title: Liposomal doxorubicin circumvents PSC 833-free drug interactions, resulting in effective therapy of multidrug-resistant solid tumors.
abstract: 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.
authors.affiliation: Department of Medical Oncology (Advanced Therapeutics), British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Krishna
authors.forename: L D
authors.initials: LD
authors.lastname: Mayer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D002784:Cholesterol; D003524:Cyclosporins / Q000627:therapeutic use* / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D004337:Drug Carriers; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy*; D008081:Liposomes; D008657:Metabolic Clearance Rate; D051379:Mice; D010713:Phosphatidylcholines; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D004337:Drug Carriers; D008081:Liposomes; D010713:Phosphatidylcholines; D004317:Doxorubicin; D002784:Cholesterol; C010942:1,2-distearoyllecithin; C070272:valspodar