Hiraga Toru, Hata Kenji, Ikeda Fumiyo, Kitagaki Jirota, Fujimoto-Ouchi Kaori, Tanaka Yutaka, Yoneda Toshiyuki
Department of Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
Oncol Rep. 2005 Sep;14(3):695-9.
5'-deoxy-5-fluorouridine (5'-DFUR) and capecitabine are oral anti-cancer agents, which are enzymatically converted to 5-fluorouracil (5-FU) by thymidine phosphorylase in humans and uridine phosphorylase in mice. Since the activity of these phosphorylases is higher in cancerous tissue than in normal tissue, systemic administration of 5'-DFUR and capecitabine achieves high intratumoral 5-FU levels and low adverse effects on non-tumoral tissue. Accordingly, 5'-DFUR and capecitabine are widely used for the treatment of cancer patients. In the present study, we examined the effects of 5'-DFUR and capecitabine on bone metastases, one of the most common complications of breast cancer, using an animal model in which inoculation of 4T1/luc mouse breast cancer cells into the mammary fat pads of female BALB/c mice developed spontaneous metastases in distant organs including bone, lung and liver. Mice received 4T1/luc cell inoculation in the mammary fat pad at day 0 and oral 5'-DFUR (31, 62, 123 or 246 mg/kg) or capecitabine (90, 180 or 359 mg/kg) daily from day 7 to day 21. Both 5'-DFUR and capecitabine significantly inhibited orthotopic tumor formation and distant metastases to bone, lung and liver in a dose-dependent manner. Of note, the lowest dose of 5'-DFUR (31 mg/kg) and capecitabine (90 mg/kg), which failed to inhibit orthotopic tumor development and the lung and liver metastases, significantly reduced the bone metastases. In conclusion, our results suggest that oral 5'-DFUR and capecitabine are effective for the treatment of primary and secondary breast tumors. Most notably, they also suggest that these agents are preferentially beneficial for bone metastases.
5'-脱氧-5-氟尿苷（5'-DFUR）和卡培他滨是口服抗癌药物，它们在人体内被胸苷磷酸化酶、在小鼠体内被尿苷磷酸化酶酶促转化为5-氟尿嘧啶（5-FU）。由于这些磷酸化酶在癌组织中的活性高于正常组织，因此全身性给予5'-DFUR和卡培他滨可使肿瘤内5-FU水平升高，且对非肿瘤组织的不良反应较低。因此，5'-DFUR和卡培他滨被广泛用于治疗癌症患者。在本研究中，我们使用一种动物模型来研究5'-DFUR和卡培他滨对骨转移（乳腺癌最常见的并发症之一）的影响，该模型是将4T1/luc小鼠乳腺癌细胞接种到雌性BALB/c小鼠的乳腺脂肪垫中，会在包括骨、肺和肝在内的远处器官发生自发性转移。小鼠在第0天接受乳腺脂肪垫接种4T1/luc细胞，并从第7天至第21天每天口服5'-DFUR（31、62、123或246 mg/kg）或卡培他滨（90、180或359 mg/kg）。5'-DFUR和卡培他滨均以剂量依赖性方式显著抑制原位肿瘤形成以及向骨、肺和肝的远处转移。值得注意的是，未能抑制原位肿瘤发展以及肺和肝转移的5'-DFUR最低剂量（31 mg/kg）和卡培他滨最低剂量（90 mg/kg）显著减少了骨转移。总之，我们的结果表明口服5'-DFUR和卡培他滨对原发性和继发性乳腺肿瘤的治疗有效。最值得注意的是，它们还表明这些药物对骨转移特别有益。
