Multi-Drug Resistance in Cancer
With the devastating complication of cancer cells becoming simultaneously resistant to many structurally and mechanistically unrelated drugs, the efficacy of chemotherapeutic management of cancer often becomes severely limited. In Multi-Drug Resistance in
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1. Introduction Cancer multidrug resistance describes a phenomenon whereby resistance to one anticancer drug is accompanied by resistance to drugs whose structures and mechanisms of action may be completely different. One might consider the following two theoretical examples; in the first, a woman is diagnosed with advanced ovarian cancer. Chemotherapy is commenced using combined carboplatin and paclitaxel and a complete remission is obtained. After an interval of 1 year, an abdominal mass is detected and combination therapy is reinstituted. However, in this case there is no significant reduction in tumour mass and after four cycles, treatment with irinotecan is initiated. No response is obtained and treatment is continued with doxorubicin, again with no response. J. Zhou (ed.), Multi-Drug Resistance in Cancer, Methods in Molecular Biology, vol. 596, DOI 10.1007/978-1-60761-416-6_1, © Humana Press, a part of Springer Science + Business Media, LLC 2010
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In the second example, a patient diagnosed with metastatic pancreatic cancer is treated with the drug gemcitabine. Both the primary tumour and a lymph node metastasis continue to grow, and chemotherapy is changed to a combination of 5-fluorouracil and oxaliplatin, but again with no effect on tumour progression. These examples demonstrate the two main types of multidrug resistance, one acquired during treatment and the other preexisting at the time of diagnosis. Early ideas on the nature of multidrug resistance were strongly influenced by studies on multidrug resistance in bacteria, in which resistant strains with an identified genetic basis for a lack of response to multiple antibiotics and/or chemotherapeutic agents can be characterised (1). Experimental models for tumour growth were based particularly on transplantable murine leukaemias where it was assumed that the majority of transplanted tumour cells were capable of forming tumours and that resistant cells could be identified or selected for. The development of stem cell theory for animal and human tissues, with its subsequent extension to tumour tissue, changed this concept by postulating that survival of normal or tumour tissue is controlled not by the whole population but by a very small proportion of the total cells that have the property of selfrenewal. The tumour stem cell model, which has had increasing general acceptance, implies that the resistance properties of the tumour stem cell population will dictate overall response to therapy. An important facet of this model is that the survival properties of the tumour stem cells are determined from the microenvironment of these cells, which is usually referred to as the niche. This model highlights two principal methodological problems in the investigation of resistance; cancer stem cells within a tumour population cannot easily be directly identified and also cannot be understood adequately when they are separated from the niche environment. Stem cells in normal tissues have multiple resistance mechanisms to preserve their integrity in the fa
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