SYNERGISTIC ANTITUMOR INTERACTION OF HUMAN MONOCYTE CHEMOTACTANT PROTEIN-1 GENE-TRANSFER AND MODULATOR FOR TUMOR-INFILTRATING MACROPHAGES

Purpose. In order to evaluate the possibility of synergistic antitumor gene therapy by the gene delivery of monocyte chemotactant protein-1 (MCP-1/MCAF/IE), the effect of a biological response modulater for mac rophages on tumor progression of gene transfected tumor cells was stud ied. Methods, Cachexia-inducing adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid or MCP-1 cDNA. Results. The production of MCP-1 reached 70-80 ng/ml in vitro wh en transfectant cells were cultured at a cell density of 1 x 10(5) cel ls/ml for 3 days. Transfection of MCP-1 cDNA did not affect the growth rate in vitro. Also, MCP-1-transfectants formed tumors after intra-fo otpad inoculation similar in size to the parental cells. The number of infiltrating macrophages in the primary tumor of the transfectant rap idly increased from the 3rd to 5th day after inoculation as revealed b y immunohistochemical staining using an antibody against mouse macroph ages. An earlier, greater, but no longer-lasting increase in tumor-inf iltrating macrophages was induced in tumors by MCP-1 transfection was compared to that induced by the parent cells. On the 10th day after th e inoculation, the tumor-infiltrating macrophages in mice inoculated M CP-1 transfectants were decreased to a level similar to that of the pa rent cells. Groups of mice were treated intraperitoneally with LPS at different times after the inoculation. Tumor cells producing high leve ls of MCP-1 were significantly lysed by macrophages treated with LPS, whereas parental or control transfected cells were not. Conclusions. C ombination immunotherapy can provide a rationale for the application o f MCP-1 treatment to increase immunological responses to cancer.