LIPOSOMAL DOXORUBICIN CIRCUMVENTS PSC 833-FREE DRUG-INTERACTIONS, RESULTING IN EFFECTIVE THERAPY OF MULTIDRUG-RESISTANT SOLID TUMORS

Conventional methods that are used to overcome multidrug resistance (M DR) often involve the coadministration of chemosensitizers and antican cer drugs, The cyclosporin analogue SDZ PSC 833 [(3'-keto-Bmt(1))-(Val (2))-cyclosporin] (PSC 833) has been shown to possess powerful chemose nsitization properties in vitro, in addition to being intrinsically no ntoxic, However, coadministration of PSC 833 with anticancer drugs, su ch as daunorubicin, doxorubicin (DOX), and Taxol, have resulted in the exacerbation of anticancer drug toxicity, which is due to altered ant icancer drug pharmacokinetics, Here, we hypothesized that optimization of the anticancer drug delivery, using liposomal carriers, may, by av oiding these adverse interactions, offer a significant advantage over nonencapsulated drugs, Toxicity-studies were conducted in normal BDF1 mice, with i,v, DOX (free or liposome encapsulated) administration and p,o, PSC 833 in single and multiple dosage regimens over a 15-day stu dy period, p,o, administration of PSC 833, al a dose of 100 mg/kg, red uced the maximum tolerated dose (MTD) of i,v administered free drug by 2.5-3-fold, in single- and multiple-dose regimens, In contrast, PSC 8 33 administration resulted in only a 20% reduction of the MTD for DOX encapsulated in 100-nm 1,2 distearoyl-sn-glycero-3-phosphocholine/lipo somes (55:45 molar lipid ratio) in a single-dose regimen and had no ef fect on the liposomal DOX MTD for the dag 1, 5, and 9 treatment schedu le, Modest modulation of P-glycoprotein-mediated MDR was observed in t he murine P388/ADR solid turner model when PSC 833 was administered wi th free DOX at the MTD, In contrast, liposomal DOX combined with PSC 8 33 resulted in tumor growth inhibition that was comparable to that obs erved for drug-sensitive P388/WT tumors, This efficacy of P388/ADR tum ors treatment was dependent on PSC 833 because treatment with liposoma l DOX alone provided significantly less antitumor activity, Pharmacoki netic and tissue distribution data demonstrated that DOX encapsulated in 1,2 distearoyl-sn-glycero-3-phosphocholine/cholesterol liposomes ex hibited comparable plasma elimination and tissue distribution properti es in the presence and absence of PSC 833, whereas free DOX displayed reduced plasma elimination rates and altered tissue distribution in th e presence of PSC 833, These results provide evidence that PSC 833 can induce P-glycoprotein modulation and chemosensitize MDR tumors in the absence of altered DOX pharmacokinetics when liposomal carriers are u sed, This suggests that the improved tumor selectivity of anticancer d rugs that are administered in liposomal formulations may avoid the com plications that are associated with free drug-MDR-reversing agent comb inations and enhance the therapy of multidrug-resistant tumors.