Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer.
Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is a well-characterized tool for cancer gene therapy; however, it does not yet exhibit sufficient efficacy to cure patients of malignancies. We have reported that adenovirally delivered monocyte chemoattractant protein (MCP)-1 augmented the antitumor effects of the HSV-tk/GCV system in an athymic nude mouse model. The current study, which uses an immunocompetent mouse model of colon cancer, was designed to evaluate the antitumor effects of MCP-1 gene delivery in conjunction with this suicide gene therapy system. Subcutaneous tumor foci were directly transduced with both recombinant adenoviruses (rAds) expressing an HSV-tk gene and either of the MCP-1, CD80 and LacZ genes, followed by GCV administration. The growth of tumors was markedly suppressed by codelivery of HSV-tk and MCP-1 genes, which was exclusively associated with the recruitment of monocytes/macrophages, T helper 1 (Th1) cytokine gene expression and cytotoxic activity of the splenocytes. Furthermore, the antitumor effects were more efficient than that obtained by the combination of HSV-tk and CD80 genes. These results suggest an immunomodulatory effect of MCP-1 in the context of suicide gene therapy of colon cancer via orchestration of innate and acquired immune responses.
Kagaya
T
T
Department of Gastroenterology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Nakamoto
Y
Y
Sakai
Y
Y
Tsuchiyama
T
T
Yagita
H
H
Mukaida
N
N
Kaneko
S
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015774:Ganciclovir / Q000627:therapeutic use*; D015316:Genetic Therapy; D005822:Genetic Vectors; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009368:Neoplasm Transplantation; D018139:Simplexvirus / Q000378:metabolism; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics*
D000998:Antiviral Agents; D018122:B7-1 Antigen; D018932:Chemokine CCL2; D016207:Cytokines; D013937:Thymidine Kinase; D015774:Ganciclovir