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[How do cancers resist to chemotherapy?]
1Institut Curie Biologie, Paris, France.
Abstract:
Resistance is often defined as a lack of therapeutic response. Cellular resistance involves a decrease in intracellular levels of the antitumor agent due to a variety of mechanisms. These mechanisms are active in tumors with initial resistance as well as in those which respond initially but fail to be completely destroyed by chemotherapy. Although acquired forms of resistance seem to be the result of selection, some studies suggest that antitumor agents may induce resistance. Four main mechanisms of resistance are currently being investigated: 1) multidrug resistance, involving expression of a membrane P-glycoprotein, responsible for resistance to hydrophobic cationic agents; 2) detoxification of hydrophilic agents by the enzyme glutathione-S-transferase; 3) increased production of enzymes targeted by antimetabolites; 4) mutation or decreased synthesis of topoisomerases I and II which are the targets of very recent antitumor agents. New data were presented at the 1992 symposium of the American Association for Cancer Research; expression of P-glycoprotein is controlled by the mutant protein P53, the oncogene ras and differentiation agents. Physiological effects of this molecule are related to the chloride pump. Bone marrow stem cells from transgenic mice obtained by transfection of the gene MDR1 in germ cells exhibit resistance. Many agents can reverse P-glycoprotein-related resistance. Results from three phase I trials with Cyclosporin A as reversion agent were reported. It is essential to conduct clinical trials in order to assess the true value of these new data which hold promise for improving the performance of antitumor agents.
Insights
Cancer cells can develop resistance to chemotherapy through several mechanisms, including multidrug resistance mediated by P-glycoprotein. New research explores ways to reverse this resistance, potentially improving antitumor agent efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cellular resistance to antitumor agents is a major challenge in cancer chemotherapy.
- Mechanisms include decreased intracellular drug levels, multidrug resistance (MDR), agent detoxification, and target enzyme alterations.
- Resistance can be intrinsic or acquired, with some evidence suggesting chemotherapy itself may induce resistance.
Purpose of the Study:
- To review current understanding of cellular resistance mechanisms to antitumor agents.
- To highlight new findings on P-glycoprotein regulation and its role in MDR.
- To discuss strategies for overcoming P-glycoprotein-mediated resistance, including clinical trials of reversal agents.
Main Methods:
- Review of mechanisms of cellular resistance to chemotherapy.
- Discussion of P-glycoprotein expression and its regulation by factors like P53 and ras.
- Presentation of data from Phase I clinical trials using Cyclosporin A to reverse P-glycoprotein-related resistance.
Main Results:
- Four primary resistance mechanisms identified: MDR (P-glycoprotein), glutathione-S-transferase detoxification, increased target enzyme production, and topoisomerase alterations.
- P-glycoprotein expression is influenced by mutant P53, the ras oncogene, and differentiation agents.
- Transgenic mice models demonstrate MDR1 gene transfection confers resistance; Cyclosporin A showed promise in reversing P-glycoprotein-mediated resistance in Phase I trials.
Conclusions:
- Understanding resistance mechanisms is crucial for improving cancer treatment outcomes.
- P-glycoprotein plays a significant role in MDR, and its expression is subject to complex regulation.
- Further clinical trials are necessary to validate the therapeutic potential of agents that reverse P-glycoprotein-mediated resistance.