sdz-psc-833 and Colorectal-Neoplasms

P-glycoprotein (Pgp), a member of the ATP-binding cassette family, is one of the major causes of multidrug resistance in tumors. Current clinical treatments to overcome MDR involve the co-delivery of a Pgp inhibitor and a chemotherapeutic. A concern for this treatment that has led to varied clinical trial success is the associated systemic toxicities involving endogenous Pgp. Local drug delivery systems, such as in situ forming implants (ISFIs), alleviate this problem by delivering a high concentration of the drug directly to the target site without the associated systemic toxicities. ISFIs are polymeric drug solutions that undergo a phase transition upon injection into an aqueous environment to form a solid drug eluting depot allowing for a high initial intratumoral drug concentration. In this study, we have developed an ISFI capable of overcoming the Pgp resistance by co-delivering a chemotherapeutic, Doxorubicin (Dox), with a Pgp inhibitor, either Pluronic P85 or Valspodar (Val). Studies investigated in vitro cytotoxicity of Dox when combined with either Pgp inhibitor, effect of the inhibitors on release of Dox from implants in PBS, in vivo Dox distribution and retention in a subcutaneous flank colorectal murine tumor, and therapeutic response characterized by tumor growth curves and histopathology. Dox + Val showed a 4-fold reduction in the 50% lethal dose (LD

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Colorectal Neoplasms; Cyclosporins; Doxorubicin; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Mice; Poloxalene; Treatment Outcome; Xenograft Model Antitumor Assays

P-Glycoprotein, which mediates multidrug resistance (MDR) in cancer chemotherapy, is a principal target of cyclosporin A and [3'-keto-Bmt(1)]-[Val(2)]-cyclosporin (valspodar; PSC 833). To clarify mechanisms contributing to the different MDR-modulating activities of valspodar and cyclosporin A, we investigated the relation of the intracellular levels of the two cyclosporin derivatives to their modulating effect on MDR in different P-glycoprotein-expressing human colorectal carcinoma HCT-15 cells (parental HCT-15 and adriamycin-resistant sublines). In this study, valspodar was found to be much more potent than cyclosporin A in both sensitizing resistant cells to MDR-related anticancer drugs (e.g., adriamycin, vincristine and paclitaxel (taxol)) and increasing 2-[6-amino-3-imino-3H-xanthen-9-yl]benzoic acid methyl ester (rhodamine 123) retention and [G-(3)H]vincristine sulfate ([(3)H]vincristine) accumulation in these cells. Furthermore, a good correlation was detected between P-glycoprotein levels and the MDR-reversing effect of valspodar. In contrast, the effects of cyclosporin A could not be linked to P-glycoprotein levels in the MDR cells. In addition, the intracellular accumulation of valspodar was found to be 3 - 6 fold higher than that of cyclosporin A in four sublines and verapamil, an inhibitor of P-glycoprotein-mediated transport, enhanced the accumulation of cyclosporin A, but not valspodar. These results suggested that valspodar accumulation is not actively regulated by the P-glycoprotein-mediated efflux system.

Topics: Adenocarcinoma; Anticarcinogenic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Division; Colorectal Neoplasms; Cyclosporine; Cyclosporins; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Inhibitory Concentration 50; Intracellular Fluid; Rhodamine 123; Tumor Cells, Cultured; Verapamil