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Host Interactions in the Effects of 5-Fluorouracil on Ehrlich Ascites Tumor Cells¹

Departments of Surgery [K. M. C.], Pharmacology [R. D. A.], and Medicine [R. B. D.], Medical College of Virginia, Richmond, Virginia 23298, and Department of Medical Microbiology and Immunology [A. M. K.], University of Kentucky School of Medicine, Lexington, Kentucky 40536

5-Fluorouracil (5-FUra) inoculated i.p. into Ehrlich ascites tumor (EATU)-bearing mice inhibited in vivo tumor cell proliferation and generated a population of EATU cells with half their normal content of DNA. The appearance of aberrant (approximately 2C) EATU cells from a normally aneuploid (approximately 4C) tumor cell line appeared to require a radiosensitive host cell population, since prior irradiation of animals later given injections of 5-FUra and EATU cells resulted in significantly fewer 2C tumor cells when compared with unirradiated tumor bearers. In contrast, when EATU cells were pulsed with 5-FUra and cultured in vitro, no 2C peak could be detected. Furthermore, results from adoptive transfer experiments showed that EATU cells incubated in vitro with 5-FUra gave rise to far fewer aberrant 2C EATU cells when injected into irradiated, as compared to normal, animals. Cell cycle analyses of peritoneal exudate cells from irradiated and normal 5-FUra-treated EATU bearers showed that, in addition to possessing few or no 2C tumor cells of reduced DNA content, irradiated animals possessed, within the remaining aneuploid EATU population, a high percentage of cells in the G₂-M phase. Therefore, in 5-FUra-treated EATU bearers, a host cell population appeared to be necessary for the tumoricidal induction of 2C tumor cells as well as the inhibition of proliferating G₂-M cells within the remaining population of aneuploid tumor cells. Further experiments are being conducted to confirm preliminary observations of macrophage-mediated host cell participation in the generation of tumor cells of reduced ploidy and in the alteration in the cell cycle distribution of the surviving tumor cells. Generation of tumor cells of reduced ploidy may be the cause or the result of a host-mediated tumoricidal mechanism.

¹ This study was supported in part by Grants RO1CA 28308 and CA23412 from the USPHS and a grant from the National Foundation for Cancer Research.

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

³ To whom requests for reprints should be addressed.

Received 2/16/82. Accepted 9/ 1/82.