Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells
The sequential addition of tamoxifen (TAM) to chemotherapy seems superior to its concurrent addition in patients with breast cancer. This study was conducted to clarify the hypothesis that there are differential interactions among TAM and chemotherapeutic agents.
Estrogen receptor (ER)-α-positive or -negative breast cancer cells were treated with 4-hydroxy TAM (4OHT), 5-fluorouracil (FU) and/or doxorubicin (Dox). Changes in the expression levels of genes related to sensitivity and resistance to TAM, 5-FU or Dox were tested.
Concurrent treatment of 4OHT with 5-FU but not with Dox additively inhibited the growth of ER-α-positive cells. 5-FU did not change the expression levels of any tested genes related to either sensitivity or resistance to TAM. Although Dox did not change the expression levels of any genes related to the sensitivity to TAM, Dox significantly increased the expression levels of some genes related to TAM resistance, Eph A-2, ER-β, Fos and vascular endothelial growth factor. 4OHT significantly decreased thymidilate synthase (TS) activity.
Although the antitumor effect of concurrent 4OHT and 5-FU was additive, that of concurrent 4OHT and Dox was less than additive in ER-α-positive cells. The increased expression of genes related to TAM resistance by Dox might be responsible for the interaction. Decreased TS activity by 4OHT might increase the antitumor activity of 5-FU. These findings may provide a preclinical rationale for concurrent use with 5-FU and TAM.
KeywordsBreast Cancer Concurrent Doxorubicin 5-Fluorouracil Tamoxifen
Analysis of variance
Fetal bovine serum
Fibroblast growth factor
Human epidermal growth factor receptor
Hypoxia inducible factor
50% inhibitory concentration
Orotate phosphoribosyl transferase
Trefoil factor 1
Reverse transcriptional polymerase chain reaction
Stromal cell-derived factor
Vascular endothelial factor
- 1.Albain KS, Green SJ, Ravdin PM, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Schneider DJ, Abeloff MD, Norton L, Henderson IC, Lew D, Livingston RB, Martino S, Osborne CK (2002) Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814). Proc ASCO 21:37a (Abstract 143)Google Scholar
- 2.Pico C, Martin M, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J (2004) Epirubicin–cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study. Ann Oncol 15:79–87PubMedCrossRefGoogle Scholar
- 4.Noguchi S, Koyama H, Uchino J, Abe R, Miura S, Sugimachi K, Akazawa K, Abe O (2005) Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials. J Clin Oncol 23:2172–2184PubMedCrossRefGoogle Scholar
- 13.Kunisue H, Kurebayashi J, Otsuki T, Kunisue H, Kurebayashi J, Otsuki T, Tang CK, Kurosumi M, Yamamoto S, Tanaka K, Doihara H, Shimizu N, Sonoo H (2000) Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2. Br J Cancer 82:46–51PubMedCrossRefGoogle Scholar
- 21.Vandermoere F, El Yazidi-Belkoura I, Adriaenssens E, Lemoine J, Hondermarck H (2005) The antiapoptotic effect of fibroblast growth factor-2 is mediated through nuclear factor-κB activation induced via interaction between Akt and IκB kinase-β in breast cancer cells. Oncogene 24:5482–5491PubMedCrossRefGoogle Scholar
- 22.McLeskey SW, Kurebayashi J, Honig SF, Zwiebel J, Lippman ME, Dickson RB, Kern FG (1993) Fibroblast growth factor 4 transfection of MCF-7 cells produces cell lines that are tumorigenic and metastatic in ovariectomized or tamoxifen-treated athymic nude mice. Cancer Res 53:2168–2177PubMedGoogle Scholar