Adenovirus-mediated GM-CSF gene and cytosine deaminase gene transfer followed by 5-fluorocytosine administration elicit more potent antitumor response in tumor-bearing mice

• Published in: Gene therapy Vol. 5; no. 8; pp. 1130 - 1136
• Main Authors: CAO, X, JU, D. W, TAO, Q, WANG, J, WAN, T, WANG, B. M, ZHANG, W, HAMADA, H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.08.1998
• Subjects: Adenoviridae; Adenovirus; Adenoviruses; Animals; Antimetabolites - therapeutic use; Antitumor activity; Apoptosis; Biological and medical sciences; Biotechnology; CD8 antigen; Colony-stimulating factor; Combined Modality Therapy; Cytokines; Cytosine; Cytosine Deaminase; Cytotoxicity; Cytotoxicity Tests, Immunologic; Dendritic cells; Escherichia coli - enzymology; Female; Flow Cytometry; Flucytosine - therapeutic use; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic Therapy - methods; Genetic Vectors; Granulocyte-macrophage colony-stimulating factor; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Growth inhibition; Health. Pharmaceutical industry; Histocompatibility antigen H-2; Industrial applications and implications. Economical aspects; Lymphocytes T; Major histocompatibility complex; Male; Melanoma; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Nucleoside Deaminases - genetics; Prodrugs - therapeutic use; Suicide; Suicide genes; Transfection; Transfection - methods; Tumor cells; Antineoplastic agent; Adenoviridae; Enzyme; Cytosine deaminase; Cytokine; Rodentia; Melanoma; Suicide gene; Genetic transfer; Virus; Cytosine derivatives; Vertebrata; Mammalia; Gene; Mouse; Hydrolases; Tumor; Combined treatment; Gene therapy; Granulocyte macrophage colony stimulating factor
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/sj.gt.3300727

Antitumor effects of combined transfer of suicide and cytokine genes were investigated in this study. Adenovirus harboring E. coli cytosine deaminase gene (AdCD) and adenovirus harboring murine granulocyte-macrophage colony-stimulating factor gene (AdGMCSF) were used simultaneously for in vivo gene transfer in melanoma-bearing mice. Growth inhibition of established tumors and prolongation of survival period were observed more significantly in tumor-bearing mice after transfection with AdGMCSF and AdCD followed by continuous injection of prodrug 5-fluorocytosine (5FC) when compared with mice treated with control adenovirus AdlacZ/5FC, AdCD/5FC or AdGMCSF alone (P < 0.01). After combined therapy the expression of MHC-I (H-2Db) and B7-1 molecules on freshly isolated tumor cells increased greatly and more dendritic cells and CD8+ T cells infiltrated into the tumor mass. The activity of specific cytotoxic T lymphocytes was also found to be induced more significantly after the combined therapy. Further experiments showed that apoptosis of tumor cells and induction of antitumor immune response might be involved in the mechanisms of the tumor cell killing by the combined therapy. Our results demonstrated that combined transfer of the GM-CSF and CD suicide genes, being able to inhibit the growth of melanoma synergistically and induce specific antitumor immune response efficiently, thus addressing the drawbacks of suicide gene therapy or cytokine gene therapy which were proved to be not satisfactory when used alone, might be of therapeutic potential for gene therapy of cancer.