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。     

唑来膦酸在乳腺癌中抗肿瘤作用的研究现状

唑来膦酸作为第3代双膦酸盐药物已广泛用于乳腺癌骨转移相关事件的防治。唑来膦酸在乳腺癌中具有抗肿瘤治疗作用。唑来膦酸通过抑制乳腺癌细胞的增殖和诱导细胞凋亡,降低肿瘤细胞的迁移、侵袭能力,防止有利于肿瘤生长的骨微环境的形成,抑制肿瘤新生血管形成,调节免疫等多种途径直接或间接发挥其抗肿瘤作用,与放化疗及内分泌等辅助治疗有序贯协同增效作用。唑来膦酸在乳腺癌患者辅助治疗中的协同抗肿瘤作用也在几项相关的前瞻性临床试验中进行。     

双膦酸盐治疗乳腺癌骨转移患者的临床病理特征及预后分析*

目的：探讨乳腺癌骨转移患者的临床、病理、治疗及预后因素。方法：收集2005年1 月至2013年4 月天津医科大学肿瘤医院收治的183 例至少接受6 个月双膦酸盐治疗的乳腺癌骨转移患者的临床资料,根据双膦酸盐类型分为帕米膦酸二钠组、唑来膦酸组及帕米膦酸二钠序贯唑来膦酸组,探讨骨转移的特点、骨相关事件（skeletal-related events,SREs）、治疗及预后特征。结果：胸椎和肋骨为骨转移的常见转移部位,骨转移至发生首次SREs的中位时间为4.2 个月,51.9%（95/ 183）患者发生SREs,累计SREs事件数达167 次,其中110 次（65.9%）发生在骨转移后1 年内,SREs类型以骨放疗为主。患者在不同双膦酸盐药物组的SREs发生率差异无统计学意义（P > 0.05）。 183 例患者骨转移后的中位生存期为43.1 个月,激素受体状态、无病生存期、是否合并内脏转移及脊柱转移与否是乳腺癌骨转移患者的独立预后因素（P < 0.05）。 结论：胸椎和肋骨是乳腺癌骨转移的常见转移部位,SREs主要发生在骨转移后1 年内并以骨放疗为主。激素受体阴性、无病生存期短、合并内脏及脊柱转移是影响乳腺癌患者骨转移不良预后的独立因素。     

唑来膦酸治疗恶性肿瘤骨转移60例的疗效观察

双膦酸盐类是目前治疗骨转移公认的有效药物.这类化合物通过抑制骨吸收来减少骨并发症的发生.唑来膦酸是一种高效、含氮基的第三代双膦酸盐类药物,能明显缓解骨转移患者疼痛,改善患者的生活质量,防止或减少骨骼相关事件发生,不良反应少.     

唑来膦酸治疗乳腺癌及其骨转移的研究进展

唑来膦酸是第三代含氮双膦酸盐类药物的典型代表,在已上市的双膦酸盐类药物中其综合疗效最好,不仅可以通过抑制甲羟戊酸途径直接作用于破骨细胞,也可直接或间接对肿瘤细胞产生抑制作用.乳腺癌属于易发生骨转移的一类恶性肿瘤,大量研究表明唑来膦酸对乳腺癌骨转移具有一定的疗效,可缓解骨痛,目前其已被纳入乳腺癌骨转移的临床常规治疗中,同时唑来膦酸在辅助性内分泌治疗乳腺癌时亦发挥重要的作用.本文就唑来膦酸对乳腺癌骨转移治疗方面的相关研究进展做一综述.     

