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Generation of Tumor Cells with Reduced DNA Content as a Result of Macrophage Tumoricidal Activity¹

Departments of Surgery and Microbiology, Medical College of Virginia, and MCV/VCU Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298

Inoculation of pyran or Corynebacterium parvum i.p. in mice with Ehrlich ascites (EA) tumor cells induced a dramatic reduction in the EA tumor content of the peritoneal exudate. Cell cycle analysis of peritoneal exudate cell DNA content revealed that cells from untreated tumor-bearing mice possessed a DNA content approximately 4C to 8C, characteristic of aneuploid EA cells, while the pyran- or C. parvum-treated animals had a larger complement of cells with a 2C DNA content and a loss of cells with an 8C DNA content. To determine what percentage of the 2C population was EA cells, the phenotype of the peritoneal exudate cell population was analyzed by indirect immunofluorescence with anti-host H-2 antisera. Since the EA cells lacked host H-2 markers, after accounting for the 2C H-2-positive host cells, we demonstrated that, in pyran- or C. parvum-treated EA-bearing mice, 11 to 53% of the 2C population was EA cells possessing approximately half their normal complement of DNA. Therefore, the tumoricidal activity of pyran- or C. parvum-activated macrophages might be due in part to their ability to cause the formation of tumor cells with a reduced content of DNA. In other experiments in vivo, thioglycollate injection failed to elicit tumoricidal activity, as did pyran injection into mice previously irradiated or given injections of silica, suggesting that tumoricidal activity was mediated by macrophages. The proposed activated macrophage-mediated tumoricidal events demonstrated in vivo were substantiated by studies in vitro showing a direct relationship between the cytotoxic properties of C. parvum-activated macrophages and their ability to induce tumor cells with a reduced DNA content, as well as a shift from G₂-M to G₁ in the remaining aneuploid tumor cells. We suggest that induction of tumor cells with a reduced content of DNA is a possible mechanism or consequence of activated macrophage tumoricidal activity.

¹ This study was supported in part by Grants CA 28308 and AI 15612 from the USPHS.

² Recipient of a postdoctoral fellowship (CA 06648) from the National Cancer Institute.

³ To whom requests for reprints should be addressed. Present address: Department of Medical Microbiology and Immunology, University of Kentucky School of Medicine, Lexington, KY. 40536.

Received 6/17/81. Accepted 3/10/82.