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12-O-Tetradecanoylphorbol 13-acetate (TPA), a known tumor promoter, enhances the morphologic transformation of Syrian hamster embryo cells induced by low transforming concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) (0.025-0.1 microgram/ml) without potentiation of cell lethality or of changes in sister chromatid exchanges (SCEs) or chromosomal aberration frequencies. When MNNG was added to logarithmically growing cultures and TPA was added 2, 24, or 48 hr later, no changes in SCE frequency relative to MNNG alone occurred. Similar results were obtained with TPA in cells that had been exposed to MNNG in stationary growth phase. Whereas no transformation occurred with TPA alone and pretreatment with TPA did not affect MNNG transformation, its addition 2 hr after MNNG reduced transformation frequency but addition 24-72 hr after MNNG increased the transformation frequency up to 6-fold. TPA had a minimal effect on increasing the transformation frequency (2-fold) induced by MNNG at 0.25 micrograms/ml, a high concentration. Of three polycyclic hydrocarbons, perylene, benzo[g,h,i]perylene, and benz[a]anthracene, known as weak or noncarcinogens, only benz[a]anthracene induced a very low transformation frequency; however, after TPA, transformation occurred with all three. Because the number of cells whose transformation was initiated by low doses of carcinogen is much larger than the number of cells giving rise to transformed colonies in the absence of TPA, the frequency of the initial event is greater than can be expected from point mutations. Furthermore, the promotional aspect of transformation is not accompanied by a parallel increase in SCE.

proceedings of the national academy of sciences of the united states of america

Enhancement of N-methyl-N'-nitro-N-nitrosoguanidine transformation of Syrian hamster cells by a phorbol diester is independent of sister chromatid exchanges and chromosome aberrations.