TITLE

Cartilage Dysplasia and Tissue Mineralization in the Rat Following Administration of a FGF Receptor Tyrosine Kinase Inhibitor

AUTHOR(S)
Brown, Alan P.; Courtney, Cynthia L.; King, Lena M.; Groom, Stephen C.; Graziano, Michael J.
PUB. DATE
July 2005
SOURCE
Toxicologic Pathology;2005, Vol. 33 Issue 4, p449
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
PD176067 is a reversible and selective inhibitor of fibroblast growth factor receptor tyrosine kinase, and was in preclinical development as an angiogenesis inhibitor for the treatment of solid tumors. A 14-day oral toxicity study of PD176067 in young female rats (7 weeks old) was conducted at doses of 2.5, 5, and 10 mg/kg/day (15, 30, and 60 mg/m 2 , respectively). Skeletal changes, and vascular and soft tissue mineralization were observed as primary drug-related toxicities. To determine if these changes are specific to young, rapidly growing animals with increased vascular and osseous development, PD176067 was administered to mature (11 months old) rats. Female rats received PD176067 by gavage for 14 days at doses of 2.5, 5, and 10 mg/kg/day and necropsied on day 15. Clinical signs of toxicity were seen at =5 mg/kg and one death occurred at 10 mg/kg. Physeal dysplasia (distal femur, proximal tibia, sternum) occurred in all drug-treated animals and was characterized by dose-related increased thickness of the zones of chondrocyte proliferation and hypertrophy, and marked thickening of the zone of ossification. Cartilage hyperplasia was characterized by proliferation of chondrocytes along margins of the synchondrosis and subperiosteum of sternebrae. Serum phosphorus levels increased 47% and 166% at 5 and 10 mg/kg, respectively. Mineralization of cardiac myocytes, aorta, various arteries, renal tubules, and gastric mucosa and muscularis was seen at 10 mg/kg, and consistent with the presence of calcium-phosphorus deposition. Physeal changes occurred at similar plasma PD176067 exposures in young and mature rats (AUC = 4.83 µ g · hr/mL). PD176067 produced morphologically similar lesions in young and adult rats.
ACCESSION #
17148012

 

Related Articles

  • Combinatorial targeting of FGF and ErbB receptors blocks growth and metastatic spread of breast cancer models. Issa, Amine; Gill, Jason W.; Heideman, Marinus R.; Sahin, Ozgur; Wiemann, Stefan; Dey, Julien H.; Hynes, Nancy E. // Breast Cancer Research;2013, Vol. 15 Issue 1, p1 

    Introduction: Targeting receptor tyrosine kinases (RTKs) with kinase inhibitors is a clinically validated anti-cancer approach. However, blocking one signaling pathway is often not sufficient to cause tumor regression and the effectiveness of individual inhibitors is often short-lived. As...

  • FGFR3IIIS: a novel soluble FGFR3 spliced variant that modulates growth is frequently expressed in tumour cells. Sturla, L.-M.; Merrick, A.E.; Burchill, S.A. // British Journal of Cancer;10/6/2003, Vol. 89 Issue 7, p1276 

    Fibroblast growth factor receptor 3 (FGFR3) is one of four high-affinity tyrosine kinase receptors for the FGF family of ligands, frequently associated with growth arrest and induction of differentiation. The extracellular immunoglobulin (IgG)-like domains II and III are responsible for ligand...

  • Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Cappellen, David; De Oliveira, Catherine; Ricol, David; de Medina, Sixtina; Bourdin, Jérôme; Sastre-Garau, Xavier; Chopin, Dominique; Thiery, Jean Paul; Radvanyi, François // Nature Genetics;Sep99, Vol. 23 Issue 1, p18 

    Studies frequent activating mutations of fibroblast growth factor receptor 3 (FGFR3) in human bladder and cervix carcinomas. Classification of FGFR3 as a member of structurally related tyrosine kinase receptors encoded by four genes; Association of specific point mutations in domains of FGFR3...

  • Tumour cell responses to new fibroblast growth factor receptor tyrosine kinase inhibitors and identification of a gatekeeper mutation in FGFR3 as a mechanism of acquired resistance. Chell, V; Balmanno, K; Little, A S; Wilson, M; Andrews, S; Blockley, L; Hampson, M; Gavine, P R; Cook, S J // Oncogene;6/20/2013, Vol. 32 Issue 25, p3059 

    Fibroblast growth factor receptors (FGFRs) can act as driving oncoproteins in certain cancers, making them attractive drug targets. Here we have characterized tumour cell responses to two new inhibitors of FGFR1-3, AZ12908010 and the clinical candidate AZD4547, making comparisons with the...

  • EphA2-Induced Angiogenesis in Ewing Sarcoma Cells Works through bFGF Production and Is Dependent on Caveolin-1. Sáinz-Jaspeado, Miguel; Huertas-Martinez, Juan; Lagares-Tena, Laura; Martin Liberal, Juan; Mateo-Lozano, Silvia; de Alava, Enrique; de Torres, Carmen; Mora, Jaume; Muro, Xavier Garcia del; Tirado, Oscar M. // PLoS ONE;Aug2013, Vol. 8 Issue 8, p1 

    Angiogenesis is the result of the combined activity of the tumor microenvironment and signaling molecules. The angiogenic switch is represented as an imbalance between pro- and anti-angiogenic factors and is a rate-limiting step in the development of tumors. Eph receptor tyrosine kinases and...

  • Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. Oki, Mariko; Yamamoto, Hiroyuki; Taniguchi, Hiroaki; Adachi, Yasushi; Imai, Kohzoh; Shinomura, Yasuhisa; Mazzanti, Roberto // World Journal of Gastroenterology;10/7/2008, Vol. 14 Issue 37, p5650 

    AIM: To clarify the expression and role of Ephrin receptor A4 (EphA4) in gastric cancer in relation to clinicopathological characteristics and the expression of fibroblast growth factor receptor I (FGFRI) and ephrin ligands. METHODS: Eleven gastric carcinoma cell lines, 24 paired surgical fresh...

  • Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) promotes glioblastoma cell chemotaxis via Lyn activation. Dhruv, Harshil D.; Whitsett, Timothy G.; Jameson, Nathan M.; Patel, Falak; Winkles, Jeffrey A.; Berens, Michael E.; Tran, Nhan L. // Carcinogenesis;Jan2014, Vol. 35 Issue 1, p218 

    The long-term survival of patients with glioblastoma is compromised by the proclivity for local invasion into the surrounding normal brain, escaping surgical resection and contributing to therapeutic resistance. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the tumor...

  • FGFR1 expression and gene copy numbers in human lung cancer. Kohler, Lukas; Mireskandari, Masoud; Knösel, Thomas; Altendorf-Hofmann, Annelore; Kunze, Almut; Schmidt, Andreas; Presselt, Norbert; Chen, Yuan; Petersen, Iver // Virchows Archiv;Jul2012, Vol. 461 Issue 1, p49 

    FGFR1 is a receptor tyrosine kinase of which the ligands belong to the fibroblast growth factor family. To evaluate the significance of FGFR1 in lung cancer, we analysed tumours by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Tissue microarrays were constructed...

  • Fibroblast growth factor signalling: from development to cancer. Turner, Nicholas; Grose, Richard // Nature Reviews Cancer;Feb2010, Vol. 10 Issue 2, p116 

    Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics