The role of nitric oxide in neoplastic transformation of C3H 10T1/2 embryonic fibroblasts.
Nitric oxide synthase inhibitors block the neoplastic transformation of C3H 10T1/2 cells in vitro. Evidence presented herein suggests that they mediate their effects early in the carcinogenic process as brief treatment with the NOS inhibitor aminoguanidine (AG) during log phase cell growth (initiation phase) is sufficient to block foci formation. In contrast, treatment initiated after formation of a confluent monolayer was associated with diminished protection, while treatment commencing late in the promotional phase had no protective effect and appeared to enhance the number and stage of foci observed. These findings suggest that while AG treatment can inhibit transformation during the early promotional phase, it most effectively inhibits transformation during the initiation phase. In general AG enhanced growth of both normal and tumor cells, suggesting that effects on growth were unrelated to its anti-transformation properties, however, these effects could be related to the effect on tumor cell stage noted above. Although induction of inducible nitric oxide synthase (iNOS) by treatment with LI during the last 2 weeks of the assay was associated with enhanced transformation, the efficacy of AG in protecting against transformation was not clearly associated with substantial reductions in NO synthesis. The data suggest that AG inhibits transformation early in the transformation process independently of iNOS inhibition and that AG may have deleterious effects late in the process, possibly through stimulation of tumor cell growth.
Burnett
T
T
University of Hawaii Cancer Research Center, 1236 Lauhala Street, Honolulu, HI 96813, USA.
Pung
A
A
Bertram
J S
JS
Cooney
R V
RV
D000588:Amines / Q000378:metabolism; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006146:Guanidines / Q000494:pharmacology; D007371:Interferon-gamma / Q000633:toxicity; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D009153:Mutagens / Q000633:toxicity; D009374:Neoplasms, Experimental / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology* / Q000633:toxicity; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D015538:Nitrosation / Q000187:drug effects
D000588:Amines; D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D009153:Mutagens; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine