唑来膦酸联合紫杉醇治疗肺腺癌骨转移的实验研究

Efficacy of the bisphosphonate alone and combined with paclitaxel against bone metastasis of human adenocarcinoma lung cancer

背景与目的:双膦酸盐制剂是肺癌骨转移治疗的主要用药之一。唑来膦酸在体外和体内能抑制小细胞肺癌瘤株的生长,具有直接的抗肿瘤作用,并且与常用的抗癌药物联用有协同作用。本文用人肺腺癌骨转移细胞株SPC-A-1BM的免疫缺陷小鼠动物实验模型,观察比较唑来膦酸钠联合紫杉醇与单用紫杉醇、单用唑来膦酸钠对非小细胞肺癌(NSCLC)骨转移荷瘤鼠的实验疗效,并进一步探讨双膦酸盐可能的作用机制。方法:①将人肺腺癌骨转移细胞株SPC-A-1BM,接种于40只等体重的NIH-BNX小鼠左心室,制成骨转移瘤治疗模型。②将40只荷瘤小鼠随机分为四组,分别为唑来膦酸钠(B组)、紫杉醇(P组)、唑来膦酸钠联合紫杉醇(B+P组)和0.9%氯化钠溶液组(对照组),每组10只。接种后第8天开始用药,治疗5周。③每只小鼠每周称体重2次,记录生存情况。至第8周放血处死小鼠,留取血清样本,ELISA法检测血清Ⅰ型胶原氨基末端肽(NTX)水平;ECT核素骨扫描和X线摄片检测骨转移部位和数量;HE染色病理检查可疑转移部位及未转移的全脊柱的骨和骨髓结构;观察小鼠肺部、肝、淋巴结和肾上腺有无转移结节,用膨胀压片法计数肺部转移灶数,HE染色病理切片检查。结果:①核素显像和X线摄片结果显示:各实验组与对照组相比骨转移均有显著差异(P=0.013,P=0.036),以B+P组骨转移鼠数较少;病理检查显示:实验组与对照组比较骨转移鼠数有边缘性统计学差异(P=0.058),以P组、B+P组骨转移较少;骨转归生物标记物-Ⅰ型胶原氨基末端肽(NTX)检测显示B+P组血清NTX水平低于对照组(P=0.017);B+P组未见肺转移(P=0.036);②唑来膦酸联合紫杉醇组生存期较对照组延长(logrank=0.022)。结论:唑来膦酸钠与紫杉醇联合处理非小细胞肺癌骨转移有协同作用。

Background and purpose：Zoledronic acid has been proved to have anti-tumour effects.The purpose of this study was to establish a human lung adenocarcinoma cell line（SPC-A-1BM）with high metastatic potential in bone of immunodeficient（SCID）mouse model,and to evaluate the efficacy of zoledronate alone and combined with paclitaxel in reducing the tumor-induced bone disease.Methods：The human lung adenocarcinoma cancer cells SPC-A-1BM were inoculated into the cardiac ventricle of 40 SCID mice（NIH-BNX）.They were randomized into 4 groups,and were treated with zoledronate alone,zoledronate combined with paclitaxel,or paclitaxel alone,or control group,respectively for 5 weeks after 7 days of tumor implantation.Bone metastases was assessed,measurement of total-body nuclei bone scan,X-rays,serum NTx were done,bone lesions for pathologic evaluation,the incidence of other organ metastasis,weight loss and survival time until 8 weeks were also analyzed.Results：The zoledronate combined with paclitaxel was very effective in reducing NSCLC bone metastases.Bone nuclei scan,radiographic and histological results revealed that there were more bone metastatic lesions in the control group than that in the treatment group.In the treatment groups,bone nuclei scan and radiographic imagine suggested that the combined group significantly reduced bone metastasis（P=0.013,P=0.036）.Histological analysis showed that there was a marginal difference（P=0.058）between the combined group and the control.The numbers of bone metastases mice in combined group equaled to that in the paclitaxel group,there were less bone metastases than the control＇s.Moreover,the bone turnover biomarker NTx level was reduced by inhibiting osteoclast activity in the combined group,there was a significant difference between the control and paclitaxel group,respectively（P=0.017,P=0.022）.The combined group inhibited lung metastases（P=0.036）.Only the combined group significantly prolonged the survival time（log rank=0.022）.Conclusions：The results indicated that zoledronate inhibited the osteoclast activity,zoledronate enhanced the effects of paclitaxel synergistically,reduced the incidence of NSCLC bone metastasis and prolonged survival time.