Preferential inhibition of bone metastases by 5'-deoxy-5-fluorouridine and capecitabine in the 4T1/luc mouse breast cancer model.
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.
Hiraga
Toru
T
Department of Biochemistry, Osaka University Graduate School of Dentistry, Suita, Osaka 565-0871, Japan.
Hata
Kenji
K
Ikeda
Fumiyo
F
Kitagaki
Jirota
J
Fujimoto-Ouchi
Kaori
K
Tanaka
Yutaka
Y
Yoneda
Toshiyuki
T
D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000517:prevention & control* / Q000556:secondary; D000069287:Capecitabine; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D005472:Fluorouracil / Q000031:analogs & derivatives; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome
D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; D008156:Luciferases; D005472:Fluorouracil; C025034:doxifluridine