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Katia Boggio^*, Giordano Nicoletti^,, Emma Di Carlo^||, Federica Cavallo^*, Lorena Landuzzi^,, Cecilia Melani^¶, Mirella Giovarelli^*, Ilaria Rossi, Patrizia Nanni, Carla De Giovanni, Page Bouchard^**, Stanley Wolf^**, Andrea Modesti^||, Piero Musiani^||, Pier Luigi Lollini, Mario P. Colombo^¶, and Guido Forni^*

From the ^* Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy; the Institute for Cancer Research, University of Bologna, 40126 Bologna, Italy; the IST Biotechnology Satellite Unit of Bologna, 40126 Bologna, Italy; the ^|| Department of Oncology and Neuroscience, G. d'Annunzio University, 66013 Chieti, Italy; the ^¶ National Tumor Institute, 20133 Milan, Italy; and the ^** Genetics Institute, Cambridge, Massachusetts 02140

The ability of interleukin (IL)-12 to prevent tumors when administered to individuals with a genetic risk of cancer was studied in two lines of transgenic mice expressing rat HER-2/neu oncogene in the mammary gland. Female BALB/c (H-2^d) mice carrying the activated HER-2/ neu oncogene show no morphological abnormalities of the mammary gland until 3 wk of age. They then progress through atypical hyperplasia to in situ lobular carcinoma and at 33 wk of age all 10 mammary glands display invasive carcinomas. Adult FVB mice (H-2^q) carrying the HER-2/neu protooncogene develop mammary carcinomas with a longer latency (38-49 wk) and a lower multiplicity (mean of 2.6 tumors/mice). Treatment with IL-12 (5 daily intraperitoneal injections, 1 wk on, 3 wk off; the first course with 50 ng IL-12/day, the second with 100 ng IL-12/day) begun at 2 wk of age in BALB/c mice and at 21 wk of age in FVB mice markedly delayed tumor onset and reduced tumor multiplicity. Analogous results were obtained in immunocompetent and permanently CD8⁺ T lymphocyte–depleted mice. In both transgenic lines, tumor inhibition was associated with mammary infiltration of reactive cells, production of cytokines and inducible nitric oxide synthase, and reduction in microvessel number, in combination with a high degree of hemorrhagic necrosis.

Key Words: interleukin 12 • adenocarcinomas • tumor prevention • angiogenesis • Her-2/neu

This work is dedicated to the memory of Giorgio Prodi, M.D., Ph.D., ten years after his untimely death.

Abbreviations used: iNOS, inducible NO synthase; IP-10, IFN-–inducible protein 10; NO, nitric oxide; MIG, monokine induced by -IFN; MMTV, mouse mammary tumor virus; MSA, mouse serum albumin; VCAM, vascular cell adhesion molecule.

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