Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells

Junichi Kurebayashi, Mamoru Nukatsuka, Hideki Nagase, Tsunehisa Nomura, Mai Hirono, Yutaka Yamamoto, Yoshikazu Sugimoto, Toshinori Oka, Hiroshi Sonoo

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)515-525
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume59
Issue number4
DOIs
Publication statusPublished - 2007 Mar
Externally publishedYes

Fingerprint

Tamoxifen
Fluorouracil
Estrogen Receptors
Doxorubicin
Cells
Breast Neoplasms
Genes
Therapeutics
Gene Expression
Chemotherapy
afimoxifene
varespladib methyl
Vascular Endothelial Growth Factor A
Drug Therapy
Growth

Keywords

  • 5-Fluorouracil
  • Breast Cancer
  • Concurrent
  • Doxorubicin
  • Tamoxifen

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Oncology

Cite this

Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells. / Kurebayashi, Junichi; Nukatsuka, Mamoru; Nagase, Hideki; Nomura, Tsunehisa; Hirono, Mai; Yamamoto, Yutaka; Sugimoto, Yoshikazu; Oka, Toshinori; Sonoo, Hiroshi.

In: Cancer Chemotherapy and Pharmacology, Vol. 59, No. 4, 03.2007, p. 515-525.

Research output: Contribution to journalArticle

Kurebayashi, Junichi ; Nukatsuka, Mamoru ; Nagase, Hideki ; Nomura, Tsunehisa ; Hirono, Mai ; Yamamoto, Yutaka ; Sugimoto, Yoshikazu ; Oka, Toshinori ; Sonoo, Hiroshi. / Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells. In: Cancer Chemotherapy and Pharmacology. 2007 ; Vol. 59, No. 4. pp. 515-525.
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abstract = "Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.",
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AU - Kurebayashi, Junichi

AU - Nukatsuka, Mamoru

AU - Nagase, Hideki

AU - Nomura, Tsunehisa

AU - Hirono, Mai

AU - Yamamoto, Yutaka

AU - Sugimoto, Yoshikazu

AU - Oka, Toshinori

AU - Sonoo, Hiroshi

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N2 - Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

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