Reversal of multidrug resistance: lessons from clinical oncology

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.