Overview of Tumor Cell Chemoresistance Mechanisms

Drug resistance of tumor cells is recognized as the primary cause of failure of chemotherapeutic treatment of most human tumors. Although pharmacological factors-including inadequate drug concentration at the tumor site-can contribute to clinical resistance, cellular factors play a major role in chemoresistance of several tumors. Although manifestations of resistance are conventionally referred to as acquired or intrinsic on the basis of the initial response to the first therapy, a common feature is the development of a phenotype resistant to a variety of structurally and functionally distinct agents. In both manifestations, drug resistance is a multifactorial phenomenon involving multiple interrelated or independent mechanisms. A heterogeneous expression of involved mechanisms may characterize tumors of the same type or cells of the same tumor and may at least in part reflect tumor progression. The relevant mechanisms that can contribute to cellular resistance include: increased expression of defense factors involved in reducing intracellular drug concentration; alterations in drug-target interaction; and changes in cellular response, in particular increased cell ability to repair DNA damage or tolerate stress conditions, and defects in apoptotic pathways. This chapter presents an overview of the drug resistance mechanisms.