Macrophage-mediated induction of drug-resistant variants in a mouse mammary tumor cell line.
The ability of macrophages to induce drug-resistant variants was studied in an in vitro macrophage-tumor cell coculture system utilizing the hypoxanthine-guanine phosphoribosyl transferase locus as measured by resistance to 6-thioguanine. Tumor cells of mouse mammary tumor line 66 were sensitive to macrophage induction of thioguanine resistance as shown by an increase in the frequency of thioguanine-resistant variants which arose following macrophage coculture to levels at least 5- to 10-fold above the spontaneous frequency. Detection of increased numbers of variants depended upon the macrophage:tumor cell ratio, with 50:1 or greater being necessary. The activity of the macrophages was dependent upon their activation stage. The induction of drug-resistant variants could be inhibited by oxygen radical scavengers. The basis for the emergence of thioguanine-resistant cells appeared to be induction of new variants rather than selection of preexisting resistant cells from the parental population, since thioguanine-sensitive and -resistant cells were equally sensitive to macrophage-mediated toxicity. In six of the six macrophage-induced variants tested, resistance was associated with loss of hypoxanthine-guanine phosphoribosyl transferase activity. The reverse variation frequency at the hypoxanthine-guanine phosphoribosyl transferase locus in five macrophage-induced variants was low and similar to that of a stable ethyl methanesulfonate-induced, thioguanine-resistant line. Macrophages isolated directly from growing mammary tumors, as well as activated peritoneal macrophages, were capable of inducing thioguanine resistance in line 66 cells.
Yamashina
K
K
Miller
B E
BE
Heppner
G H
GH
D000818:Animals; D002374:Catalase / Q000378:metabolism; D004351:Drug Resistance; D005609:Free Radicals; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000503:physiopathology*; D008353:Mannitol / Q000378:metabolism; D051379:Mice; D009154:Mutation; D013482:Superoxide Dismutase / Q000378:metabolism; D013866:Thioguanine / Q000494:pharmacology
D005609:Free Radicals; D008353:Mannitol; D002374:Catalase; D013482:Superoxide Dismutase; D007041:Hypoxanthine Phosphoribosyltransferase; D013866:Thioguanine