Duivenvoorden W C M, Vukmirović-Popović S, Kalina M, Seidlitz E, Singh G
Juravinski Cancer Centre, Hamilton, Ontario, Canada L8V 5C2.
Br J Cancer. 2007 May 21;96(10):1526-31. doi: 10.1038/sj.bjc.6603740. Epub 2007 Apr 17.
Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.
骨是乳腺癌患者最常见的转移部位之一，常导致严重的临床发病率和死亡率。双膦酸盐类药物目前是乳腺癌骨转移患者的标准治疗药物。我们之前已经表明，四环素类抗生素之一的强力霉素，在人乳腺癌实验性骨转移小鼠模型中可降低肿瘤总负荷。在本研究中，我们将强力霉素治疗与最有效的双膦酸盐唑来膦酸联合使用。在注射MDA-MB-231细胞前3天开始给药。当小鼠单独使用唑来膦酸时，与安慰剂治疗相比，肿瘤总负荷降低了43%。与未治疗的小鼠相比，唑来膦酸和强力霉素联合给药导致肿瘤总负荷降低了74%。在强力霉素和唑来膦酸盐治疗的小鼠中，通过成骨细胞数量、类骨质表面和体积的增加确定骨形成显著增强，同时也观察到骨吸收减少。强力霉素大大降低了肿瘤负荷，还可以补偿增加的骨吸收。在治疗方案中加入唑来膦酸进一步降低了肿瘤负荷，导致骨相关软组织肿瘤负荷大幅下降（93%），并维持了骨量，这可能会降低骨折风险。唑来膦酸与强力霉素联合治疗可能对有溶骨性骨转移风险的乳腺癌患者非常有益。
