Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Oncol Rep. 2010 Jul;24(1):233-9. doi: 10.3892/or_00000851.
Third-generation bisphosphonates are known to inhibit bone resorption and also appear to exhibit direct anti-tumour activity. We previously reported that third-generation bisphosphonates such as zoledronic acid (ZOL) have a direct antitumour effect, and synergistically augment the effects of antitumor agents in osteosarcoma cells. There has been no report on the antitumor effect of ZOL against soft tissue sarcoma. The aim of this study was to evaluate the antitumor effect of this drug on a human fibrosarcoma cell line, in terms of proliferation and apoptosis, and, moreover, to evaluate the combined effects of ZOL with other antitumor drugs against the human fibrosarcoma cell line. HT1080 cells were treated with ZOL at various concentrations up to 10 microM, and then cell proliferation, cell cycle, nuclear morphology, and Western blot analyses were performed to study the antitumor effects of ZOL alone, and, moreover, HT1080 cells were treated with ZOL and other anticancer drugs such as paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, cisplatin, or methotrexate to investigate the combined effects using proliferation and cell cycle analyses. We found that ZOL strongly inhibited in vitro proliferation, arrested the cell cycle between S and G2/M phases, and induced the apoptosis of human fibrosarcoma cells. Moreover, ZOL augmented the effect of antitumor agents when administered concurrently with paclitaxel, docetaxel, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, and cisplatin in human fibrosarcoma cells. The treatment of fibrosarcoma with ordinary antitumor drugs is not fully effective. These findings suggest that ZOL directly affects the proliferation and survival of fibrosarcoma cells, and that the combined administration of ZOL with other antitumor agents may improve the efficacy of fibrosarcoma treatment. These results support the possibility that their combined use could be beneficial in the treatment of patients not only with various types of cancer or osteosarcoma, but also with soft tissue sarcoma.
第三代双膦酸盐已知能抑制骨吸收，并且似乎也具有直接的抗肿瘤活性。我们之前报道过第三代双膦酸盐如唑来膦酸（zoledronic acid，ZOL）具有直接的抗肿瘤作用，并与骨肉瘤细胞中的抗肿瘤药物协同增强作用。目前尚未有关于 ZOL 对软组织肉瘤的抗肿瘤作用的报道。本研究旨在评估该药对人纤维肉瘤细胞系的抗肿瘤作用，包括增殖和凋亡，并评估 ZOL 与其他抗肿瘤药物联合应用对人纤维肉瘤细胞系的联合作用。将 HT1080 细胞用不同浓度的 ZOL 处理至 10 μM，然后进行细胞增殖、细胞周期、核形态和 Western blot 分析，以研究 ZOL 单独的抗肿瘤作用，此外，还将 HT1080 细胞用 ZOL 和其他抗癌药物如紫杉醇、多西他赛、多柔比星、依托泊苷、5-氟尿嘧啶、吉西他滨、顺铂或甲氨蝶呤联合处理，通过增殖和细胞周期分析研究联合作用。我们发现 ZOL 强烈抑制体外增殖，将细胞周期阻滞在 S 和 G2/M 期，并诱导人纤维肉瘤细胞凋亡。此外，当 ZOL 与紫杉醇、多西他赛、多柔比星、依托泊苷、5-氟尿嘧啶、吉西他滨和顺铂联合应用于人纤维肉瘤细胞时，增强了抗肿瘤药物的作用。普通抗肿瘤药物治疗纤维肉瘤的效果并不完全有效。这些发现表明，ZOL 直接影响纤维肉瘤细胞的增殖和存活，并且 ZOL 与其他抗肿瘤药物联合给药可能改善纤维肉瘤的治疗效果。这些结果支持这样一种可能性，即它们的联合使用可能有益于治疗不仅患有各种类型癌症或骨肉瘤，而且患有软组织肉瘤的患者。