唑来膦酸治疗非小细胞肺癌骨转移疗效及安全性的临床研究

[目的]观察唑来膦酸治疗非小细胞肺癌骨转移的疗效及安全性。[方法]临床确诊的41例非小细胞肺癌骨转移患者,唑来膦酸4mg,溶于100ml生理盐水,静脉滴注15min,每3~5周重复。[结果]用药第7d骨转移疼痛缓解有效率为78.0%。骨不良事件发生率中,骨放疗为12.2%,椎体压缩、变形为7.3%,脊髓压迫为4.9%,无1例病理性骨折、骨手术及高钙血症的发生。不良反应有流感样症状、发热、肾功能降低及眼结膜炎。[结论]唑来膦酸可以有效控制非小细胞肺癌骨转移性癌痛,预防、减少和延缓骨不良事件的发生,临床应用安全性好,无严重不良反应。     

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。     

唑来膦酸在乳腺癌中抗肿瘤作用的研究进展

唑来膦酸(ZOL)是第三代双膦酸盐类药物的典型代表,在已上市的双膦酸盐类药物中应用最广泛、综合疗效最好,现已作为乳腺癌骨转移的常规治疗药物.多项临床前研究及临床研究已证实,唑来膦酸对肿瘤细胞有直接或间接的抑制作用,联合其他辅助治疗(化疗和内分泌治疗)可发挥协同作用,对改善乳腺癌患者术后生存、抑制复发及转移具有重要作用,本文就上述研究进展作一综述.     

双膦酸盐联合化疗治疗多发性骨髓瘤骨并发症的临床观察

 目的　比较唑来膦酸联合化疗及伊班膦酸联合化疗预防和治疗多发性骨髓瘤（MM）骨并发症的效果及其安全性。方法　选择2005年3月至2008年3月中山大学附属第一医院治疗的MM患者77例,按照用药情况分为唑来膦酸联合化疗组24例,伊班膦酸联合化疗组26例,单纯化疗组27例。结果　唑来膦酸联合化疗组、伊班膦酸联合化疗组和单纯化疗组患者发生1次骨相关事件（SRE）的比例分别为25.0 ％、26.9 ％、48.1 ％（P＝0.145）。唑来膦酸联合化疗组、伊班膦酸联合化疗组发生脊柱压缩性骨折（VCF）的比例分别为4.2 ％和7.7 ％,少于单纯化疗组的14.8 ％（P＝0.115）。三组的中位首次发生SRE时间（T-SRE）分别为7.5、6.5和4.5个月（P＜0.001）。唑来膦酸联合化疗组止痛有效率为66.7 ％,伊班膦酸联合化疗组有效率为69.2 ％,单纯化疗组为29.6 %,差异有统计学意义（P＝0.028）。唑来膦酸联合化疗组治疗后的血钙水平低于伊班膦酸联合化疗组（P＝0.016）,降至正常水平所需时间也较伊班膦酸联合化疗组短（P＝0.04）。唑来膦酸联合化疗组和伊班膦酸联合化疗组的不良反应发生率低,两组不良反应发生率差异无统计学意义（P＞0.05）。结论　应用双膦酸盐可减少MM患者SRE的发生率和VCF。唑来膦酸在减少VCF发生率、减轻骨痛上与伊班膦酸类似,优于单纯化疗组;唑来膦酸在降低血钙水平方面优于伊班膦酸。唑来膦酸临床应用不良反应少,患者均可耐受。     

唑来膦酸联合化疗治疗乳腺癌骨转移疗效分析

[目的]评价唑来膦酸联合化疗治疗激素受体阴性甩乳腺癌多发骨转移的疗效及安全性。[方法]58例乳腺癌风转移患者随机分为唑来膦酸联合化疗（A组）及单用唑来膦酸（B组）治疗，对两组疗效进行分析比较。[结果]两组骨痛缓解率、生存质量改善率及毒副作用差异无显著性。A组骨转移灶修复率55.2%（16/29），B组13.8（4/29），差异有显著性。[结论]唑来膦酸联合化疗对激素受体阴性乳腺癌多发骨转移有较好的治疗作用，毒性可耐受。     

