[Antimetastatic and antitumor effects of fluoropyrimidines alone and combined with taxanes in a murine model of breast cancer metastatic to the lung].
To evaluate the antitumor efficacy against metastatic breast cancer of fluoropyrimidines alone and combined with other chemotherapeutic agents, we developed a murine model of breast cancer metastatic to the lung by orthotopically implanting MDA-MB-435S breast tumors into mice. MDA tumor cells greatly metastasized to lung tissue only after the orthotopically implanted tumors were surgically removed. Measurement of the expression of enzymes involved in 5-FU metabolism showed significantly higher activity of dihydropyrimidine dehydrogenase (DPD) and lower activity of thymidylate synthase (TS) in the MDA metastases than in the orthotopically implanted tumors. Based on the enzymatic properties of metastatic tumors, the minimum toxic doses of UFT (17.5 mg/kg/day) as a DPD-inhibitory fluoropyrimidine (DIF), and of 5'-DFUR (120 mg/kg/day) as a non-DIF, were orally administered to mice with pulmonary metastasis of the breast tumor. The results showed that UFT significantly inhibited the growth of pulmonary metastases of the breast tumors, but 5'-DFUR did not. UFT seemed to inhibit the growth of the pulmonary metastases of the breast tumors in combination with paclitaxel (50 mg/kg) more than in combination with 5'-DFUR, although the antitumor efficacy of neither combination was significantly different from that of paclitaxel alone. These results suggest that combination of DIF with other chemotherapeutic drugs, such as taxanes, is required to attain high antimetastatic and antitumor efficacy against breast tumor metastases, based on the molecular characteristics of the metastatic tumors.
Nukatsuka
Mamoru
M
Cancer Research Laboratory, Taiho Pharmaceutical Co., Ltd.
Fujioka
Akio
A
Nakagawa
Fumio
F
Ohshimo
Hideyuki
H
Fukushima
Masakazu
M
D000609:Aminoacridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D005467:Floxuridine / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D043823:Taxoids; D005641:Tegafur / Q000494:pharmacology; D014498:Uracil / Q000494:pharmacology
D000609:Aminoacridines; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D004338:Drug Combinations; D043823:Taxoids; C096910:UFT(R) drug; D005467:Floxuridine; D005641:Tegafur; C080625:taxane; C034633:fluoroquinacrine; D014498:Uracil; C025034:doxifluridine