The pharmacological point of view of resistance to therapy in tumors.

Resistance to therapy is a challenging clinical problem, whose solution is far from being reached. Gains in current knowledge have identified key elements at the basis of drug resistance and have suggested possible ways to overcome it. However, some points have always to be kept in mind whatever the type of tumor or drug (cytotoxic or targeted agent) when considering treatment resistance in tumors. In this review we discuss these points and their impact in resistance to cancer therapy: the importance of reaching active tumor drug concentration, reviewing the various micro- and macro-components of the host that can influence their concentrations and activity, the evolving complex heterogeneity of tumors, the intrinsic tumor cell susceptibility to the drug, and the emerging role of the tumor microenvironment. Both the data from the molecular and biological characterization of human tumors allow a better rational and timing use of the available arsenal of anticancer therapy and new strategies to improve the penetration of antitumor drugs in tumors are the new chances to delay and possibly eliminate the emergence of resistance in tumors.