Ottewell Penelope D, Deux Blandine, Mönkkönen Hannu, Cross Simon, Coleman Robert E, Clezardin Philippe, Holen Ingunn
School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom.
Clin Cancer Res. 2008 Jul 15;14(14):4658-66. doi: 10.1158/1078-0432.CCR-07-1545.
Breast cancer patients with bone metastases are commonly treated with chemotherapeutic agents such as doxorubicin and zoledronic acid to control their bone disease. Sequential administration of doxorubicin followed by zoledronic acid has been shown to increase tumor cell apoptosis in vitro. We have therefore investigated the antitumor effects of clinically relevant doses of these drugs in a mouse model of breast cancer bone metastasis.
MDA-MB-231/BO2 cells were injected via the tail vein into athymic mice. Tumor-induced osteolytic lesions were detected in all animals following X-ray analysis 18 days after tumor cell inoculation (day 18). Mice were administered saline, 100 microg/kg zoledronic acid, 2 mg/kg doxorubicin, doxorubicin and zoledronic acid simultaneously, or doxorubicin followed 24 h later by zoledronic acid. Doxorubicin-treated animals received a second injection on day 25. Tumor growth in the marrow cavity and on the outside surface of the bone was measured as well as tumor cell apoptosis and proliferation. The effects of treatments on bone were evaluated following X-ray and muCT analysis.
Sequential treatment with doxorubicin followed by zoledronic acid caused decreased intraosseous tumor burden, which was accompanied by increased levels of tumor cell apoptosis and decreased levels of proliferation, whereas extraosseous parts of the same tumors were unaffected. Administration of zoledronic acid, alone or in combination with doxorubicin, resulted in significantly smaller tumor-induced osteolytic lesions compared with control or doxorubicin-treated animals.
This is the first study to show that sequential treatment with clinically relevant doses of doxorubicin, followed 24 h later by zoledronic acid, reduces intraosseous but not extraosseous growth of BO2 breast tumors. Our results suggest that breast cancer patients with metastatic bone disease may benefit from sequential treatment using doxorubicin and zoledronic acid.
患有骨转移的乳腺癌患者通常采用化疗药物如阿霉素和唑来膦酸进行治疗，以控制其骨病。体外实验表明，先给予阿霉素再给予唑来膦酸可增加肿瘤细胞凋亡。因此，我们研究了这些药物的临床相关剂量在乳腺癌骨转移小鼠模型中的抗肿瘤作用。
将MDA-MB-231/BO2细胞经尾静脉注射到无胸腺小鼠体内。在接种肿瘤细胞18天后（第18天）进行X射线分析，所有动物均检测到肿瘤诱导的溶骨性病变。给小鼠注射生理盐水、100μg/kg唑来膦酸、2mg/kg阿霉素、阿霉素和唑来膦酸同时给药，或阿霉素给药24小时后再给予唑来膦酸。阿霉素治疗的动物在第25天接受第二次注射。测量骨髓腔内和骨外表面的肿瘤生长情况以及肿瘤细胞凋亡和增殖情况。通过X射线和微计算机断层扫描（μCT）分析评估治疗对骨的影响。
阿霉素后序贯给予唑来膦酸导致骨内肿瘤负荷降低，同时肿瘤细胞凋亡水平升高，增殖水平降低，而同一肿瘤的骨外部分未受影响。与对照组或阿霉素治疗的动物相比，单独给予唑来膦酸或与阿霉素联合使用，可使肿瘤诱导的溶骨性病变明显减小。
这是第一项表明临床相关剂量的阿霉素给药24小时后序贯给予唑来膦酸可减少BO2乳腺肿瘤的骨内生长但不影响骨外生长的研究。我们的结果表明，患有转移性骨病的乳腺癌患者可能从阿霉素和唑来膦酸的序贯治疗中获益。
