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Pharmacologic circumvention of multidrug resistance
Abstract:
The ability of malignant cells to develop resistance to chemotherapeutic drugs is a major obstacle to the successful treatment of clinical tumors. The phenomenon multidrug resistance (MDR) in cancer cells results in cross-resistance to a broad range of structurally diverse antineoplastic agents, due to outward efflux of cytotoxic substrates by the mdr1 gene product, P-glycoprotein (P-gp). Numerous pharmacologic agents have been identified which inhibit the efflux pump and modulate MDR. The biochemical, cellular and clinical pharmacology of agents used to circumvent MDR is analyzed in terms of their mechanism of action and potential clinical utility. MDR antagonists, termed chemosensitizers, may be grouped into several classes, and include calcium channel blockers, calmodulin antagonists, anthracycline and Vinca alkaloid analogs, cyclosporines, dipyridamole, and other hydrophobic, cationic compounds. Structural features important for chemosensitizer activity have been identified, and a model for the interaction of these drugs with P-gp is proposed. Other possible cellular targets for the reversal of MDR are also discussed, such as protein kinase C. Strategies for the clinical modulation of MDR and trials combining chemosensitizers with chemotherapeutic drugs in humans are reviewed. Several novel approaches for the modulation of MDR are examined.
Insights
Multidrug resistance (MDR) in cancer hinders treatment. Chemosensitizers, like calcium channel blockers, can overcome MDR by inhibiting P-glycoprotein efflux pumps, potentially improving chemotherapy efficacy.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Malignant cells develop resistance to chemotherapy, a major challenge in cancer treatment.
- Multidrug resistance (MDR) involves cross-resistance to various antineoplastic agents due to P-glycoprotein (P-gp) mediated efflux.
- P-gp, the mdr1 gene product, actively pumps cytotoxic drugs out of cancer cells.
Purpose of the Study:
- To analyze the pharmacology of agents that circumvent MDR.
- To evaluate the mechanism of action and clinical utility of chemosensitizers.
- To explore novel strategies for modulating MDR in cancer therapy.
Main Methods:
- Review of biochemical, cellular, and clinical pharmacology of MDR-modulating agents.
- Classification of chemosensitizers including calcium channel blockers, calmodulin antagonists, and cyclosporines.
- Analysis of structural features and proposed interaction models for chemosensitizers with P-gp.
Main Results:
- Identified various pharmacologic agents that inhibit P-gp and modulate MDR.
- Grouped chemosensitizers into classes based on their chemical properties and mechanisms.
- Proposed a model for drug interaction with P-gp and discussed other potential targets like protein kinase C.
Conclusions:
- Chemosensitizers offer potential to reverse MDR and enhance chemotherapy effectiveness.
- Clinical trials combining chemosensitizers with chemotherapeutic drugs are being reviewed.
- Novel approaches for MDR modulation are under examination for improved cancer treatment outcomes.