title: Antimetastatic and anticancer activity of S-1, a new oral dihydropyrimidine-dehydrogenase-inhibiting fluoropyrimidine, alone and in combination with paclitaxel in an orthotopically implanted human breast cancer model.
abstract: To evaluate the antitumor and antimetastatic efficacy of oral fluoropyrimidines, alone and combined with taxane on human breast cancer xenografts model, we developed a breast cancer model that spontaneously metastasizes to the lung by orthotopic implantation of MDA-MB-435S-HM tumors into the mammary fat pad (mfp) of SCID mice. The activity of the 5-fluorouracil (5-FU)-degrading enzyme dihydropyrimidine dehydrogenase (DPD) was significantly higher in the metastatic tumors than in the primary tumors. Based on this enzymatic characteristic of pulmonary metastases of breast cancer in regard to 5-FU metabolism, we investigated the antitumor activity of two types of oral 5-FU prodrugs, with and without paclitaxel, on both orthotopically implanted breast tumors and metastatic lung tumors in mice. The drugs and doses used were: S-1, a new oral DPD-inhibiting fluoropyrimidine (DIF) 8.3 mg/kg/day, capecitabine 360 mg/kg/day as a non-DIF, and paclitaxel 50 mg/kg, all of which display minimal toxicity in mice. In the primary tumors, paclitaxel and S-1 displayed a significant antitumor activity, with 57 and 41%, respectively inhibition of tumor growth (p < 0.01), but capecitabine had no effect. When S-1 and paclitaxel were combined, they synergistically caused tumor regression (tumor growth inhibition ratio 94%, p < 0.01) in mice compared to capecitabine plus paclitaxel, without any toxicity. In the pulmonary metastasis model, paclitaxel, and both S-1 alone and combined with paclitaxel, but not capecitabine alone or combined with paclitaxel, diaplayed almost complete antimetastatic activity. These results strongly suggest that combination of S-1, as a DIF with taxanes will show a potent high antitumor and antimetastatic effect on refractory human breast cancers, especially those expressing strong DPD activity.
authors.affiliation: Applied Oncology Section, Postmarketing Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima 771-0194, Japan. m-nukatsuka@taiho.co.jp
authors.forename: Mamoru
authors.initials: M
authors.lastname: Nukatsuka
authors.forename: Akio
authors.initials: A
authors.lastname: Fujioka
authors.forename: Fumio
authors.initials: F
authors.lastname: Nakagawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oshimo
authors.forename: Kenji
authors.initials: K
authors.lastname: Kitazato
authors.forename: Jyunji
authors.initials: J
authors.lastname: Uchida
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Sekio
authors.initials: S
authors.lastname: Nagayama
authors.forename: Masakazu
authors.initials: M
authors.lastname: Fukushima
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000662:veterinary; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010094:Oxonic Acid / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D005641:Tegafur / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D017239:Paclitaxel