Drug resistance is a major concern associated with chemotherapy. Malignant cells are resistant to chemotherapy, or become resistant to chemotherapy, by many mechanisms. Inadequate blood flow, confluence of cell growth and tissue turgor might interfere with drug penetration into the tumor. The drug may be inactivated by way of glucuronyl- or glutathione-S- transferases (alkylating agents, including platinum complexes). There may be failure of drug activation, such as failure of activation of cyclophosphamide by the liver. Drugs may be solubilized and excreted by way of hepatic microsomal enzymes. Drugs that alter a specific intracellular target, like methotrexate, might be susceptible to resistance by overexpression of the target by gene amplification. Physical and kinetic factors influence drug resistance; quiescent cells are generally resistant to antimetabolites. Pharmacokinetic factors may also influence drug resistance. Repeated exposure to a drug may lead to enhanced ability to excrete or metabolize that agent. For example, for drugs excreted in the urine, like carboplatin, toxicity and antitumor efficacy are related to renal function. For some drugs, reduced expression of transport systems, or reduced affinity for the drug, may cause resistance. Other mechanisms leading to resistance include quantitative and qualitative alterations of topoisomerase II, or enhanced DNA repair.  

An important mechanism of acquired drug resistance is increased drug efflux, via p-glycoprotein. In this circumstance, drug exposure may confer multidrug resistance as a result of induction or amplification of the mdr1 gene. mdr1 codes a 170D protein which rapidly exports hydrophobic chemicals out of the cell. A variety of substances are being tested clinically to bind to or modulate the phosphorylation of p-glycoprotein. These substances include verapamil and its analogues, diltiazem, the phenothiazines, cyclosporin and its analogues, tamoxifen and others.  Drug resistance is a major concern associated with chemotherapy. Malignant cells are resistant to chemotherapy, or become resistant to chemotherapy, by many mechanisms. Inadequate blood flow, confluence of cell growth and tissue turgor might interfere with drug penetration into the tumor. The drug may be inactivated by way of glucuronyl- or glutathione-S- transferases (alkylating agents, including platinum complexes). There may be failure of drug activation, such as failure of activation of cyclophosphamide by the liver. Drugs may be solubilized and excreted by way of hepatic microsomal enzymes. Drugs that alter a specific intracellular target, like methotrexate, might be susceptible to resistance by overexpression of the target by gene amplification. Physical and kinetic factors influence drug resistance; quiescent cells are generally resistant to antimetabolites. Pharmacokinetic factors may also influence drug resistance. Repeated exposure to a drug may lead to enhanced ability to excrete or metabolize that agent. For example, for drugs excreted in the urine, like carboplatin, toxicity and antitumor efficacy are related to renal function. For some drugs, reduced expression of transport systems, or reduced affinity for the drug, may cause resistance. Other mechanisms leading to resistance include quantitative and qualitative alterations of topoisomerase II, or enhanced DNA repair.