y
Al-Refaie
W
W
Bouvet
M
M
Makuuchi
M
M
Moossa
A R
AR
Hoffman
R M
RM
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D013437:Carbon-Sulfur Lyases / Q000235:genetics* / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D000432:Methanol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D016566:Organoselenium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D012645:Selenomethionine / Q000493:pharmacokinetics* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D003574:Cytochrome c Group; D016566:Organoselenium Compounds; D011355:Prodrugs; C019003:methaneselenol; D012645:Selenomethionine; D013437:Carbon-Sulfur Lyases; C021558:L-methionine gamma-lyase; D000432:Methanol