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Trastuzumab and Liposomal Doxorubicin in the Treatment of MCF-7 Xenograft Tumor-Bearing Mice: Combination Does Not Affect Drug Serum Levels

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Purpose

We assessed the combination of doxorubicin or liposomal doxorubicin with trastuzumab for alterations in peak serum drug levels, as these agents are increasingly being paired in the treatment of aggressive breast cancer. We hypothesized that trastuzumab would exhibit a slower rate of elimination from the serum when in combination with liposomal doxorubicin based on the known effects of liposomal doxorubicin on phagocytic cells of the mononuclear phagocyte system (MPS), which are responsible in part for the uptake and degradation of antibodies.

Methods

Doxorubicin and trastuzumab serum levels were assessed following injection of free doxorubicin, liposomal doxorubicin, or trastuzumab into female RAG2-M mice bearing subcutaneous MCF-7HER-2 tumors. The effects of combination drug treatment on tumor growth were compared to single-agent treatment.

Results

Peak serum trastuzumab levels were not altered as a result of addition of doxorubicin therapy, nor were doxorubicin levels altered over 24 h as a result of coadministration of trastuzumab. Liposomal doxorubicin administration did result in serum doxorubicin levels 200- to 1000-fold higher than with injection of free doxorubicin.

Conclusions

For the specific combination of trastuzumab with doxorubicin, either in free or liposomal form, coadministered in mice, there was no impact of one drug on the other in terms of peak serum drug levels or efficacy.

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Abbreviations

AC:

doxorubicin and cyclophosphamide

AUC:

area under the curve

i.p.:

intraperitoneal

PBS:

phosphate-buffered saline

TMB:

tetramethylbenzidine

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Acknowledgments

D.N. Waterhouse was supported by a Postgraduate Fellowship from the Canadian Breast Cancer Foundation. M.B. Bally was supported by the National Cancer Institute of Canada.

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Authors and Affiliations

  1. BC Cancer Agency, USA

    Dawn N. Waterhouse, Tetyana Denyssevych, Norma Hudon, Stephen Chia & Karen A. Gelmon

  2. University of British Columbia, USA

    Marcel B. Bally

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  1. Dawn N. Waterhouse
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  2. Tetyana Denyssevych
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Correspondence to Dawn N. Waterhouse.

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Waterhouse, D.N., Denyssevych, T., Hudon, N. et al. Trastuzumab and Liposomal Doxorubicin in the Treatment of MCF-7 Xenograft Tumor-Bearing Mice: Combination Does Not Affect Drug Serum Levels. Pharm Res 22, 915–922 (2005). https://doi.org/10.1007/s11095-005-4586-z

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