Tumor-specific transcriptional targeting of suicide gene therapy

• Published in: Gene therapy Vol. 9; no. 3; pp. 168 - 175
• Main Authors: QIAO, J, DOUBROVIN, M, WOOL, S. L. C, SAUTER, B. V, HUANG, Y, GUO, Z. S, BALATONI, J, AKHURST, T, BLASBERG, R. G, TJUVAJEV, J. G, CHEN, S-H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.02.2002
• Subjects: Adenoviridae - genetics; Adenoviruses; Animals; Antitumor activity; Biological and medical sciences; Breast Neoplasms - therapy; Carcinoembryonic antigen; Carcinoembryonic Antigen - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene Targeting - methods; Gene therapy; Genetic Therapy - methods; Genetic Vectors - administration & dosage; HeLa Cells; Herpes simplex; Herpes Simplex Virus Protein Vmw65 - genetics; Humans; Injection; Injections, Intralesional; Intravenous administration; Kinases; Liver; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Metastases; Mice; Mice, Inbred BALB C; Molecular and cellular biology; Nucleoside analogs; Promoter Regions, Genetic; Radioactivity; Retroviruses, Simian - enzymology; Simplexvirus - enzymology; Suicide; Suicide genes; Thymidine; Thymidine kinase; Thymidine Kinase - genetics; TK gene; Toxicity; Transcription; Transcription, Genetic; Tumor Cells, Cultured; Tumors; Tumor; Specificity; Targeting; Transcription; Suicide gene; Gene therapy
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3301618

Transcriptional targeting of gene expression has been plagued by the weakness of tissue-specific promoters. Thus, to increase promoter strength while maintaining tissue specificity, we constructed a recombinant adenovirus containing a binary promoter system with a tumor-specific promoter (CEA; carcinoembryonic antigen) driving a transcription transactivator, which then activates a minimal promoter to express a suicide gene (HSV-tk; herpes simplex virus thymidine kinase). This ADV/binary-tk induced equal or greater cell killing in a CEA-specific manner in vitro compared with the CEA-independent killing of a vector with a constitutive viral promoter driving HSV-tk (ADV/RSV-tk). To monitor adenovirus-mediated HSV-tk gene expression in vivo, we employed noninvasive nuclear imaging using a radioiodinated nucleoside analog ([((1)31)I]-FIAU) serving as a substrate for HSV-tk. [((1)31)I]-FIAU-derived radioactivity accumulated after intratumoral injection of ADV/binary-tk only in the area of CEA-positive tumors with significantly less spread to the adjacent liver tissue than after administration of the universally expressed ADV/RSV-tk. Both viruses exhibited similar antitumor efficacy upon injection of liver metastases. Importantly, in vivo dose escalation studies demonstrated significantly reduced toxicity after intravenous administration of ADV/binary-tk versus ADV/RSV-tk. In summary, the increased therapeutic index of this novel, amplified CEA-driven suicide gene therapy vector is a proof of principle for the powerful enhancement of a weak tissue-specific promoter for effective tumor restricted gene expression.