Targeting cellular and microenvironmental multidrug resistance

Multidrug resistance (MDR) is one of the major factors restricting the efficacy of chemotherapy. Several pathophysiological mechanisms contribute to MDR, including the overexpression of drug efflux pumps. Strategies to overcome MDR have mostly focused on the modulation of cellular resistance, such as the use of drugs and drug delivery systems to inhibit or bypass drug efflux pumps. Much less attention has been devoted to microenvironmental resistance, both mechanistically and therapeutically. As a reciprocal response to cellular MDR, cancer cells might remodel their microenvironment, resulting in changes in vascularization and oxygenation, as well as in the expression of cell adhesion molecules, extracellular matrix components and matrix metalloproteinases. We here describe the basic principles of cellular and microenvironmental MDR, and discuss drug delivery systems and drug targeting strategies to more efficiently deal with cellular and microenvironmental resistance.