title: In vivo effect of imatinib on progression of cecal GIST-like tumors in exon 17-type c-kit knock-in mice.
abstract: Two families with a germline Asp820Tyr mutation at exon 17 of the c-kit gene and multiple gastrointestinal stromal tumors (GISTs) have been reported. Recently, we generated a knock-in mouse model of the family, and mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal GIST-like tumor. In this report, we examined the in vivo effect of imatinib on tumor progression in knock-in mice. Imatinib of 100 microg/g body weight was administered to heterozygous (KIT-Asp818Tyr/+) mice orally for 7, 14 and 28 days, and cecal tumors were dissected. Both macroscopic size and the measured volume of cecal tumors were not significantly reduced after a 7-, 14- and 28-day administration of imatinib when compared with those before imatinib administration. Cell proliferation was assessed by Ki-67 immunohistochemistry and the labeling index significantly decreased after imatinib administration, but the value of the index after imatinib was only about half compared with that before imatinib. Western blotting and real-time PCR revealed that KIT expression was almost equivalent, but KIT phosphorylation was significantly but not completely inhibited in tumor tissues after 7, 14 and 28 days of imatinib administration when compared with that before imatinib administration. Phosphorylation of Akt and Stat1 was accordingly inhibited after imatinib administration. Thus, imatinib seemed to inhibit in vivo tumor proliferation but not decrease tumor volume on this mouse model, probably because of an insufficient inhibition of phosphorylation of KIT and its downstream signaling molecules. These results suggested that progression of multiple GISTs in patients with germline Asp820Tyr might be partially controlled by imatinib and that model mice provide an opportunity to examine the effect of various other targeted drugs on in vivo tumor progression.
authors.affiliation: Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Norihiro
authors.initials: N
authors.lastname: Nakai
authors.forename: Ning-Ning
authors.initials: NN
authors.lastname: Liu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.forename: Koji
authors.initials: K
authors.lastname: Isozaki
authors.forename: Ikuo
authors.initials: I
authors.lastname: Matsuda
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Hatakeyama
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D002430:Cecal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005091:Exons; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D006579:Heterozygote; D000068877:Imatinib Mesylate; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D019394:Ki-67 Antigen; D010879:Piperazines; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit