Mechanism of Macrophage-Mediated Tumor Cell Cytotoxicity

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Abstract
Activated macrophages inhibit the incorporation of 125IUDR into the DNA of Lewis lung cells and lead to the cytotoxicity of these target tumor cells. Despite this apparent inhibition of DNA synthesis, an early increase in the number of Lewis lung (LL) cells occurs when LL is cultured with activated macrophages. This increase in the number of LL is similar to the increase in LL that occurs when LL is cultured alone or with normal macrophages for the first 18 hr of culture (approximately one doubling of cells). To resolve this apparent paradox of increased cell number without DNA synthesis, the DNA content of LL cells that were cultured with activated macrophages for 16 hr was analyzed by flow microfluorometry. These experiments indicated that subsequent to co-culture with activated macrophages, LL cells with a 50% reduction in their normal DNA content could be detected. Furthermore, after a 2-hr incubation with colcemid a >95% reduction in metaphase cells occurred in LL cells cultured with activated macrophages. However, dividing nuclei without chromosome condensation appeared to be a prominent feature of these cultures. This would suggest that the genotypic or phenotypic program for cell division in the tumor cells is such that under these unique circumstances of tumor cell-activated macrophage interaction, a “reductive” cell division can proceed in the absence of DNA synthesis. We suggest that this aberrant division may be related to the lethal event that leads to activated macrophage-mediated tumor cell cytotoxicity.