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Molecular cytogenetics of multiple drug resistance
1Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta 30912.
Abstract:
The refractory nature of many human cancers to multi-agent chemotherapy is termed multidrug resistance (MDR). In the past several decades, a major focus of clinical and basic research has been to characterize the genetic and biochemical mechanisms mediating this phenomenon. To provide model systems in which to study mechanisms of multidrug resistance, in vitro studies have established MDR cultured cell lines expressing resistance to a broad spectrum of unrelated drugs. In many of these cell lines, the expression of high levels of multidrug resistance developed in parallel to the appearance of cytogenetically-detectable chromosomal anomalies resulting from gene amplification. This review describes cytogenetic and molecular-based studies that have characterized DNA amplification structures in MDR cell lines and describes the important role gene amplification played in the cloning and characterization of the mammalian multidrug resistance genes (mdr). In addition, this review discusses the genetic selection generally used to establish the MDR cell lines, and how drug selections performed in transformed cell lines generally favor the genetic process of gene amplification, which is still exploited to identify drug resistance genes that may play an important role in clinical MDR.
Insights
Multidrug resistance (MDR) in cancer hinders chemotherapy. Gene amplification in cell lines is key to understanding MDR mechanisms and identifying resistance genes for clinical applications.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy, rendering treatments ineffective.
- Understanding the genetic and biochemical mechanisms of MDR is crucial for developing effective therapies.
- In vitro studies using multidrug-resistant cell lines have been instrumental in characterizing MDR.
Purpose of the Study:
- To review the cytogenetic and molecular studies on DNA amplification structures in MDR cell lines.
- To highlight the role of gene amplification in identifying mammalian multidrug resistance (mdr) genes.
- To discuss the use of genetic selection in establishing MDR cell lines and identifying clinically relevant drug resistance genes.
Main Methods:
- Analysis of cytogenetic and molecular data from MDR cell lines.
- Review of studies characterizing DNA amplification structures.
- Examination of genetic selection strategies for inducing and studying drug resistance.
Main Results:
- Gene amplification is frequently observed in MDR cell lines, often correlating with high-level drug resistance.
- DNA amplification has been critical for the cloning and characterization of mammalian mdr genes.
- Drug selection in transformed cell lines predominantly favors gene amplification, a process exploited for gene discovery.
Conclusions:
- Gene amplification is a significant mechanism underlying multidrug resistance in cancer.
- MDR cell line models and gene amplification studies are vital for discovering novel drug resistance genes.
- Continued exploitation of gene amplification is essential for advancing MDR research and clinical strategies.