Chapter 37 : Development of Resistance to Anticancer Agents

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This chapter focuses on development of resistance to anticancer agents. In recent years there has been great progress made in identifying new mechanisms of resistance. From these studies, it has become clear that genomic instability and the tumor microenvironment strongly influence the development of resistance and play a major role in the evolution of resistance. A large number of scientific studies have focused on the identification and characterization of mechanisms of drug resistance using tissue culture-based models. In general, the mechanisms of microenvironment-related drug resistance can be subdivided into those that lead to reduced drug effect and those mechanisms that provide increased tolerance to damage. In a study with small cell lung cancer (SCLC) cells, extracellular matrix (ECM) proteins were found to protect the cells from chemotherapy induced apoptosis. While the focus on these highly resistant cell lines facilitated the elucidation of the mechanisms behind high level drug resistance, it is possible that the initial lines in which resistance was two-to-fourfold, relative to the original parent cell line, contained the secrets to understanding clinically relevant cancer drug resistance. Ultimately, the identification of the cellular factors that mediate this form of resistance may provide novel strategies for circumventing both intrinsic and acquired drug resistance. It was clear almost from the beginning that multidrug resistance in vitro and in vivo involved multiple mechanisms acting in concert to modulate chemo-sensitivity, although often this was not readily appreciated.

Citation: Modrak D, Jones G, Draper M. 2005. Development of Resistance to Anticancer Agents, p 500-513. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch37

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Generic image for table
Table 1.

PC4 cell lines resulting from adriamycin selection

Reprinted from ( ) with permission from the publisher.

Fold resistance was defined as the IC for the cell line divided by the IC of the parental (wt) cell line.

Percent accumulation was defined as the amount of tritiated daunorubicin present in resistant cells relative to the amount present in the parental cells after a 30 min incubation at 37°C. For some cell lines, adriamycin accumulation was not determined (ND).

expression was assayed by reverse transcriptase-polymerase chain reaction (RT-PCR).

Citation: Modrak D, Jones G, Draper M. 2005. Development of Resistance to Anticancer Agents, p 500-513. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch37
Generic image for table
Table 2.

PC4 cell lines resulting from vincristine selection

Reprinted from ( ) with permission from the publisher.

Fold resistance was defined as the IC for the cell line divided by the IC of the parental (wt) cell line.

Percent accumulation was defined as the amount of tritiated vincristine present in resistant cells relative to the amount present in the parental cells after a 30 min incubation at 37°C. For some cell lines, vincristine accumulation and/or gene expression was not determined (ND).

and expression was assayed by Northern blot.

Citation: Modrak D, Jones G, Draper M. 2005. Development of Resistance to Anticancer Agents, p 500-513. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch37

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