MOLECULAR CYTOGENETICS OF MULTIPLE-DRUG RESISTANCE

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.