Cartilage dysplasia and tissue mineralization in the rat following administration of a FGF receptor tyrosine kinase inhibitor
Cartilage dysplasia and tissue mineralization in the rat following administration of a FGF receptor tyrosine kinase inhibitor
复制标题
DOI：
10.1080/01926230590961845
复制
发表时间：
2005-01-01
影响因子：
1.5
通讯作者：
Graziano, MJ
中科院分区：
文献类型：
--
作者：
Brown, AP;Courtney, CL;Graziano, MJ
PD176067是一种可逆性和选择性的成纤维细胞生长因子受体酪氨酸激酶抑制剂，作为治疗实体瘤的血管生成抑制剂处于临床前开发阶段。PD176067以2.5、5和10 mg/kg/d剂量(15、30和60 mg/m(2))对7周龄雌性幼鼠进行了14天的经口毒性研究。骨骼改变、血管和软组织矿化被观察到是主要的药物相关毒性。为了确定这些变化是否特定于血管和骨骼发育增加的年轻、快速生长的动物，对成年(11个月大)的大鼠进行了PD176067试验。雌性大鼠按2.5、5和10 mg/kg/d剂量灌胃给药14天，第15天剖检。在剂量为5 mg/kg时出现临床毒性体征，10 mg/kg时出现1例死亡。植骨发育不良(股骨远端、胫骨近端、胸骨)在所有药物处理的动物中均可见，其特征是软骨细胞增殖区和肥大区的厚度随剂量增加而增加，骨化区明显增厚。软骨增生的特点是软骨细胞沿联合软骨边缘和胸骨骨膜下增生。血清磷水平在5 mg/kg和10 mg/kg时分别增加47%和166%。心肌细胞、主动脉、各种动脉、肾小管、胃粘膜和肌层的矿化在10 mg/kg时可见，并与钙磷沉积的存在相一致。幼年和成年大鼠在类似的血浆PD176067暴露下也发生了生理变化(AUC>；=4.83mU/g中心点小时/毫升)。PD176067在幼年和成年大鼠中产生了形态相似的损伤。
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 mu g center dot hr/mL). PD176067 produced morphologically similar lesions in young and adult rats.