This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bourbeau, D. Articles by Massie, B. Search for Related Content PubMed PubMed Citation Articles by Bourbeau, D. Articles by Massie, B.

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]