Human epidermal growth factor receptor 2-positive breast cancer : which cytotoxic agent best complements trastuzumab's efficacy in vitro?
INTRODUCTION: Despite trastuzumab having enhanced selectivity for human epidermal growth factor receptor 2 (HER-2) overexpressing breast cancer cells, treatment is hampered by interindividual variation and tumors with high mitogenic potential. The lack of significant clinical benefit in certain patient cohorts suggests that HER-2 expression is ineffective as a sole prognostic indicator of response to therapy. Therefore, optimizing the clinical role of trastuzumab in drug combinations remains critical for clinical success.
AIM: To investigate the effects of trastuzumab in combination with either doxorubicin or geldanamycin on in vitro cell viability, cell cycling, apoptosis and relative HER-2 expression in HER-2-positive (SK-BR-3) and estrogen receptor-positive (MCF-7) breast adenocarcinoma models.
RESULTS: HER-2-rich SK-BR-3 cells demonstrated a greater sensitivity to the effects of doxorubicin than MCF-7 cells. Concurrent trastuzumab exposure resulted in a further reduction in cell viability. This decreased cell viability induced by doxorubicin was associated with activation of executioner caspases as well as with alterations in cell-cycle kinetics, primarily promoting S-phase accumulation. Doxorubicin had no effect on surface HER-2 density expression. Geldanamycin reduced cell viability significantly greater in SK-BR-3 than MCF-7 cells, and was associated with G2 cell-cycle accumulation. The addition of trastuzumab did not augment these effects. Geldanamycin promoted substantial reductions in relative surface HER-2 density in SK-BR-3 cells.
CONCLUSION: The in vitro data supported the rationale for using doxorubicin in trastuzumab-based therapies. Therefore, despite the incidence of cardiotoxicity, doxorubicin could retain a fundamental role in treating HER-2-positive breast cancer. While geldanamycin is a potent cytotoxic agent, its concurrent use with trastuzumab requires further research into the transient or permanent nature of alterations in HER-2 status in cell progeny.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6 |
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| Enthalten in: |
OncoTargets and therapy - 6(2013) vom: 01., Seite 693-701 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hurrell, Tracey [VerfasserIn] |
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| Links: |
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| Themen: |
Doxorubicin |
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| Anmerkungen: |
Date Completed 02.07.2013 Date Revised 21.10.2021 published: Electronic-Print Citation Status PubMed-not-MEDLINE |
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| doi: |
10.2147/OTT.S46883 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM228784352 |
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| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Electronic-Print | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a INTRODUCTION: Despite trastuzumab having enhanced selectivity for human epidermal growth factor receptor 2 (HER-2) overexpressing breast cancer cells, treatment is hampered by interindividual variation and tumors with high mitogenic potential. The lack of significant clinical benefit in certain patient cohorts suggests that HER-2 expression is ineffective as a sole prognostic indicator of response to therapy. Therefore, optimizing the clinical role of trastuzumab in drug combinations remains critical for clinical success | ||
| 520 | |a AIM: To investigate the effects of trastuzumab in combination with either doxorubicin or geldanamycin on in vitro cell viability, cell cycling, apoptosis and relative HER-2 expression in HER-2-positive (SK-BR-3) and estrogen receptor-positive (MCF-7) breast adenocarcinoma models | ||
| 520 | |a RESULTS: HER-2-rich SK-BR-3 cells demonstrated a greater sensitivity to the effects of doxorubicin than MCF-7 cells. Concurrent trastuzumab exposure resulted in a further reduction in cell viability. This decreased cell viability induced by doxorubicin was associated with activation of executioner caspases as well as with alterations in cell-cycle kinetics, primarily promoting S-phase accumulation. Doxorubicin had no effect on surface HER-2 density expression. Geldanamycin reduced cell viability significantly greater in SK-BR-3 than MCF-7 cells, and was associated with G2 cell-cycle accumulation. The addition of trastuzumab did not augment these effects. Geldanamycin promoted substantial reductions in relative surface HER-2 density in SK-BR-3 cells | ||
| 520 | |a CONCLUSION: The in vitro data supported the rationale for using doxorubicin in trastuzumab-based therapies. Therefore, despite the incidence of cardiotoxicity, doxorubicin could retain a fundamental role in treating HER-2-positive breast cancer. While geldanamycin is a potent cytotoxic agent, its concurrent use with trastuzumab requires further research into the transient or permanent nature of alterations in HER-2 status in cell progeny | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a SK-BR-3 cells | |
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| 650 | 4 | |a trastuzumab | |
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