Chronic Exposure to Ionizing Radiation as a Tumor Promoter in Mouse Skin

We have tested chronic exposure to${}^{90}{\rm Y}$ β radiation for its action as a complete tumor promoter, a stage I tumor promoter, or a stage II tumor promoter in SENCAR mouse skin. In skin initiated with a single application of 7,12,dimethylbenz[a]anthracene (DMBA, 10 nmol), chronic exposure to β radiation as a complete promoter (0.5 Gy, twice/week, 13 weeks) produced no tumors and, when added to a complete chemical promoter (TPA), reduced tumor frequency about 30%. A similar result was observed when β radiation was tested as a stage II promoter. DMBA-initiated mice that received chemical (12-O-tetradecanoylphorbol-13-acetate, TPA) stage I promotion followed by 13 weeks of β-radiation exposure (0.5 Gy, twice/week) as stage II promotion produced essentially no tumors, and combining the same chronic β-radiation exposure with chemical (mezerein) stage II promotion reduced tumor frequency about 20% when compared to a similar group that was not irradiated. Chronic β-radiation exposure was tested two ways as a stage I tumor promoter in initiated skin that was subsequently treated with mezerein as a stage II promoter. Stage I promotion was shown to proceed with the passage of time, indicating this process occurs naturally in the absence of chemical or physical stimulation. Hyperthermia, previously shown to be a potent inhibitor of chemically stimulated stage I promotion, had no effect on the natural process, indicating at least some differences in mechanism between the two processes. The natural process was, in fact, inhibited by chemical tumor promoters, but not by radiation. In addition to the increase resulting from this natural process, tumor frequency was further increased slightly but significantly (12-15%, P ≤0.05) when chronic radiation exposure was given as a stage I promoter (0.5 Gy, twice/week, 13 weeks) subsequent to initiation, in spite of the expected 20% reduction resulting from this dose. Exposure of initiated animals to radiation (0.5 or 1.0 Gy, twice/week, 2 weeks) in addition to TPA as stage I promotion produced a similar increase in tumor frequency (P < 0.02). At higher radiation doses, however, tumor frequency was reduced compared to unirradiated controls. In a third test as a stage I promoter, β radiation (0.5 Gy twice/week, 4 weeks) was given prior to initiation with N-methyl-N′-nitro-N-nitrosoguanidine in animals subsequently promoted by TPA (twice/week, 13 weeks), and again the radiation slightly but significantly (P < 0.03) increased tumor frequency compared to the unirradiated control group. As before, a higher dose prevented the increase and reduced tumor frequency. These results indicate no action of chronic β irradiation either as a complete tumor promoter or as a stage II promoter. However, three different tests of chronic β irradiation as a stage I promoter all indicated a weak but positive action. Stage I-promoting activity by radiation may result from stimulation of a natural process, but as dose or dose rate increases, the net effect may be reduced or eliminated by killing of initiated cells.