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Apoptosis and chemoresistance in transgenic cancer models
Clemens A Schmitt1, Scott W Lowe
1Max Delbrück Center for Molecular Medicine, Department of Hematology/Oncology, Charité/Campus and Virchow-Hospital, Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany. clemens.schmitt@charite.de
Abstract:
Multidrug resistance remains an unresolved problem in clinical oncology. Over a decade ago genes encoding cellular efflux pumps were shown to confer resistance to a broad spectrum of biochemically unrelated anticancer drugs even before the compounds reached their intracellular targets. More recently it has become apparent that many drugs induce a common apoptotic program, such that mutations in this program can also produce multidrug resistance. However, a thorough evaluation of the contribution of apoptotic defects to this "postdamage" drug resistant phenotype is technically complicated, and this has led to uncertainty about the overall significance of apoptosis in therapy-induced cell death. For example, correlative analyses using patient specimens are limited by unknown background mutations in the biopsy material, and assays using cancer cell lines can be biased by unphysiological conditions. We sought to circumvent these restrictions by utilizing a tractable transgenic cancer model to examine the impact of apoptosis on treatment outcome. Here we discuss potential caveats of cell culture based assays, highlight features of genetically engineered mice as potential model systems, and describe a tractable transgenic mouse model to study drug responses in a series of primary lymphomas with genetically defined lesions treated at their natural site.
Insights
Multidrug resistance in cancer is complex. This study uses a transgenic mouse model to investigate how defects in apoptosis, a cell death program, contribute to drug resistance, offering new insights beyond efflux pump mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multidrug resistance (MDR) is a major challenge in cancer therapy.
- Cellular efflux pumps and apoptotic pathway defects are known mechanisms of MDR.
- The precise contribution of apoptosis to MDR is uncertain due to experimental limitations.
Purpose of the Study:
- To evaluate the impact of apoptotic defects on drug resistance in cancer.
- To overcome limitations of cell culture and patient specimen analyses.
- To utilize a transgenic cancer model for studying therapy response.
Main Methods:
- Development and utilization of a tractable transgenic mouse model.
- Examination of drug responses in primary lymphomas within the model.
- Genetic definition of lesions in the studied lymphomas.
- Treatment of lymphomas at their natural site.
Main Results:
- The study highlights the potential of genetically engineered mice as model systems for cancer research.
- It describes a specific transgenic mouse model for investigating drug responses.
- The model allows for studying lymphomas with defined genetic lesions.
Conclusions:
- Transgenic mouse models offer a viable approach to study complex biological processes like drug resistance.
- Understanding the role of apoptosis in MDR is crucial for improving cancer treatment outcomes.
- This model system facilitates the study of drug responses in a physiologically relevant context.