Ligand-specific antibodies to insulin-like growth factors suppress intestinal polyp formation in Apc+/- mice.
Insulin-like growth factors (IGF-I and IGF-II) play important roles in intestinal tumorigenesis. To investigate the effectiveness of IGF-targeting strategies, we conducted an in vivo study using anti-mouse neutralizing antibodies IGF-I (KM3168) and IGF-II (KM1468). Six- and 10-week-old Apc(+/-) mice were given KM3168 and/or KM1468 i.p. at two doses (0.01 or 0.1 microg/g weight) once or twice weekly for 4 weeks. To clarify the source of IGFs in vivo, we evaluated the expression levels of IGFs in the liver, normal small intestine, and polyps of the small intestine of Apc(+/-) mice. The phosphorylation status of IGF signal-related molecules was examined using immunostaining to understand the mechanism underlying the effects of IGF-neutralizing antibody. The plasma half-life was 168 for KM3168 and 85 hours for KM1468. In two lineages of Apc(+/-) mice (Apc(1309) and Apc(Min/+)), a low dose (0.01 microg/g weight) of KM3168 and KM1468 significantly reduced the number of polyps when given once and twice weekly, respectively. Combined administration of the effective dose of each antibody had an additive effect. The liver was the main source of IGF-I, whereas the polyps of the small intestine and normal small intestine were the main source of IGF-II. IGF-neutralizing antibodies decreased the phosphorylation of IGF type 1 receptor and inhibited the signal transduction of the Akt pathway. These results suggest that IGF-I and IGF-II play important roles in polyp formation in Apc(+/-) mice and that specific antibodies to IGF-I and IGF-II may be promising antitumor agents.
Matsunaka
Toshihiro
T
Department of Gastroenterology and Hepatolology, Kyoto University Graduate School of Medicine, Kyoyo, Japan.
Miyamoto
Shin'ichi
S
Shitara
Kenya
K
Ochiai
Atsushi
A
Chiba
Tsutomu
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007417:Intestinal Polyps / Q000473:pathology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D015398:Signal Transduction; D013002:Somatomedins / Q000737:chemistry*
D000970:Antineoplastic Agents; D008024:Ligands; D013002:Somatomedins