Pulsed exposure of SDZ PSC 833 to multidrug resistant P388/ADR and MCF7/ADR cells in the absence of anticancer drugs can fully restore sensitivity to doxorubicin.
OBJECTIVE
An in vitro cellular pharmacological study was undertaken to characterize the latency of modulating activity by the chemosensitizer, PSC 833.


METHODS
PSC 833 was evaluated for cytotoxicity in the MDR P388/ADR and MCF7/ADR cell lines. Cellular uptake levels and intracellular DOX distribution characteristics were assessed by flow cytometry and fluorescence microscopy, respectively. These parameters were correlated with the chemosensitivity of the MDR cells under varying conditions of exposure to PSC 833 and DOX.


RESULTS
PSC 833 (1 microM) provided near complete MDR reversal and exhibited significant latent modulating activity indicative of a sustained inhibition of the PGP pump in P388/ADR and MCF7/ADR cells after removal of the MDR modulator. Interestingly, complete latent chemosensitizing activity could be achieved by pulsing cells with PSC 833 prior to DOX exposure. Increases in cellular DOX uptake by individual P388/ADR and MCF7/ADR cells induced by MDR modulators correlated well with their ability to chemosensitize the resistant tumor cells where intracellular DOX levels approaching those obtained for sensitive wild type cells was observed for PSC 833.


CONCLUSIONS
The MDR modulator PSC 833 exhibits latent MDR modulating activity that appears well suited for modulating PGP mediated MDR in vivo where chemosensitization is complicated by difficulties in synchronizing therapeutic levels of modulator and anticancer drug at the tumor site.
Krishna
R
R
Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
de Jong
G
G
Mayer
L D
LD
D000818:Animals; D003524:Cyclosporins / Q000008:administration & dosage*; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D006801:Humans; D007941:Leukemia P388 / Q000378:metabolism; D051379:Mice; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D003524:Cyclosporins; D004317:Doxorubicin; D014700:Verapamil; C070272:valspodar