The use of zoledronic acid in Japanese men with stage D2 prostate cancer

Zoledronic acid (ZOL) is a new generation bisphosphonate with improved efficacy benefits over pamidronate in preclinical testing. In addition, ZOL is superior to pamidronate in the treatment of hypercalcemia of malignancy. ZOL is also the first bisphosphonate to demonstrate efficacy in patients with bone metastases from solid tumors other than breast cancer, such as prostate cancer. In this study, we investigated ZOL treatment in 17 Japanese men with advanced prostate cancer, treated at the Aichi Medical University Hospital between August 2006 and November 2007. The 17 patients had biopsy-confirmed prostate cancer and were found to harbor bone metastasis upon bone scintigraphy. ZOL was administered intravenously at a dose of 4 mg over 15 min every 4 weeks. ZOL was well tolerated with mild renal dysfunction in 2 patients (11.8%), while 1 patient (5.8%) developed skin rash. No significant side effects were observed. Subjective improvement in bone pain was reported in 14 patients (32.4%). ZOL, therefore, is a safe and effective drug that remains an important component of the urologist's armamentarium against advanced prostate cancer.     

唑来膦酸在乳腺癌辅助治疗中的临床应用及机制探讨

第三代双膦酸盐类药物唑来膦酸是治疗乳腺癌骨转移公认的标准药物之一,但其在乳腺癌辅助治疗中的应用地位尚存在争议。目前临床研究结果表明,唑来膦酸辅助治疗不仅可以提高骨密度．而且可以降低乳腺癌的复发和转移。在低雌激素水平环境下,唑来膦酸可使早期乳腺癌患者得到生存获益．而且早期应用的益处优于延迟应用。唑来膦酸通过抑制肿瘤转移过程中的多条途径而发挥抗肿瘤作用。但唑来膦酸的最佳剂量、治疗周期及持续时间尚有待进一步的研究予以确认。     

Zoledronic acid use in cancer patients

Bone is the most common site for metastasis from solid tumors, and the majority of patients will develop bone metastases during the natural course of their disease. Bisphosphonates are an effective treatment for preventing skeletal-related events in patients with bone metastases and may preserve functional independence and quality of life. Although several bisphosphonates have been investigated in patients with solid tumors, only zoledronic acid (ZOL) is approved by the US Food and Drug Administration and the European Medicines Agency for preventing skeletal-related events in patients across a broad range of solid tumors. In addition, bisphosphonates, notably ZOL, prevent cancer treatment-induced bone loss in breast and prostate cancer patients who are receiving endocrine therapy. It also has been demonstrated that ZOL directly and indirectly inhibits cancer cell growth in vitro and growth and tumorigenesis in animal model systems. These properties may produce clinically meaningful benefits. In recent clinical studies in patients with cancer, ZOL improved overall and prolonged disease-free survival. Ongoing clinical trials in patients with solid tumors will provide further insight into the potential of ZOL to prevent distant metastases and improve survival.     

Zoledronic acid protects against osteosarcoma‐induced bone destruction but lacks efficacy against pulmonary metastases in a syngeneic rat model

Osteosarcoma (OS) is the most common primary malignant tumor of bone in children and adolescents. In spite of successful control of the primary tumor, death from lung metastasis occurs in more than a third of patients. To investigate the efficacy of zoledronic acid (ZOL) on the development, progression and metastatic spread of OS, we used a rat model of OS, with features of the disease similar to human patients, including spontaneous metastasis to lungs. Rat OS cells were inoculated into the tibial marrow cavity of syngeneic rats. OS development was associated with osteolysis mixed with new bone formation, adjacent to the periosteum and extended into the surrounding soft tissue. Metastatic foci in the lungs formed 3–4 weeks postcancer cell transplantation. Treatment with a clinically relevant dose of ZOL was initiated 1 week after tumors were established and continued once weekly or as a single dose. ZOL preserved the integrity of both trabecular and cortical bone and reduced tumor‐induced bone formation. However, the overall tumor burden at the primary site was not reduced because of the persistent growth of cancer cells in the extramedullary space, which was not affected by ZOL treatment. ZOL treatment failed to prevent the metastatic spread of OS to the lungs. These findings suggest that ZOL as a single agent protects against OS‐induced bone destruction but lacks efficacy against pulmonary metastases in this rat model. ZOL may have potential value as an adjuvant therapy in patients with established OS.     

