The development of drug resistance remains a major obstacle in curing cancer patients. Mechanisms of drug resistance occur primarily at the cellular level. Genetic changes can lead to altered gene products, which may be directly involved in the development of drug resistance. Individual mechanisms of resistance depend on the tumor type and class of drug used in treatment. Specific alterations may involve drug transport into and out of the cell, altered drug metabolism leading to enhanced detoxification, changes in the drug target resulting in reduced drug cytotoxicity, and repair of drug-induced damage. To overcome drug resistance at the cellular level, we must be able to identify individual mechanisms of resistance so that we may develop approaches to modulate it. Once a mechanism of drug resistance is discovered in the laboratory, then methods of analysis must be developed to determine if it occurs in patients. Multiple mechanisms of resistance may occur for any given drug and each will need to be addressed in order to overcome clinical drug resistance. Only through well-designed clinical trials will we be able to determine clinically relevant drug resistance mechanisms and means of overcoming it.
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