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Current Gene Therapy
ISSN (Print): 1566-5232
ISSN (Online): 1875-5631
VOLUME: 14
ISSUE: 3
DOI: 10.2174/1566523214666140424152734      Price:  $58









A Suicide Gene Therapy Combining the Improvement of Cyclophosphamide Tumor Cytotoxicity and the Development of an Anti-Tumor Immune Response

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Author(s): Walid Touati, Thi Tran, Johanne Seguin, Monique Diry, Jean-Pierre Flinois, Claude Baillou, Geraldine Lescaille, Francois Andre, Eric Tartour, Francois M. Lemoine, Philippe Beaune and Isabelle de Waziers
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Pages 236-246 (11)
Abstract:
Gene-directed enzyme prodrug therapy (GDEPT) consists in targeted delivery to tumor cells of a suicide gene responsible for in situ conversion of a prodrug into cytotoxic metabolites. One of the major limitations of this strategy in clinical application was the poor prodrug activation capacity of suicide gene. We built a highly efficient suicide gene capable of bioactivating the prodrug cyclophosphamide (CPA) by fusing a CYP2B6 triple mutant with NADPH cytochrome P450 reductase (CYP2B6TM-RED). Expression of this fusion gene via a recombinant lentivirus (LV) vector converted resistant human (A549) and murine (TC1) pulmonary cell lines into CPA-susceptible cell lines. We tested the efficiency of our GDEPT strategy in C57Bl/6 immunocompetent mice, using TC1 cells expressing the HPV-16 E6/E7 oncoproteins. In mice bearing tumors composed only of TC1-CYP2B6TM-RED cells, four CPA injections (140 mg/Kg once a week) completely eradicated the tumors for more than two months. Tumors having only 25% of TC1-CYP2B6TM-RED cells were also completely eradicated by five CPA injections, demonstrating a major in vivo bystander effect. Moreover, surviving mice were rechallenged with parental TC1 cells. The tumors regressed spontaneously 7 days after cell inoculation or grew more slowly than in control naive mice due to a strong immune response mediated by anti-E7CD8+T cells. These data suggest that combining the CYPB6TM-RED gene with CPA may hold promise as a highly effective treatment for solid tumors in humans.
Keywords:
Cytochrome P450 2B6, lentivirus, cyclophosphamide, lung cancer.
Affiliation:
INSERM UMR-S1147, 45 rue des Saints Peres, 75006 Paris, France.