Human epidermal growth factor receptor 2-positive breast cancer : which cytotoxic agent best complements trastuzumab's efficacy in vitro?

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dc.contributor.author Hurrell, Tracey
dc.contributor.author Outhoff, Kim
dc.date.accessioned 2013-10-23T10:00:40Z
dc.date.available 2013-10-23T10:00:40Z
dc.date.issued 2013-06-15
dc.description.abstract 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. en_US
dc.description.librarian am2013 en_US
dc.description.sponsorship The authors would like to acknowledge Roche Pharmaceuticals for the kind donation of trastuzumab and the Cancer Association of South Africa (CANSA) as well as the Research and Development Program (RDP), University of Pretoria, for providing their generous funding, and to Dr AD Cromarty and Dr JJ van Tonder without which this project would not have been possible. en_US
dc.description.uri http://www.dovepress.com en_US
dc.identifier.citation Hurrell, T & Outhoff, K 2013, 'Human epidermal growth factor receptor 2-positive breast cancer: which cytotoxic agent best complements trastuzumab's efficacy in vitro?', OncoTargets and Therapy, vol. 6, pp. 693-701. en_US
dc.identifier.issn 1178-6930
dc.identifier.other 10.2147/OTT.S46883
dc.identifier.uri http://hdl.handle.net/2263/32126
dc.language.iso en en_US
dc.publisher Dove Medical Press en_US
dc.rights © 2013 Hurrell and Outhoff, publisher and licensee Dove Medical Press Ltd. en_US
dc.subject Trastuzumab en_US
dc.subject Geldanamycin en_US
dc.subject Doxorubicin en_US
dc.subject SK-BR-3 cells en_US
dc.subject Human epidermal growth factor receptor-2 (HER-2) en_US
dc.subject Estrogen receptor-positive (MCF-7) en_US
dc.title Human epidermal growth factor receptor 2-positive breast cancer : which cytotoxic agent best complements trastuzumab's efficacy in vitro? en_US
dc.type Article en_US


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