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19.1 INTRODUCTION

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A major problem with systemic treatment of cancers is the presence or induction of drug resistance in the tumor cells. In practice many types of cancer that occur commonly in humans (eg, colon cancer, most types of non–small cell lung cancer, pancreatic cancer) have a limited response to treatment with current anticancer drugs. Other human tumors (eg, breast cancer, ovarian cancer, or small cell lung cancer) often respond to initial treatment, but acquired resistance to further therapy usually prevents drug treatment from being curative. Resistance to chemotherapy may have multiple causes, and the most widely studied of these are genetically determined mechanisms that lead to resistance of the individual tumor cells. Sensitivity to drugs may differ widely among cell populations from tumors and normal tissues and also among the cells of a single tumor. The selection or induction of a drug resistant subpopulation in human tumors is a major factor limiting the efficacy of clinical chemotherapy. Even if drug-resistant cells are present initially only at low frequency (eg, 1 drug resistant cell per 105 drug-sensitive cells), their selective advantage during drug treatment will lead to their rapid emergence as the dominant cell population, giving the clinical impression of "acquired resistance."

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There is substantial evidence, reviewed below, that drug resistance may occur through mutation, deletion, or amplification of genes that influence the uptake, metabolism, and efflux of anticancer drugs from target cells. Factors other than genetically determined mechanisms of resistance can lead to clinical resistance of human tumors to anticancer drugs (Sharma et al, 2010). Transient changes in cellular phenotype may occur through epigenetic mechanisms (see Chap. 2, Sec. 2.3): These mechanisms influence the expression of genes (and hence of the proteins encoded by them) as compared to genetic resistance which relates to information transmitted by the DNA sequence of a gene.

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The activity of many drugs is dependent on the proliferative status of the cells, and for many of them, on the phase of the cell cycle (see Chap. 17, Sec. 17.5.2). Thus a tumor may appear resistant if many of its constituent cells are nonproliferating or are spared in a drug-resistant phase of the cell cycle. Rapid proliferation of surviving tumor cells (ie, repopulation) between courses of chemotherapy can counter the effects of cell killing and lead to effective resistance. Cure or long-term remission of tumors may be governed by a small population of cells with high proliferative potential (although not necessarily high proliferative rate), so called tumor stem cells (see Chap. 13, Sec. 13.4), and it is the sensitivity of these cells that may ultimately determine success of chemotherapy.

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Sensitivity to drugs may depend not only on the intrinsic sensitivity of the constituent tumor cells, but also on the microenvironment and on contact between the tumor cells. Drugs can only exert their lethal effects if they reach the cells at a sufficient concentration ...

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