title: Membrane-bound form of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy in a model of hepatocellular carcinoma.
abstract: Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monocyte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P<0.01). The numbers of Mac-1-, CD4- and CD8a-positive cells were significantly higher in tumor tissues (P<0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC.
authors.affiliation: Department of Disease Control and Homeostasis, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Marukawa
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamoto
authors.forename: K
authors.initials: K
authors.lastname: Kakinoki
authors.forename: T
authors.initials: T
authors.lastname: Tsuchiyama
authors.forename: N
authors.initials: N
authors.lastname: Iida
authors.forename: T
authors.initials: T
authors.lastname: Kagaya
authors.forename: Y
authors.initials: Y
authors.lastname: Sakai
authors.forename: M
authors.initials: M
authors.lastname: Naito
authors.forename: N
authors.initials: N
authors.lastname: Mukaida
authors.forename: S
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015774:Ganciclovir / Q000493:pharmacokinetics / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D006561:Herpes Simplex / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; D013937:Thymidine Kinase; D015774:Ganciclovir