Active oxygen transforms murine myeloid progenitor cells in vitro

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Abstract
Active oxygen (AO) is ubiquitous in nature and its many forms can act as natural carcinogens. Their effect on the transformation of a mouse myeloid progenitor cell line was studied using anchorage-independent colony formation in methylcellulose as the primary assay. Both cytotoxic and non-toxic concentrations of t-butylhydroperoxide, hydrogen peroxide and menadione were examined. At non-cytotoxic concentrations, no AO transformation of these cells from interleukin-3 dependence to factor independence (FI) was observed, even after as many as 25 treatments. At cytotoxic concentrations, however, all 3 classes of AO transformed the cells to FI growth. The most potent agent was t-butyl hydroperoxide (43-fold induction), followed by hydrogen peroxide and then menadione. As little as one exposure to cytotoxic levels of these oxidants induced significant transformation, with relative potencies the same as those observed for multiple exposures. These inductions were not due to general cytotoxic effects, since sodium fluoride and heat-shock treatment gave minimal inductions. AO-induced colonies in methylcellulose that were removed, examined and then injected into pre-irradiated mice uniformly produced tumors. Control, non-treated cells did not form tumors. Tumorigenic cells did not form colonies in methylcellulose at lower plating densities. Furthermore, low numbers of transformed cells supplemented to high density with normal cells showed a small but insufficient increase in colony number as compared with high-density cultures of transformed cells. Our results suggest that the transformants depend upon a paracrine mechanism of growth that is mediated by the transformed cells. Studies on selected factor-dependent cell lines and antibodies to interleukin-3, interleukin-4, granulocyte-macrophage- and macrophage-colony stimulating factors, suggest that this putative paracrine factor is unique.