Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, UK.
Curr Cancer Drug Targets. 2009 Nov;9(7):807-23. doi: 10.2174/156800909789760339.
Bisphosphonates are extensively used to treat cancer-induced bone disease in a range of solid tumours and multiple myeloma, where they reduce the incidence of skeletal related events and improve patients' quality of life. Recent reports indicate that bisphosphonates may also prevent recurrence of breast cancer at peripheral sites, suggesting that these drugs may have anti-tumour effects outside the skeleton. Anti-tumour effects of several bisphosphonates have been reported in a range of tumour cell types in vitro. These positive results have subsequently been supported by investigations of effects of bisphosphonates on tumour growth in vivo, both in bone and at peripheral sites. A reduction of tumour burden and also in cancer-induced bone disease has been reported following bisphosphonate treatment in several model systems, including breast and prostate cancer, osteosarcoma and multiple myeloma. In addition, bisphosphonates have been shown to significantly reduce growth of human tumour cells (including breast, prostate, lung and mesothelioma) implanted subcutaneously in immunocompromised mice. However, the majority of in vivo studies showing a reduction in bone disease and reduced tumour burden have used high doses and frequent administration of bisphosphonates, and the clinical relevance of these data have therefore been the subject of considerable debate. Bisphosphonates may hold greater promise as anti-tumour agents when used in combination with cytotoxic drugs, and several in vivo studies have reported substantial increased inhibition of tumour growth and improved survival when bisphosphonates have been added to standard chemotherapy regimens. This review will summarise the published data on anti-tumour effects of bisphosphonates from in vivo models, alone and in combination with other anti-cancer agents, and highlight the main lessons learned and future challenges in this field.
双膦酸盐被广泛用于治疗多种实体瘤和多发性骨髓瘤引起的癌性骨病，可降低骨骼相关事件的发生率并提高患者的生活质量。最近的报告表明，双膦酸盐还可能预防乳腺癌外周部位的复发，这表明这些药物在骨骼以外可能具有抗肿瘤作用。几种双膦酸盐在体外的多种肿瘤细胞类型中都具有抗肿瘤作用。这些阳性结果随后得到了双膦酸盐在体内对肿瘤生长的影响的研究的支持，包括在骨骼和外周部位。在包括乳腺癌和前列腺癌、骨肉瘤和多发性骨髓瘤在内的几种模型系统中，双膦酸盐治疗后，肿瘤负担减少，癌症引起的骨病也减少。此外，双膦酸盐已被证明可显著抑制植入免疫功能低下小鼠皮下的人肿瘤细胞（包括乳腺癌、前列腺癌、肺癌和间皮瘤）的生长。然而，大多数显示骨病减少和肿瘤负担减少的体内研究都使用了高剂量和频繁的双膦酸盐给药，因此这些数据的临床相关性一直是激烈争论的主题。当与细胞毒性药物联合使用时，双膦酸盐作为抗肿瘤药物可能具有更大的前景，并且几项体内研究报告称，当将双膦酸盐添加到标准化疗方案中时，肿瘤生长的抑制作用显著增加，生存率提高。这篇综述将总结来自体内模型的双膦酸盐抗肿瘤作用的已发表数据，单独使用和与其他抗癌药物联合使用，并强调该领域的主要经验教训和未来挑战。