Tumor-targeting Salmonella typhimurium A1-R inhibits human prostate cancer experimental bone metastasis in mouse models

Bone metastasis is a frequent occurrence in prostate cancer patients and often is lethal. Zoledronic acid (ZOL) is often used for bone metastasis with limited efficacy. More effective models and treatment methods are required to improve the outcome of prostate cancer patients. In the present study, the effects of tumor-targeting Salmonella typhimurium A1-R were analyzed in vitro and in vivo on prostate cancer cells and experimental bone metastasis. Both ZOL and S. typhimurium A1-R inhibited the growth of PC-3 cells expressing red fluorescent protien in vitro. To investigate the efficacy of S. typhimurium A1-R on prostate cancer experimental bone metastasis, we established models of both early and advanced stage bone metastasis. The mice were treated with ZOL, S. typhimurium A1-R, and combination therapy of both ZOL and S. typhimurium A1-R. ZOL and S. typhimurium A1-R inhibited the growth of solitary bone metastases. S. typhimurium A1-R treatment significantly decreased bone metastasis and delayed the appearance of PC-3 bone metastases of multiple mouse models. Additionally, S. typhimurium A1-R treatment significantly improved the overall survival of the mice with multiple bone metastases. The results of the present study indicate that S. typhimurium A1-R is useful to prevent and inhibit prostate cancer bone metastasis and has potential for future clinical use in the adjuvant setting.     

Synergistic inhibitory activity of zoledronate and paclitaxel on bone metastasis in nude mice

Zoledronic acid (Zometa, ZOL) and cytotoxic chemotherapy agents have been reported to have synergistic antitumor activities. However, there is limited data on the effects of combination therapies on the development of bone metastasis in animal models of lung cancer. The purpose of this study was to establish a human lung adenocarcinoma cell line with high bone metastatic potential in an immunodeficient mouse model and to evaluate the synergistic inhibitory activity of zoledronate and paclitaxel (P) on bone metastasis in nude mice. A human lung adenocarcinoma cell line with high bone metastatic potential (SPC-A1-BM) was established by 10 rounds of in vivo selection. Cells were inoculated into the cardiac ventricle of NIH-BNX mice, which were treated 8 days later with: ZOL (0.2 mg/kg s.c. twice weekly) alone, P (6.0 mg/kg every week, i.p.) alone, P + ZOL, or vehicle (10 mice per group). Tumor growth was evaluated with bone scans, X-rays and in situ immunohistochemistry. Serum n-telopeptide of type I collagen (NTX) was measured by ELISA. Survival was assessed using the Kaplan-Meier method. Bone scan, radiographic and histological assessments revealed fewer bone metastases in all treatment groups vs. vehicle, with P + ZOL significantly reducing the incidence of bone metastases detected by bone scans (P=0.020) and X-rays (P=0.036). A histological analysis revealed marginal differences in the number of bone metastases between P + ZOL and vehicle (P=0.058). There was a trend towards differences in survival between the groups (P=0.1511) and survival was significantly longer for the P + ZOL group vs. vehicle (P=0.022). Compared with vehicle and ZOL alone, cancerous cells in the bone of mice treated with P + ZOL expressed higher levels of Bax and lower levels of Bcl-2 and Bcl-xl. ZOL produced a trend towards reduced NTX levels vs. vehicle and P + ZOL produced a profound reduction in NTX vs. vehicle (P=0.022). The results of this study indicated that zoledronate enhanced the efficacy of paclitaxel synergistically, by reducing the incidence of bone metastasis from lung cancer and prolonging survival in a mouse model of non-small cell lung cancer with a high potential for metastasis to bone.     

Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model.

