Increased intracellular drug accumulation and complete chemosensitization achieved in multidrug-resistant solid tumors by co-administering valspodar (psc 833) with sterically stabilized liposomal doxorubicin

We have previously demonstrated that liposome encapsulation of doxorubicin (DOX) can alleviate adverse interactions with non-encapsulated DOX and the cyclosporine multidrug-resistant (MDR) modulator Valspodar. We have now inv estigated the behavior of different liposomal DOX formulations in MDA435LCC 6/MDR-1 human breast cancer solid tumor xenograft models to identify liposo me characteristics associated with enhanced therapeutic activity and the me chanism whereby increased chemosensitization is achieved, Toxicity studies incorporating conventional phosphatidylcholine (PC)/cholesterol (chol) and sterically stabilized (polyethylene glycol 2000 [PEG]-containing) formulati ons of DOX indicated that whereas PC/Chol DOX was approximately 3-fold more toxic in the presence of Valspodar, PEG containing distearoylglycerophosph ocholine (DSPC)/Chol DOX was minimally affected. In mice bearing MDR tumors , coadministration of Valspodar and egg phosphocholine (EPC)/Chol DOX resul ted in modest MDR modulation and efficacy, whereas the sterically stabilize d formulation induced reductions in tumor growth equivalent to that achieve d for drug-sensitive tumors treated with non-encapsulated DOX. Pharmacokine tic studies revealed a 2.5-fold increase in plasma DOX area under the curve (AUC) upon co-administration of Valspodar with EPC/Chol DOX whereas no suc h alterations were observed with the sterically stabilized liposomes, Compa red to non-encapsulated DOX combined with Valspodar, improvements in effica cy and toxicity correlated with the extent to which liposomal DOX formulati ons were able to circumvent pharmacokinetic interactions. Confocal microsco py demonstrated that Valspodar increased cell-associated DOX which correlat ed with the level of anti-tumor efficacy. (C) 2000 Wiley-Liss, Inc.