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Improvement of Antitumor Activity by Gene Amplification with a Replicating but Nondisseminating Adenovirus

¹ Groupe de Vecteurs de Génomique et Thérapie Génique, Biotechnology Research Institute, National Research Council; Departments of ² Experimental Medicine and ³ Neurology and Neurosurgery, McGill University; ⁴ Montreal Neurological Institute; ⁵ Centre de recherche du CHUM/Institut du cancer de Montréal, Département de médecine and ⁶ Département de Microbiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montreal, Quebec, Canada; and ⁷ Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada

Requests for reprints: Bernard Massie, Biotechnology Research Institute, National Research Council, 6100 Royalmount, Montreal, QC, Canada H4P 2R2. Phone: 514-496-6131; Fax: 514-496-5143; E-mail: bernard.massie{at}cnrc-nrc.gc.ca or Josephine Nalbantoglu, Montreal Neurological Institute, 3801 University Street, Montreal, QC, Canada H3A 2B4. Phone: 514-398-5920; Fax: 514-398-7371; E-mail: josephine.nalbantoglu{at}mcgill.ca.

Gene therapy is a promising approach for cancer treatment; however, efficacy of current vectors remains insufficient. To improve the success of suicide gene therapy, we constructed a replication-competent adenoviral vector that has its protease gene deleted and expresses bacterial cytosine deaminase fused with bacterial uracil phosphoribosyltransferase (CU). The prodrug, 5-fluorocytosine, is transformed into the highly toxic and tissue-diffusible 5-fluorouracil by CU in infected cells. This vector is incapable of producing infectious particles but is able to undergo a single round of replication, thereby increasing transgene copy number and expression. In the presence of 5-FC, compared with the first-generation vector (AdCU), the replication-competent vector, Ad(dPS)CU-IRES-E1A, was significantly more efficacious for in vitro tumor cell killing and in bystander assays, whereas 25-fold fewer viral particles were required in a three-dimensional spheroid model. For in vivo experiments, in which virus was injected into preestablished intracranial glioma xenografts, followed by 5-FC treatment, mice receiving Ad(dPS)CU-IRES-E1A had significantly smaller tumors at 35 days postinjection as well as significantly longer median survival than mice treated with the replication-deficient, protease-deleted vector [Ad(dPS)CU]. In an immunocompetent syngeneic model, Ad(dPS)CU + 5-FC–treated mice had a median survival of only 23 days, whereas Ad(dPS)CU-IRES-E1A + 5-FC–treated animals had a survival of 57.1% at 365 days. In conclusion, Ad(dPS)CU-IRES-E1A in the presence of 5-FC produces more potent tumoricidal effects than its replication-deficient counterparts. [Cancer Res 2007;67(7):3387–95]