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Inhibitors of endogenous nitrogen oxide formation block the promotion of neoplastic transformation in C3H 10T1/2 fibroblasts
Molecular Oncology Program, Cancer Research Center of Hawaii, University of Hawaii at Manoa 1236 Lauhala Street, Honolulu, HI 96813, USA
The endogenous production of nitric oxide (NO) and its role in the neoplastic transformation of C3H 10T1/2 mouse fibroblasts were investigated. NO production, as indicated by NO2
in the culture medium, was increased in cells initiated with 3-methylcholanthrene or stimulated with the combination of interferon-
(IFN, 10 ng/ml) plus bacterial lipopoly-saccharide (LPS, 1 µg/ml). NO2- was detectable within 24–48 h of IFN/LPS treatment and accumulated to micromolar concentrations within 4 days. NO production was inhibited in a dose-dependent manner by analogs of L-arginine in which the terminal guanidino nitrogen is blocked, consistent with NO production by the oxidative deamination of L-arginine by nitric oxide synthase (NOS). IFN/LPS-stimulated cells expressed a 4.4 kb mRNA which hybridized to a probe for the mouse macrophage-inducible NOS. Expression of the rat cerebellar constitutive NOS was not detected in these cells. Arginine analogs added to the culture medium during the post-confluence promotional stages of the C3H 10T1/2 transformation assay blocked the formation of transformed foci in a dose-dependent manner comparable to their inhibition of NO production. These data demonstrate that C3H 10T1/2 mouse fibroblasts are a useful model for the study of the effects of endogenous NO production in carcinogenesis and suggest that NO plays a significant role in the promotional phase of neoplastic transformation of these cells.
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