Treatment of HER-2/neu overexpressing breast cancer xenograft models with trastuzumab (Herceptin) and gefitinib (ZD1839):: Drug combination effects on tumor growth, HER-2/neu and epidermal growth factor receptor expression, and viable hypoxic cell fraction

被引:70
作者
Warburton, C
Dragowska, WH
Gelmon, K
Chia, S
Yan, H
Masin, D
Denyssevych, T
Wallis, AE
Bally, MB
机构
[1] British Columbia Canc Agcy, Dept Adv Therapeut, Vancouver, BC V5Z 4E6, Canada
[2] British Columbia Canc Agcy, Dept Med Oncol, Vancouver, BC V5Z 4E6, Canada
[3] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada
[4] Celator Technol Inc, Vancouver, BC, Canada
关键词
D O I
10.1158/1078-0432.CCR-03-0244
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The purpose of this research was to assess the effects of single agent and combination treatment with trastuzumab and gefitinib on tumor growth and tumor microenvironment in two HER-2/neu overexpressing breast xenograft models, MDA-MB-435/LCC6(HER-2) (LCC6(HER-2); estrogen receptor negative) and MCF-7(HER-2) (estrogen receptor positive). Experimental Design: LCC6(HER-2) and MCF-7(HER-2) cells, both in tissue culture and xenografts grown in SCID-Rag 2M mice, were treated with trastuzumab and gefitinib, alone or in combination. The rate of tumor growth was determined. In addition, tumor HER-2/neu and epidermal growth factor receptor expression, cell viability, cell cycle distribution, and proportion of viable hypoxic cells were determined by flow cytometric analyses of single tumor cell suspensions. Results: Both tumor models were very sensitive to trastuzumab and moderately sensitive to gefitinib in vivo. The combination resulted in therapeutic effects, as judged by inhibition of tumor growth, which was greater (albeit not statistically significant) than that observed with trastuzumab administered as a single agent. Trastuzumab was effective in down-regulating HER-2/neu, and gefitinib mediated a reduction in epidermal growth factor receptor expression on tumor cells. In LCC6(HER-2) tumors, trastuzumab significantly reduced tumor cell viability, which was not improved by the addition of gefitinib. Gefitinib dramatically reduced the proportion of viable hypoxic cells in LCC6(HER-2) and MCF-7(HER-2) tumors. This effect was abrogated by the addition of trastuzumab. Conclusions: Although in vivo efficacy studies in two HER-2/neu overexpressing breast xenograft models showed that the combination of trastuzumab and gefitinib was effective, analyses of various cellular parameters failed to reveal beneficial effects and argue that this drug combination may not be favorable.
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页码:2512 / 2524
页数:13
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