PURPOSE: It is established that bisphosphonates (BPs), specific inhibitors of osteoclasts, have beneficial effects on bone metastases of breast cancer. In addition, recent studies have reported that BPs have anticancer effects and suppress visceral metastases, too. However, the results of clinical studies are still conflicting. In the present study, we examined the effects of the BP zoledronic acid (ZOL), one of the most potent BPs currently available, on visceral metastases of breast cancer using an animal model in which mouse breast cancer cells 4T1/luc implanted at the orthotopic mammary fat pad spontaneously metastasize to multiple organs including bone, lung, and liver in female BALB/c mice. Experimental Design and RESULTS: The 4T1/luc-bearing mice received single or four i.v. injections of ZOL (0.5 or 5 microg/mouse) during the whole experimental period. Bone metastases were reduced by the ZOL treatment. More importantly, ZOL significantly suppressed lung and liver metastases. Furthermore, ZOL prolonged overall survival of the tumor-bearing mice. Of interest, apoptosis in 4T1/luc cells colonized in bone was increased by ZOL; however, those in lung were not changed. In vitro studies demonstrated that ZOL inhibited cell migration and invasion and promoted apoptosis of 4T1/luc cells. CONCLUSIONS: These results are consistent with the notion that ZOL affects breast cancer metastasis to visceral organs as well as bone. These effects of ZOL may be attributable to inhibition of migration and invasion of breast cancer cells. Clinical relevance of our experimental results needs to be determined in breast cancer patients with visceral metastases.     

Effects of intravenous zoledronic acid and oral ibandronate on early changes in markers of bone turnover in patients with bone metastases from non-small cell lung cancer

Background

The aim of this study was to assess the early effects of zoledronic acid (ZOL) and oral ibandronate (IBA) on the bone resorption marker s-CTX (serum C-telopeptide of collagen type I) and the bone formation marker B-ALP (bone-alkaline phosphatase) in patients with bone metastases from non-small cell lung cancer (NSCLC).

Methods

Fifty-five patients with at least one site of bone metastasis secondary to NSCLC were randomly assigned to receive intravenous ZOL 4?mg every 4?weeks, or oral IBA 50?mg/day.

Results

At 1?month of treatment, s-CTX was reduced by 54.8% (95% CI 40.4?C59.8%) in the ZOL group (26 evaluable patients) compared with 38.2% (95% CI 29.8?C48.7%) in the oral IBA group (27 evaluable patients) (p?=?0.03). At 3?months, s-CTX was reduced by 72.6% (95% CI 58.6?C71.3%) in the ZOL group, compared with 66.4% (95% CI 54.3?C79.5%) in the oral IBA group (p?=?0.22). Both bisphosphonates similarly decreased the bone marker B-ALP at 1?month (ZOL 24.7%, 95% CI 3.6?C39.5%, and IBA 24.2%, 95% CI 2.8?C43.4%) and 3?months (ZOL 28.6%, 95% CI +2.8?C43.3%, and IBA 24.2%, 95% CI 3.2?C47.4%). Both bisphosphonates were well tolerated.

Conclusion

Considering the changes in bone markers, ZOL and oral IBA show comparable efficacy in patients with NSCLC and bone metastases.     

The impact of zoledronic acid therapy in survival of lung cancer patients with bone metastasis

Bone metastases occur in 20–40% of patients with lung cancer. Recent studies demonstrate a direct antiproliferative effect of 3rd generation bisphosphonates (BPs) on lung tumors, which may influence the survival. Therefore, we examined the clinical impact of zoledronic acid (ZOL; Zometa®), a 3rd generation BP, with a focus on the survival, time to progression and pain effect in lung cancer patients with bone metastases. Lung cancer patients (n = 144, Stage IV) with evidence of metastasis bone scan were included. Eighty‐seven of 144 experienced bone pain and received ZOL, 4 mg i.v. every 21 days (Group A), whereas the other 57 patients received no ZOL (Group B). All patients were treated with a combination chemotherapy consisted of docetaxel 100 mg/m² and carboplatin AUC = 6. It was found that Group A had a statistically significant longer survival (p < 0.01) when compared to Group B. A statistically significant positive correlation was found between the number of cycles of therapy with ZOL and total patient survival (p < 0.01, Pearson correlation) and time to progression (p < 0.01). Pain effect of ZOL had no significant difference between the 2 groups of patients (p > 0.05). Urine N‐telopeptide of type I collagen (NTx) levels decreased in patients with NTx ≤ 29 nM BCE/mM creatinine at baseline after treatment with ZOL. The results of our study suggest that the addition of ZOL increases overall survival in lung cancer patients with bone metastases. The longer period of receiving ZOL, the better effect on survival and time to progression. © 2009 UICC