A bioassay for the activity of PSC 833 in human serum for modulation of P-glycoprotein-mediated multidrug resistance.

We established a rapid and sensitive ex vivo bioassay to detect the multidrug resistance (MDR)-inhibitory activity of SDZ PSC 833 ([3'-keto-Bmt1]-[Val2]-cyclosporin (PSC 833)) in two RPMI 8226 human myeloma sublines (parent 8226 and doxorubicin-resistant subline Dox6) in 75% human serum. In vitro sensitivity of the tumor to doxorubicin was determined by 3-h drug exposure growth inhibition assay (MTT assay). PSC 833 in serum restored the IC50 of doxorubicin in the P-glycoprotein (P-gp)-positive resistant subline to the same level as in the sensitive cells at 1 microg/ml, which has been shown to be an achievable concentration in clinical trials. In addition, the cytotoxic effect of doxorubicin was enhanced by PSC 833 in the sera of the patient in whom the blood level was 705.7 ng/ml. However, 10 microg/ml PSC 833 in serum does not cause a complete recovery in the IC90 of doxorubicin in the resistant sublines. This MDR-inhibitory activity was supported by the finding that PSC 833 in serum does not increase accumulation of rhodamine 123 in doxorubicin-resistant cells in an in vitro functional assay. The present study provides evidence that PSC 833 in human serum is effective to modulate P-gp-mediated MDR but insufficient for the reversal of MDR from the clinicopharmacological point of view.