Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice.
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.
Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Italy.
K
K
Boggio
G
G
Nicoletti
E
E
Di Carlo
F
F
Cavallo
L
L
Landuzzi
C
C
Melani
M
M
Giovarelli
I
I
Rossi
P
P
Nanni
C
C
De Giovanni
P
P
Bouchard
S
S
Wolf
A
A
Modesti
P
P
Musiani
P L
PL
Lollini
M P
MP
Colombo
G
G
Forni
D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002278:Carcinoma in Situ / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018275:Carcinoma, Lobular / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000235:genetics; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D000970:Antineoplastic Agents; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D007371:Interferon-gamma; D018664:Interleukin-12; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D018719:Erb-b2 Receptor Tyrosine Kinases; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C111954:CXC chemokine Mig; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat