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Genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors

Oncogene volume 19, pages 1114–1122 (2000)Cite this article

Abstract

Several transgenic mouse tumor models were utilized to explore how specific genetic alterations affect the tumor cell response to chemotherapeutic agents in vivo. Specifically, MMTV-ras transgenic mice were interbred to p53 knock-out mice to create a model for assessing the role of p53 in chemotherapeutic responses. In addition, MMTV-ras tumors were compared to MMTV-myc and MMTV-ras/myc tumors. Mice of each genotype reproducibly develop mammary and/or salivary tumors, but tumor growth dynamics vary considerably between genotypes. MMTV-ras/p53−/− tumors exhibit higher S phase fractions than MMTV-ras/p53+/+ tumors, although both tumor types display very low apoptosis levels. In contrast, MMTV-myc tumors exhibit both high S phase fractions and spontaneous apoptosis levels. Tumor-bearing mice of each genotype were treated with either doxorubicin or paclitaxel, and effects on overall tumor growth, cell cycle distribution and apoptosis were evaluated. Surprisingly, neither agent efficiently induced apoptosis in any of the tumor models, including those with wildtype p53. Rather, tumor responses were mediated primarily by changes in cell cycle distribution. However, the spontaneous apoptosis levels did serve as a predictor of tumor growth response, in that only those tumors with high pretreatment apoptosis levels underwent significant regression following treatment with either agent.

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Acknowledgements

This work was supported in part by American Cancer Society grant DHP-150 (to JJ Windle), and by the San Antonio Cancer Institute Cancer Center Support Grant P30 CA54174.

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Authors and Affiliations

  1. Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, 78284, Texas, TX, USA

    D J Bearss, J E Hundley & J J Windle

  2. Department of Pathology, University of Texas Health Science Center at San Antonio, San Antonio, 78284, Texas, TX, USA

    D A Troyer

  3. Cancer Therapy and Research Center, San Antonio, 78229, Texas, TX, USA

    M A Subler, R A Salinas & J J Windle

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  1. D J Bearss
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Bearss, D., Subler, M., Hundley, J. et al. Genetic determinants of response to chemotherapy in transgenic mouse mammary and salivary tumors. Oncogene 19, 1114–1122 (2000). https://doi.org/10.1038/sj.onc.1203275

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