In Vivo Molecular Chemotherapy and Noninvasive Imaging With an Infectivity-Enhanced Adenovirus

• Published in: JNCI : Journal of the National Cancer Institute 2002-05, Vol.94 (10), p.741-749
• Main Authors: Hemminki, Akseli, Zinn, Kurt R., Liu, Bin, Chaudhuri, Tandra R., Desmond, Renee A., Rogers, Buck E., Barnes, Mack N., Alvarez, Ronald D., Curiel, David T.
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - physiology; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Coxsackie and Adenovirus Receptor-Like Membrane Protein; Diagnostic Imaging - methods; Disease Models, Animal; Female; Genetic Therapy - methods; Genetic Vectors - genetics; Genetic Vectors - physiology; Humans; Medical sciences; Mice; Neoplasm Transplantation; Organ Specificity; Other treatments; Ovarian Neoplasms - diagnosis; Ovarian Neoplasms - genetics; Ovarian Neoplasms - therapy; Ovarian Neoplasms - virology; Radioisotopes; Receptors, Somatostatin - genetics; Receptors, Somatostatin - metabolism; Receptors, Virus - metabolism; Thymidine Kinase - genetics; Thymidine Kinase - therapeutic use; Time Factors; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Treatment. General aspects; Tumor Cells, Cultured; Tumors
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/94.10.741

Background: Adenovirus-based gene therapy is a promising approach to treat advanced cancers that are resistant to other treatments. However, many primary cells lack the requisite coxsackie-adenovirus receptor (CAR), limiting the in vivo efficacy of gene therapy. Recently, a modified adenovirus that is not dependent on CAR expression for infectivity was developed. We used noninvasive imaging to investigate the in vivo antitumor efficacy of gene therapy using this adenovirus in an animal model of ovarian cancer. Methods: The adenoviral vectors RGDTKSSTR (CAR-independent) and AdTKSSTR (CAR-dependent) express herpes simplex virus thymidine kinase (TK) for molecular chemotherapy and the human somatostatin receptor subtype 2 (SSTR) for noninvasive nuclear imaging. Subcutaneous or peritoneal human xenograft ovarian cancers were established from highly aggressive SKOV3.ip1 cells in immune-deficient mice. Adenoviral constructs were infected intratumorally or intraperitoneally once a day for 3 days. Control mice received three injections, one per day, of Ad5Luc1, a CAR-dependent adenoviral vector that includes a luciferase marker gene. The somatostatin analogue 99mTc-P2045 was used for noninvasive in vivo imaging of RGDTKSSTR that was injected into subcutaneous tumors. For mice with peritoneal tumors, survival was compared among the different treatment groups using Kaplan–Meier analysis with the log-rank statistic. All statistical tests were two-sided. Results: Tumor-associated RGDTKSSTR could be detected 15 days after introduction of the vector. In the subcutaneous model, tumors injected with RGDTKSSTR were statistically significantly smaller than those injected with AdTKSSTR (P