Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors - Implications for bone metastases
Dual focal adhesion kinase/Pyk2 inhibitor has positive effects on bone tumors - Implications for bone metastases
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DOI：
10.1002/cncr.23429
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发表时间：
2008-05-15
期刊：
影响因子：
6.2
通讯作者：
Andresen, Catharine J.
中科院分区：
文献类型：
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作者：
Bagi, Cedo M.;Roberts, Gregory W.;Andresen, Catharine J.
背景资料。溶骨性骨转移常见于癌症患者，临床上主要问题包括缺乏有效的治疗方法。溶骨性骨转移的机制涉及肿瘤细胞、骨基质和骨细胞之间的相互作用。粘着斑激酶(FAK)和PYK2均与骨和肿瘤的生物学和生理学有关。方法采用裸鼠胫骨移植瘤细胞模型，评价PF-562、271的药效。该药以5 mg/kg剂量口服，每周7天，共28天。血清和尿液生物标记物、成像和组织学技术被用于监测肿瘤发生率、疾病进展和治疗反应。结果：该化合物耐受性良好。两个复合治疗组的骨钙素和松质骨参数显示出显著和相似的增加。对携带肿瘤的胫骨的放射学评估显示，与PF-562,271治疗的大鼠相比，未治疗的大鼠肿瘤扩大，肿瘤生长减少，骨愈合迹象减少。抗酒石酸酸性磷酸酶和荧光原位杂交分析表明，肿瘤部位的骨吸收主要由大鼠的破骨细胞完成。结论口服PF-562、271 5 mg/kg可抑制肿瘤的生长和局部扩散，恢复肿瘤引起的骨丢失。PF-562,271独特的抑制肿瘤生长和安全增加骨形成的能力可能是许多癌症患者骨转移和癌症相关骨质疏松症的有效治疗方法。
BACKGROUND. Lyric bone metastases occur frequently in cancer patients and present major clinical issues including lack of effective therapies. The mechanism of lytic bone metastases involves interactions between tumor cells, bone matrix, and bone cells. Both focal adhesion kinase (FAK) and Pyk2 are implicated in the biology and physiology of bone and cancer.METHODS. The efficacy of PF-562,271 was evaluated using MDA-MB-231 cells implanted in the tibia of nude rats. The drug was administered orally at a dose of 5 mg/kg, 7 days per week for 28 days. Serum and urine biomarkers, imaging, and histologic techniques were deployed to monitor tumor take rate, disease progression, and response to therapy.RESULTS. The compound was well tolerated. Both compound-treated groups demonstrated significant and similar increases in osteocalcin and cancellous bone parameters. Radiographic evaluation of tumor-bearing tibiae revealed tumor expansion in nontreated rats compared with a decrease in tumor growth and signs of bone healing in rats treated with PF-562,271. Tartrate-resistant acid phosphatase and fluorescent in situ hybridization analysis revealed that the majority of bone resorption at the tumor site was performed by osteoclasts of rat origin.CONCLUSIONS. The oral administration of PF-562,271 at a dose of 5 mg/kg suppressed the growth and local spread of intratibial tumors and restored tumor-induced bone loss. The unique ability of PF-562,271 to both curb tumor growth and safely increase bone formation may be an effective therapy for many cancer patients with bone metastases and cancer-associated osteoporosis.