Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells

Valerie Wiebe, Steven Koester, Michele Lindberg, Vernon Emshoff, Jeffery Baker, Gregory Wurz, Michael DeGregorio

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50=< 0.1 μg/ml MDA 231; IC 50=100 μg/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156% increase) versus wild type MDA 231 cells (6% increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114%, 128% and 42% respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose. Toremifene remains a very promising agent for modulating doxorubicin cytotoxicity in multidrug resistance.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalInvestigational New Drugs
Volume10
Issue number2
DOIs
StatePublished - Jun 1992
Externally publishedYes

Fingerprint

Toremifene
Estrogen Receptors
Doxorubicin
Breast Neoplasms
Multiple Drug Resistance
Cell Cycle
S Phase
Area Under Curve

Keywords

  • breast cancer
  • multidrug resistance
  • toremifene

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells. / Wiebe, Valerie; Koester, Steven; Lindberg, Michele; Emshoff, Vernon; Baker, Jeffery; Wurz, Gregory; DeGregorio, Michael.

In: Investigational New Drugs, Vol. 10, No. 2, 06.1992, p. 63-71.

Research output: Contribution to journalArticle

Wiebe, Valerie ; Koester, Steven ; Lindberg, Michele ; Emshoff, Vernon ; Baker, Jeffery ; Wurz, Gregory ; DeGregorio, Michael. / Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells. In: Investigational New Drugs. 1992 ; Vol. 10, No. 2. pp. 63-71.
@article{295b9d0719ff4e1f84a03aa3b75a1e28,
title = "Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells",
abstract = "The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50=< 0.1 μg/ml MDA 231; IC 50=100 μg/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156{\%} increase) versus wild type MDA 231 cells (6{\%} increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114{\%}, 128{\%} and 42{\%} respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose. Toremifene remains a very promising agent for modulating doxorubicin cytotoxicity in multidrug resistance.",
keywords = "breast cancer, multidrug resistance, toremifene",
author = "Valerie Wiebe and Steven Koester and Michele Lindberg and Vernon Emshoff and Jeffery Baker and Gregory Wurz and Michael DeGregorio",
year = "1992",
month = "6",
doi = "10.1007/BF00873119",
language = "English (US)",
volume = "10",
pages = "63--71",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "2",

}

TY - JOUR

T1 - Toremifene and its metabolites enhance doxorubicin accumulation in estrogen receptor negative multidrug resistant human breast cancer cells

AU - Wiebe, Valerie

AU - Koester, Steven

AU - Lindberg, Michele

AU - Emshoff, Vernon

AU - Baker, Jeffery

AU - Wurz, Gregory

AU - DeGregorio, Michael

PY - 1992/6

Y1 - 1992/6

N2 - The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50=< 0.1 μg/ml MDA 231; IC 50=100 μg/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156% increase) versus wild type MDA 231 cells (6% increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114%, 128% and 42% respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose. Toremifene remains a very promising agent for modulating doxorubicin cytotoxicity in multidrug resistance.

AB - The enhanced accumulation of doxorubicin by agents known to reverse multidrug resistance provides a good functional test for evaluating modulating activity. In the present study, the non-steroidal triphenylethylene toremifene selectively increased doxorubicin accumulation in multidrug resistant estrogen receptor negative MDA A-1 human breast cells compared to the MDA 231 wild type cells. MDA A-1 cells were noted to be 1,000 fold resistant to doxorubicin (IC 50=< 0.1 μg/ml MDA 231; IC 50=100 μg/ml MDA A-1). Total accumulation of doxorubicin, expressed as area under the time concentration curve (AUC), was increased significantly in doxorubicin resistant cells (156% increase) versus wild type MDA 231 cells (6% increase). Correction of the accumulation defect to doxorubicin in drug resistant cells required a 18-20 hour pre-incubation with toremifene. The effects of toremifene on cell cycle in MDA A-1 cells was analyzed by flow cytometric techniques. Toremifene had a dose response relationship in blocking cells in G0-G1 reducing the number of cells entering S phase of the cell cycle. This effect was maximal at concentrations which increased the accumulation of doxorubicin in MDA A-1 cells. Several metabolites of toremifene were also noted to increase doxorubicin accumulation in MDA A-1 doxorubicin resistant cells. Tore XVIII (deaminocarboxytoremifene), Tore IV (4-hydroxy-N-desmethyltoremifene) and N-desmethyltoremifene all increased the accumulation of doxorubicin significantly (114%, 128% and 42% respectively). Finally, we show evidence that toremifene and its active metabolites are present in high concentrations in human plasma following a single 200 mg oral dose. Toremifene remains a very promising agent for modulating doxorubicin cytotoxicity in multidrug resistance.

KW - breast cancer

KW - multidrug resistance

KW - toremifene

UR - http://www.scopus.com/inward/record.url?scp=0026625972&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026625972&partnerID=8YFLogxK

U2 - 10.1007/BF00873119

DO - 10.1007/BF00873119

M3 - Article

VL - 10

SP - 63

EP - 71

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 2

ER -