唑来膦酸抗肿瘤血管生成作用研究进展

唑来膦酸是第三代双膦酸盐药物,主要用于治疗恶性高钙血症及骨转移癌。目前的研究发现,除抑制骨吸收外唑来膦酸还具有直接和间接的抗肿瘤活性。其中抑制肿瘤血管形成是其间接抗肿瘤作用机制之一。其抗肿瘤血管生成作用可能机制如下：（1）抑制肿瘤细胞及肿瘤间质细胞分泌VEGF,调节VEGF-VEGFR自分泌环抑制血管生成;（2）抑制血管内皮细胞迁移、黏附作用;（3）诱导循环内皮细胞祖细胞凋亡,抑制肿瘤细胞及肿瘤浸润巨噬细胞分泌MMPs;（4）抑制肿瘤细胞血管生成拟态。但唑来膦酸抗肿瘤活性的用药剂量不同于目前治疗骨转移的剂量,其抗肿瘤血管生成拟态的作用机制尚未明确,需要进一步研究。     

放疗同步及序贯唑来膦酸治疗骨转移瘤的疗效分析

目的分析放疗同步及序贯唑来膦酸对骨转移瘤的治疗效果。方法75例患者,观察组39例在放疗的同时予唑来膦酸治疗,对照组36例放疗结束2～3周后予唑来磷酸治疗。结果放疗同步组与序贯唑来膦酸组有效率分别为92.31%、86.11%,差异无统计学意义(P＞0.05);疼痛缓解时间平均为7、10天,无痛维持时间平均为65、55天,差异均无统计学意义(P＞0.05)。结论放疗同时或序贯唑来膦酸在骨转移瘤的综合治疗中效果相似,不良反应相似。     

化疗联合唑来膦酸治疗肺癌骨转移的临床疗效分析

目的探讨化疗联合唑来膦酸治疗肺癌骨转移的临床效果。方法将收治的64例肺癌骨转移患者,随机分为对照组和观察组,对照组患者采用诺维本联合顺铂（NP）方案治疗,观察组患者在对照组的基础上加用唑来膦酸治疗。比较两组患者的疼痛缓解情况,活动能力改善情况,骨病灶改善情况,生存质量改善情况及不良反应发生情况。结果观察组患者疼痛总缓解率、活动能力恢复总有效率、骨病灶疗效总有效率和生存质量改善率（84.4%、84.4%、68.8%和81.3%）显著高于对照组（53.1%、56.3%、50.0%和46.9%）,差异有统计学意义（P〈0.05）。两组患者不良反应发生情况差异无统计学意义（P〉0.05）。结论化疗联合唑来膦酸用于治疗肺癌骨转移,可显著减轻骨痛等相关事件,显著改善患者的生活质量及活动能力,不良反应少,使用方便,值得临床推广应用。     

尿N-乙酰-β-D氨基葡萄糖酶、丙氨酸氨肽酶和α1-微球蛋白检测在唑来膦酸致肾损伤早期诊断作用

目的探讨尿N-乙酰-β-D氨基葡萄糖酶(NAG)、丙氨酸氨肽酶(AAP)和α1-微球蛋白(α1-MG)检测在唑来膦酸致肾损伤早期诊断中的作用。方法选取2012年2月至2014年7月沈阳军区总医院收治的100例应用唑来膦酸治疗的恶性肿瘤骨转移患者为研究对象。其中,男性48例,女性52例,年龄25~82岁,平均(60±11)岁。患者接受唑来膦酸注射液4 mg静脉滴注,1次/25~35 d,30 min滴完,连续应用3次。每次用药前和用药次日,留取患者清晨尿液及静脉血,检测并比较尿NAG、AAP、α1-MG和血肌酐(Scr)、尿素氮(BUN)水平。结果每次用药前、后比较尿NAG水平,差异均有统计学意义(P<0.05)。第1次用药前后,尿α1-MG水平比较,差异无统计学意义(P>0.05);而第2次和第3次用药前后,尿α1-MG水平比较,差异有统计学意义(P<0.05)。第1次和第3次用药前后,尿AAP水平比较,差异有统计学意义(P<0.05);而第2次用药前后,尿AAP水平比较,差异无统计学意义(P>0.05)。每次用药前后,Scr、BUN水平比较,差异均无统计学意义(P>0.05)。3次用药后,尿NAG、α1-MG水平组间比较,差异均有统计学意义(P<0.05);Scr、BUN水平组间比较,差异均无统计学意义(P>0.05)。结论唑来膦酸致肾损伤患者尿NAG、AAP和α1-MG水平变化早于血肌酐。尿NAG、AAP和α1-MG联合检测可作为肾损伤的早期诊断指标。     

