Hiraga Toru, Ueda Akimi, Tamura Daisuke, Hata Kenji, Ikeda Fumiyo, Williams Paul J, Yoneda Toshiyuki
Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan.
Int J Cancer. 2003 Oct 10;106(6):973-9. doi: 10.1002/ijc.11330.
Bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Therefore, intervention of bone metastases is one of the important targets in the management of breast cancer. In the present study, we examined the effects of the orally administrable chemotherapeutic agent UFT (a combination of tegafur and uracil at a molar ratio of 1:4) on bone metastases using an animal model of the 4T1/luc mouse breast cancer. The 4T1/luc cells developed spontaneous metastases to bone following orthotopic cell inoculation. Oral daily administration of UFT (20 mg/kg/day) significantly reduced the orthotopic tumor burden; however, the lower dose (15 mg/kg/day) did not. In contrast, histologic examination showed that both doses of UFT significantly suppressed bone metastases in a dose-dependent manner. Since clinical studies have demonstrated that bisphosphonates (BPs), specific inhibitors of osteoclastic bone resorption, are beneficial for breast cancer patients with bone metastases, we next examined the effects of UFT combined with the BP zoledronic acid (ZOL) on established bone metastases. The combination of UFT (20 mg/kg/day) with ZOL (250 microg/kg) caused an enhanced reduction of bone metastases compared with UFT alone. In vitro studies showed that 5-fluorouracil (5-FU), an active metabolite of UFT, and ZOL increased apoptosis in 4T1/luc cells and inhibited osteoclast-like cell formation in an additive fashion. Our results suggest that oral UFT is an effective chemotherapeutic agent for advanced breast cancer accompanying bone metastases and that the combination with BP increases its benefits for bone metastases.
骨转移是乳腺癌患者发病率增加和最终死亡的主要原因之一。因此，干预骨转移是乳腺癌治疗的重要目标之一。在本研究中，我们使用4T1/luc小鼠乳腺癌动物模型，研究了口服化疗药物优福定（替加氟与尿嘧啶摩尔比为1:4的组合）对骨转移的影响。4T1/luc细胞原位接种后会自发转移至骨。每日口服优福定（20毫克/千克/天）可显著降低原位肿瘤负荷；然而，较低剂量（15毫克/千克/天）则无此效果。相比之下，组织学检查表明，两种剂量的优福定均以剂量依赖性方式显著抑制骨转移。由于临床研究已证明双膦酸盐（BPs），即破骨细胞骨吸收的特异性抑制剂，对患有骨转移的乳腺癌患者有益，我们接下来研究了优福定与双膦酸盐唑来膦酸（ZOL）联合使用对已形成的骨转移的影响。与单独使用优福定相比，优福定（20毫克/千克/天）与唑来膦酸（250微克/千克）联合使用可增强对骨转移的抑制作用。体外研究表明，优福定的活性代谢产物5-氟尿嘧啶（5-FU）和唑来膦酸可增加4T1/luc细胞的凋亡，并以相加方式抑制破骨细胞样细胞的形成。我们的结果表明，口服优福定是治疗伴有骨转移的晚期乳腺癌的有效化疗药物，与双膦酸盐联合使用可增加其对骨转移的疗效。
