Histopathology and host response associated with reduced tumorigenicity of 5-bromodeoxyuridine--treated murine...

Growth of B16 murine melanoma cells (clone B559) with low concentrations of 5-bromodeoxyuridine (BrdUrd) has previously been shown to have little effect upon cell proliferation in culture but to significantly reduce the tumorigenicity of the cells when they are injected into adult syngeneic mice. To determine the fate of BrdUrd-grown cells in vivo, we compared the sites of injection of control, fully tumorigenic B559 cells, and BrdUrd-grown cells (3 micrograms/ml for 3 days, termed 3BRM cells) with greatly reduced tumorigenicity (only 8%). We found no evidence of even a transitory period of progressive growth in vivo of BrdUrd-grown cells. At sites of injection of 3BRM cells, as early as Day 1 after injection, there was a significantly lower proliferation rate of the melanoma cells, significantly greater numbers of infiltrating host mononuclear cells, and a significantly higher ratio of host mononuclear to melanoma cells. There was no evidence of endothelial cell proliferation or neovascularization at the sites of 3BRM cells. When sites of injection at 1 day after injection were examined electron-microscopically, evidence of host melanoma cell interactions was more frequently observed at sites of 3BRM cells. The results suggest that the reduced tumorigenicity of BrdUrd-grown melanoma cells may be due to cytostatic and/or cytotoxic influences generated by an enhanced mononuclear cell response. Because the host response occurs so quickly, the involvement of natural killer cells is postulated.