Conventional methods that are used to overcome multidrug resistance (MDR) often involve the coadministration of chemosensitizers and anticancer drugs. The
cyclosporin analogue
SDZ PSC 833 [(3'-keto-Bmt1)-(Val2)-
cyclosporin] (
PSC 833) has been shown to possess powerful chemosensitization properties in vitro, in addition to being intrinsically nontoxic. However, coadministration of
PSC 833 with anticancer drugs, such as
daunorubicin,
doxorubicin (DOX), and
Taxol, have resulted in the exacerbation of anticancer
drug toxicity, which is due to altered anticancer
drug pharmacokinetics. Here, we hypothesized that optimization of the anticancer
drug delivery, using liposomal carriers, may, by avoiding 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 study period. p.o. administration of
PSC 833, at a dose of 100 mg/kg, reduced 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 833 administration resulted in only a 20% reduction of the MTD for DOX encapsulated in 100-nm 1,2 distearoyl-sn-glycero-3-
phosphocholine/
cholesterol liposomes (55:45 molar
lipid ratio) in a single-dose regimen and had no effect on the liposomal DOX MTD for the day 1, 5, and 9 treatment schedule. Modest modulation of
P-glycoprotein-mediated MDR was observed in the murine P388/ADR solid
tumor model when
PSC 833 was administered with free DOX at the MTD. In contrast, liposomal DOX combined with
PSC 833 resulted in
tumor growth inhibition that was comparable to that observed for
drug-sensitive P388/WT
tumors. This efficacy of P388/ADR
tumors treatment was dependent on
PSC 833 because treatment with liposomal DOX alone provided significantly less antitumor activity. Pharmacokinetic and tissue distribution data demonstrated that DOX encapsulated in 1,2 distearoyl-sn-glycero-3-
phosphocholine/
cholesterol liposomes exhibited comparable plasma elimination and tissue distribution properties in the presence and absence of
PSC 833, whereas free DOX displayed reduced plasma elimination rates and altered tissue distribution in the 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 used. This suggests that the improved
tumor selectivity of anticancer drugs that are administered in liposomal formulations may avoid the complications that are associated with free
drug-MDR-reversing agent combinations and enhance the
therapy of multidrug-resistant
tumors.