ABSTRACT
Drug resistance is a major cause for the failure of both chemotherapies and targeted drugs. This chapter reviews reasons for the failure of systemic cancer therapies and attempts to reverse drug resistance, particularly multidrug resistance related to expression of P-glycoprotein. The blood-brain and blood-testicular barriers are major potential physiological causes of treatment failure in acute lymphocytic leukemias and high-grade lymphomas and have resulted in the use of prophylactic intrathecal drug administration and radiation. Drug resistance may be intrinsic, i.e., present from the outset of therapy, or acquired, i.e., developing during or after the course of treatment. Although most anticancer agents enter cells via passive diffusion, some drugs are transported into cells by membrane proteins, whose expression is a potential determinant of cellular sensitivity or resistance to antifolates. Most anticancer drugs and ionizing radiation exert their therapeutic effects by activating apoptosis or programmed cell death.
