Oral fluoropyrimidine may augment the efficacy of aromatase inhibitor via the down-regulation of estrogen receptor in estrogen-responsive breast cancer xenografts.
The present preclinical study was designed to evaluate a new combination therapy comprised of the aromatase inhibitor anastrozole (ANA) and the oral fluoropyrimidines, UFT and S-1 against the estrogen receptor (ER)-positive human breast cancer cell line MCF-7/Arom 14, which was stably transfected with the cDNA of human aromatase. MCF-7/Arom 14 cells showed a high aromatase activity and notably were able to grow in the presence of testosterone and estradiol (E(2)) in vitro. ANA and 5-fluorouracil (5-FU) inhibited cell growth at concentrations of 0.005-10 and 0.2-5 μM, respectively, and the combination of both drugs additively inhibited cell growth. The growth of MCF-7/Arom 14 tumors was significantly inhibited by ANA and S-1 or UFT in vivo. The combination of ANA with S-1 or UFT administered using a 21-day consecutive, metronomic-like regimen significantly enhanced the antitumor efficacy, suppressing tumor growth for 2-4 times longer than monotherapy. To investigate the mechanisms by which S-1 enhances the antitumor activity of ANA, the protein and mRNA expression levels of ER-α in tumor tissue after treatment with S-1, ANA, and the typical chemotherapeutic agents doxorubicin (ADM) or paclitaxel (TXL) were analyzed. The protein and mRNA expression levels of ER-α in the tumor tissue were markedly decreased after treatment with S-1 or S-1 + ANA, but not after treatment with either ADM or TXL. The reduced ER-α level after S-1 treatment might contribute to the increased antitumor activity of ANA by reducing ER-α-induced growth signaling in addition to the decrease in estrogen production induced by ANA. Based on these results, the combination of ANA and S-1 might yield a greater benefit than other chemotherapeutic agents in postmenopausal women with ER-positive breast cancer.
Nukatsuka
Mamoru
M
Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno Hiraishi, Kawauchi-Cho, Tokushima-Shi, Tokushima 771-0194, Japan. m-nukatsuka@taiho.co.jp
Saito
Hitoshi
H
Nakagawa
Fumio
F
Abe
Masaaki
M
Uchida
Junji
J
Shibata
Jiro
J
Matsuo
Ken-ichi
K
Noguchi
Shinzaburo
S
Kiniwa
Mamoru
M
D000077384:Anastrozole; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage; D004338:Drug Combinations; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009570:Nitriles / Q000627:therapeutic use*; D010094:Oxonic Acid / Q000008:administration & dosage; D017239:Paclitaxel / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D005641:Tegafur / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D014230:Triazoles / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014498:Uracil / Q000008:administration & dosage
D047072:Aromatase Inhibitors; D004338:Drug Combinations; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009570:Nitriles; D012333:RNA, Messenger; D014230:Triazoles; C096910:UFT(R) drug; C079198:S 1 (combination); D005641:Tegafur; D000077384:Anastrozole; D014498:Uracil; D010094:Oxonic Acid; D004317:Doxorubicin; D017239:Paclitaxel; D005472:Fluorouracil