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Oral fluoropyrimidine may augment the efficacy of aromatase inhibitor via the down-regulation of estrogen receptor in estrogen-responsive breast cancer xenografts

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Abstract

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 (E2) 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.

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Abbreviations

ANA:

Anastrozole

CI:

Combination index

DCC:

Dextran-coated charcoal-stripped

ADM:

Doxorubicin hydrochloride

Ct:

Threshold cycle

DIF:

DPD inhibitory fluoropyrimidine

DPD:

Dihydropyrimidine dehydrogenase

E2 :

17β-Estradiol

ER:

Estrogen receptor

5-FU:

5-Fluorouracil

FCS:

Fetal calf serum

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GD:

Growth delay

HPMC:

Hydroxypropyl methylcellulose

HRP:

Horseradish peroxidase

IC50 :

50% Inhibitory concentration

TXL:

Paclitaxel

RT-PCR:

Reverse transcriptional polymerase chain reaction

RTV:

Relative tumor volume

S-1:

Tegaful–gimeracil–oteracil

TAM:

Tamoxifen

Tes-P:

Testosterone pellet

TGI:

Tumor growth inhibition

UFT:

Tegafur-uracil

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Acknowledgments

We thank Prof. J Patrick Barron of the Department of International Medical Communications of Tokyo Medical University for helpful advice and revision of grammatical errors of the manuscript.

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Authors and Affiliations

  1. Tokushima Research Center, Taiho Pharmaceutical Co., Ltd., 224-2, Ebisuno Hiraishi, Kawauchi-Cho, Tokushima-Shi, Tokushima, 771-0194, Japan

    Mamoru Nukatsuka, Hitoshi Saito, Fumio Nakagawa, Masaaki Abe, Junji Uchida & Mamoru Kiniwa

  2. Hanno Research Center, Taiho Pharmaceutical Co., Ltd., 1-27, Misugidai, Hanno-Shi, Saitama, 357-8527, Japan

    Jiro Shibata & Ken-ichi Matsuo

  3. Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, 2-2-E10 Yamadaoka Suita, Osaka, 565-0871, Japan

    Shinzaburo Noguchi

Authors
  1. Mamoru Nukatsuka
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  2. Hitoshi Saito
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  3. Fumio Nakagawa
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  4. Masaaki Abe
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Correspondence to Mamoru Nukatsuka.

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Nukatsuka, M., Saito, H., Nakagawa, F. et al. Oral fluoropyrimidine may augment the efficacy of aromatase inhibitor via the down-regulation of estrogen receptor in estrogen-responsive breast cancer xenografts. Breast Cancer Res Treat 128, 381–390 (2011). https://doi.org/10.1007/s10549-010-1141-3

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