唑来膦酸加益肾健骨汤治疗老年性骨质疏松65例疗效观察

目的：观察唑来膦酸加益肾健骨汤治疗老年性骨质疏松的临床疗效。方法：选取2011年9月-2013年9月开封市第二中医院收治的65例老年性骨质疏松症患者作为研究对象,予以唑来膦酸治疗,观察治疗前后血磷、血钙及碱性磷酸酶（AKP）水平变化,不同部位骨密度（BMD）,及不良反应发生情况。结果：治疗前后血磷、血钙水平比较差异均无统计学意义（P＞0.05）;治疗后 AKP 水平呈逐年下降趋势,各时间点比较差异均有统计学意义（P＜0.05）。治疗后腰椎 L1-4、股骨颈、Ward 氏三角区及大转子BMD均逐年升高,差异均有统计学意义（P＜0.05）。不良反应主要包括肌痛、头痛、发热及关节痛等,发生率为66.15%（43/65）。结论：唑来膦酸加益肾健骨汤治疗老年性骨质疏松症可有效提高BMD,临床疗效显著。     

Clinically relevant dose of zoledronic acid inhibits spontaneous lung metastasis in a murine osteosarcoma model

Clinically obtainable concentrations of zoledronic acid (ZOL) inhibited the production of vascular endothelial growth factor and reduced the migration, adhesion, and invasiveness of osteosarcoma (OS) cells in vitro. The in vivo effects of ZOL were investigated by using a murine model of spontaneous lung metastasis. The higher dose of ZOL (80 microg/kg three times/week) inhibited the growth of OS at the primary site, accompanied by inhibition of neovascularization in the tumor. Interestingly, while the lower dose of ZOL (80 microg/kg once a week) could not inhibit the growth of OS at the primary site, it significantly prevented lung metastasis.     

Osteonecrosis of the maxilla and mandible in patients with advanced cancer treated with bisphosphonate therapy

Cases of osteonecrosis of the jaw (ONJ) have been reported with an increasing frequency over the past 5 years. ONJ is most often identified in patients with cancer who are receiving intravenous bisphosphonate (IVBP) therapy, but it has also been diagnosed in patients receiving oral bisphosphonates for nonmalignant conditions. To further categorize risk factors associated with ONJ and potential clinical outcomes of this condition, we performed a retrospective study of patients with metastatic bone disease treated with intravenous bisphosphonates who have been evaluated by the Memorial Sloan-Kettering Cancer Center Dental Service between January 1, 1996 and January 31, 2006. We identified 310 patients who met these criteria. Twenty-eight patients were identified as having ONJ at presentation to the Dental Service and an additional 7 patients were subsequently diagnosed with ONJ. Statistically significant factors associated with increased likelihood of ONJ included type of cancer, duration of bisphosphonate therapy, sequential IVBP treatment with pamidronate followed by zoledronic acid, comorbid osteoarthritis or rheumatoid arthritis, and benign hematologic conditions. Our data do not support corticosteroid use or oral health as a predictor of risk for ONJ. Clinical outcomes of patients with ONJ were variable with 11 patients demonstrating improvement or healing with conservative management. Our ONJ experience is presented here.     

唑来膦酸对骨肉瘤细胞生物学行为的影响

目的研究唑来膦酸对骨肉瘤LM8细胞株黏附、迁移、侵袭和基质金属蛋白酶（MMP-2、MMP-9）的影响。方法不同浓度的唑来膦酸处理LM8细胞,用CCK-8法检测细胞毒作用和LM8细胞的黏附力;细胞划痕试验检测LM8细胞的迁移力;transwell小室模型测定LM8细胞对细胞外基质（ECM）的侵袭力;采用酶联免疫吸附实验（ELISA）检测培养上清液中基质金属蛋白酶（MMP-2、MMP-9）的含量。结果经过6．25μmol／L、12．5μmol／L、25μmol／L的唑来膦酸处理后,LM8细胞的黏附、迁移和侵袭力均明显下调,培养上清液中的基质金属蛋白酶（MMP-2、MMP-9）的含量也明显下降。结论唑来膦酸可抑制骨肉瘤LM8细胞的体外黏附、迁移和侵袭力,并同时明显降低LM8细胞分泌基质金属蛋白酶。     

Bisphosphonates induce apoptosis in CLL cells independently of MDR phenotype

Purpose The anti-tumoral activity of bisphosphonates (BPs) has been reported in leukemia. In this study, we attempted to evaluate the apoptotic effects of the BPs pamidronate (PAM) and zoledronic acid (ZOL) in chronic lymphocytic leukemia (CLL) samples, and to correlate it with clinical parameters and multidrug resistance (MDR) phenotype (P-glycoprotein and multidrug resistance-related protein expression and/or their functional activity). Results Both BPs were able to induce apoptosis significantly. No correlation was observed between BP-induced apoptosis and clinical parameters or MDR phenotype. Conclusion Our data suggest that concurrent or sequential administration of BPs with conventional chemotherapeutic drugs may have significant therapeutic potential for CLL patients. Karina Lani Silva and Deborah Vidal Vasconcellos were contributed equally to this paper.