Modulation of the co-promoting activity of gamma interferon in SENCAR and C57BL/6 mouse skin by difluoromethyllornithine and the scheduling and duration of interferon treatment

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Abstract
The murine skin multistage carcinogenesis model was used to characterize the co-promoting and tumor progressing activities of i.p. administered recombinant DNA-derived murine gamma interferon (rMuIFN-.gamma.). The dorsal skins of female SENCAR mice were topically initiated with 7,12-dimethylbenz(a)anthracene (DMBA) and promoted twice a week for 20 weeks with 1 .mu.g of 12-O-tetradecanoylphorbol-13-acetate (TPA). Doses of rMuIFN-.gamma. that had no effect on papilloma multiplicities when administered 1 day prior to TPA treatment increased the numbers of papillomas per mouse by 33-38% when administered immediately prior (zero time) to TPA application. A minimum of 6 weeks of co-treatment with TPA and rMuIFN-.gamma. (zero time) were necessary for demonstration of rMuIFN-.gamma.-dependent co-promotion. The ad libitum administration of either 0.25 or 1% (w/v) solutions of .alpha.-difluoromethylornithine (DFMO) in the drinking water inhibited by 90% the TPA-dependent elevation of epidermal ornithine decarboxylase activity but had minimal effect on papilloma multiplicities in TPA-promoted mice. However, both doses of DMFO completely suppressed rMuIFN-.gamma.-dependent co-promotion. Carcinoma incidence and multiplicities by weeks 46-48 of the promotion progression period were statistically indistinguishable for initiated mice treated with TPA, TPA + DFMO, TPA + IFN-.gamma. or TPA + DFMO + IFN-.gamma.. Similarly, i.p. administration of rMuIFN-.gamma. to papilloma-bearing mice in a tumor progression study, with and without simultaneous topical TPA treatment, did not affect carcinoma latency or carcinoma multiplicities. C57BL/6 mice initiated with DMBA developed few papillomas (0.2 paps/mouse) after 19 weeks of TPA promotion. The i.p. administration of rMuIFN-.gamma. to C57BL/6 mice at the time of TPA treatment, at doses that were co-promoting in SENCAR mice, did not increase papilloma multiplicities. Collectively, our studies suggest that the co-promoting activity of rMuIFN-.gamma. is exceptionally sensitive to inhibition by DFMO and dependent upon the scheduling and duration of rMuIFN-.gamma. treatment, and the mouse strain/stock employed for the studies.

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