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Ability of Systemic Interleukin-12 to Hamper Progressive Stages of Mammary Carcinogenesis in HER2/neu Transgenic Mice¹

Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy [K. B., S. R., F. C., E. Q., G. F.]; Institute for Cancer Research, University of Bologna, 40126 Bologna, Italy [P. L. L., P. N.]; IST Biotechnology Satellite Unit of Bologna, 40126 Bologna, Italy [G. N.]; Department of Oncology and Neuroscience, G. d’Annunzio University, 66013 Chieti, Italy [E. D. C., P. M.]; and Genetics Institute, Cambridge, Massachusetts 02140 [S. W.]

Previous studies in mice have shown that chronic administration of recombinant interleukin-12 (IL-12) hampers the progression of both chemical- and oncogene-dependent carcinogenesis. This suggests that a new preventive strategy may be envisaged for individuals with a genetic risk of cancer or carrying preneoplastic lesions. Starting at progressive stages of mammary carcinogenesis, female BALB/c and FVB mice carrying the activated rat HER2/neu oncogene (BALB-neuT) or the proto-oncogene (FVB-neuN) under the mouse mammary tumor virus promoter received multiple 5-day courses of different doses of IL-12. The times of tumor appearance, multiplicity, and histopathological features of the neoplastic lesions were evaluated. In both BALB-neuT and FVB-neuN mice, 5-day i.p. courses of 50/100 ng of IL-12/day inhibited mammary carcinogenesis when they coincided with the progression of early preneoplastic lesions. Inhibition appears to depend primarily on the ability of IL-12 to interfere with early tumor angiogenesis. Later treatments are much less effective, and daily doses of 10 and 2 ng are useless. The efficacy of early IL-12 courses suggests that they could be used to prevent mammary tumors in individuals at risk, whereas their lower efficacy in later stages of carcinogenesis and the dose range required pose some constraints on their use in the management of overt preneoplastic lesions. Precise understanding of tumor progression means that effective treatments can be commenced relatively late in the life of individuals at risk and that no lifetime administration is required.

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