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Cyclosporins as drug resistance modifiers
1MRC Clinical Oncology and Radiotherapeutics Unit, Cambridge, U.K.
Biochemical Pharmacology
|January 9, 1992
Summary
Cyclosporin A (CsA) modifies multidrug resistance by affecting T-cell proliferation and P-glycoprotein activity. Non-immunosuppressive analogues like PSC-833 show greater potency, offering potential clinical applications.
Area of Science:
- Pharmacology
- Immunology
- Biochemistry
Background:
- Cyclosporin A (CsA) is a key immunosuppressant for organ transplant patients.
- CsA's mechanism involves binding to cyclophilin, impacting T-cell proliferation.
- CsA also exhibits multidrug resistance (MDR) modifying effects.
Purpose of the Study:
- To investigate the mechanisms of CsA's effect on T-cell proliferation.
- To explore CsA's role as a multidrug resistance modifier.
- To evaluate the potential of CsA analogues in overcoming drug resistance.
Main Methods:
- Analysis of CsA's interaction with cyclophilin.
- Assessment of CsA's effect on drug accumulation in resistant cells.
- Comparison of MDR reversal activity between CsA and its analogues.
Main Results:
- CsA binds cyclophilin, possessing peptidyl-prolyl cis-trans isomerase activity.
- CsA modifies multidrug resistance in various cell types at specific concentrations.
- Non-immunosuppressive analogues, such as PSC-833, demonstrate enhanced MDR reversal potency.
Conclusions:
- CsA's immunosuppressive and MDR-modifying actions are distinct but linked.
- PSC-833 and similar analogues represent promising agents for clinical trials.
- Reversal of multidrug resistance may become a viable clinical strategy with these agents.