Effect of targeting janus kinase 3 on the development of intestinal tumors in the adenomatous polyposis coli(min) mouse model of familial adenomatous polyposis.
Familial adenomatous polyposis (FAP) is associated with germ-line mutations in the tumor suppressor gene, adenomatous polyposis coli (APC) located on chromosome 5q21. Multiple intestinal neoplasia (Min) in mice resembles FAP in humans, resulting from a single point mutation in the murine homolog of the APC gene. The effects of the rationally-designed Janus kinase 3 (JAK3) inhibitor JANEX-1 (4-(4'-hydroxyphenyl) amino-6,7-dimethoxy-quinazoline, WHI-P131, CAS 202475-60-3) on the development of intestinal tumors in the APC (min/+) mouse model of FAP were examined. The Min mice were fed with rodent chow or chow supplemented with JANEX-1 once a week starting at 1.5 months of age. The cumulative proportions of mice remaining alive at 7 months were 13 +/- 6% for control mice versus 72 +/-12% for JANEX-1 treated mice (P<0.0002). In contrast, Compound DDE24, a synthetically activated genistein, an inhibitor of Epidermal Growth Factor receptor (EGF-R), cellular homologue of oncogene product from Raus Avian sarcoma virus (SRC) and Syk tyrosine kinases, which Thus, selective targeting of JAK3 was highly effective in preventing development of intestinal tumors in Min mice resulting in markedly improved survival outcomes. JAK3 inhibitors may therefore be useful in the prevention of colorectal cancer in individuals with FAP.
Uckun
Fatih M
FM
Parker Hughes Cancer Center, 2665 Long Lake Road, St. Paul, Minnesota 55113, USA. fatih_uckun@ih.org
Erbeck
Douglas
D
Qazi
Sanjive
S
Venkatachalam
Taracad
T
Tibbles
Heather E
HE
Vassilev
Alexei
A
D011125:Adenomatous Polyposis Coli / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017354:Point Mutation / Q000502:physiology; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D016019:Survival Analysis; D014018:Tissue Distribution; D051176:beta Catenin / Q000096:biosynthesis
D004791:Enzyme Inhibitors; D011799:Quinazolines; C116180:WHI P131; D051176:beta Catenin; D053616:Janus Kinase 3