Chapter 5 - Drug resistance pathways as targets

Abstract

The chapter focuses on various drug resistance pathways such as drug transporters, cellular stress response, and DNA repair that can act as potential therapeutic targets. The effectiveness of chemotherapy has been often limited by drug resistance of tumors, and by the side effects on normal tissues and cells. In fact, many tumors are intrinsically resistant to many of the most potent cytotoxic agents used in cancer therapy. Other tumors, initially sensitive, recur and are resistant not only to initial therapeutic agents but to other drugs that were not used for treatment. Drug resistance, intrinsic or acquired, can be attributed to mutational (genetic) or nonmutational (epigenetic) processes in cancer cells. Cancer cells become resistant to anticancer drugs because of various biochemical mechanisms such as decreased intracellular drug accumulation by decreased inward transport or by increased drug efflux, increased drug inactivation or detoxification, decreased conversion of drug to an active form, altered quantity or activity of target proteins, increased DNA repair capacity, and decreased susceptibility of apoptotic response. Cellular responses to microenvironmental stresses, such as hypoxia and glucose deprivation, can induce cellular drug resistance. Modulation of drug resistance genes or proteins is a promising approach, while the development of new drugs, which are not substrates of drug transporters, is another way to circumvent drug resistance.