Related Experiment Videos
Reversal of multidrug resistance: lessons from clinical oncology
Susan F Bates1, Clara Chen, Robert Robey
1Molecular Therapeutics Section, Medicine Branch, National Cancer Institute, Bethesda, MD 20892, USA.
Abstract:
Modulation of P glycoprotein (Pgp) in clinical oncology has had limited success. Contributing factors have included the limitation in our understanding of the tumours in which Pgp overexpression is mechanistically important in clinical drug resistance; the failure to prove that concentrations of modulators achieved in patients were sufficient to inhibit Pgp; and the inability to conclusively prove that Pgp modulation was occurring in tumours in patients. New approaches are needed to determine the clinical settings in which Pgp overexpression plays a major role in resistance. (Clinical trials with third generation modulators are ongoing, including trials with the compounds LY335979, R101933 and XR9576. Using the Pgp substrate Tc-99m Sestamibi as an imaging agent, increased uptake has been seen in normal liver and kidney after administration of PSC 833, VX710 and XR9576. These studies confirm that the concentrations of modulator achieved in patients are able to increase uptake of a Pgp substrate. Furthermore, CD56+ cells obtained from patients treated with PSC 833 demonstrate enhanced rhodamine retention in an ex vivo assay after administration of the antagonist. Finally, a subset of patients treated with Pgp antagonists show enhanced Sestamibi retention in imaged tumours. These results suggest that Pgp modulators can increase drug accumulation in Pgp-expressing tumours and normal tissues in patients. Using third generation Pgp antagonists and properly designed clinical trials, it should be possible to determine the contribution of modulators to the reversal of clinical drug resistance.
Insights
New P-glycoprotein (Pgp) modulators show promise in overcoming cancer drug resistance. Clinical trials demonstrate these agents can increase drug accumulation in Pgp-expressing tumors, potentially improving treatment outcomes.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- P-glycoprotein (Pgp) overexpression is a key mechanism of clinical drug resistance in cancer.
- Previous attempts to modulate Pgp in oncology have faced challenges due to limited understanding of its role and insufficient drug concentrations.
- Novel strategies are required to identify clinical settings where Pgp is crucial for resistance.
Purpose of the Study:
- To evaluate the efficacy of third-generation Pgp modulators in overcoming clinical drug resistance.
- To confirm that achieved modulator concentrations in patients are sufficient to inhibit Pgp activity.
- To demonstrate Pgp modulation within patient tumors.
Main Methods:
- Utilized Tc-99m Sestamibi, a Pgp substrate, as an imaging agent to assess modulator activity in vivo.
- Administered Pgp antagonists (e.g., PSC 833, VX710, XR9576) to patients.
- Performed ex vivo assays on patient-derived CD56+ cells to measure rhodamine retention.
- Analyzed Sestamibi retention in tumors of patients treated with Pgp antagonists.
Main Results:
- Increased uptake of Tc-99m Sestamibi in normal liver and kidney confirmed modulator activity in patients.
- Ex vivo assays showed enhanced rhodamine retention in cells from patients treated with PSC 833.
- A subset of patients exhibited enhanced Sestamibi retention in imaged tumors, indicating Pgp modulation in vivo.
- Results suggest Pgp modulators can increase drug accumulation in Pgp-expressing tumors and normal tissues.
Conclusions:
- Third-generation Pgp antagonists demonstrate the ability to inhibit Pgp in patients.
- These modulators can increase drug accumulation in Pgp-expressing tumors.
- Well-designed clinical trials with advanced Pgp antagonists are crucial for determining their role in reversing clinical drug resistance.