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Tumor cell drug resistance and its reversal
A Mansouri1, K J Henle, W A Nagle
1John L. McClellan Memorial Veterans Hospital, Little Rock, AR.
Abstract:
Tumors that formerly were uniformly fatal can now be cured by cancer chemotherapy. However, successful anticancer therapy is faced by many obstacles, such as excessive normal tissue toxicity and drug resistance. Tumor drug resistance may be either intrinsic or acquired. The multidrug resistance (MDR) is a unique phenomenon and is characterized by tumor resistance to various structurally unrelated drugs. Known mechanisms for MDR include overexpression of a membrane P-glycoprotein 170 and elevated cellular levels of reducing agents, such as glutathione (GSH). Currently available strategies for overcoming drug resistance include competitive inhibitors of the P-glycoprotein 170, inhibitors of GSH synthesis, and adjuvant therapy with hyperthermia. Development of drug resistance is analogous to a physiological detoxification mechanism and may continue to limit the effectiveness of cancer chemotherapy in the near future.
Insights
Cancer chemotherapy faces challenges like multidrug resistance (MDR), where tumors resist multiple drugs. Strategies to overcome MDR include targeting P-glycoprotein 170 and glutathione (GSH).
Area of Science:
- Oncology
- Pharmacology
Background:
- Cancer chemotherapy has advanced, curing previously fatal tumors.
- Significant obstacles remain, including normal tissue toxicity and acquired tumor drug resistance.
- Multidrug resistance (MDR) is a critical challenge, characterized by tumor resistance to structurally unrelated drugs.
Purpose of the Study:
- To review the mechanisms of multidrug resistance (MDR) in cancer.
- To discuss current strategies for overcoming MDR.
- To highlight the implications of MDR for future cancer chemotherapy.
Main Methods:
- Literature review of mechanisms and strategies related to MDR.
- Analysis of known molecular mechanisms, including P-glycoprotein 170 and glutathione (GSH).
- Evaluation of therapeutic approaches such as competitive inhibitors, GSH synthesis inhibitors, and hyperthermia.
Main Results:
- Multidrug resistance (MDR) is mediated by factors like P-glycoprotein 170 overexpression and elevated cellular glutathione (GSH) levels.
- Current strategies to combat MDR involve targeting these specific mechanisms.
- Drug resistance development is akin to physiological detoxification, potentially limiting chemotherapy efficacy.
Conclusions:
- Multidrug resistance (MDR) remains a significant hurdle in effective cancer chemotherapy.
- Understanding MDR mechanisms is crucial for developing novel therapeutic strategies.
- Continued research into overcoming MDR is essential for improving patient outcomes in oncology.