A Phase I study of infusional vinblastine in combination with the p-glycoprotein antagonist PSC 833 (valspodar)

Abstract

In immunoassays, non‐specific bindings to biosensing surfaces can be effectively prevented by formation of biocompatible and hydrophilic self‐assembled monolayer (SAM) on the surfaces. A thin gold (Au) layer on magnetic microspheres, 15 μm in diameter, enables facile SAM formation and thereby accepts second layer of filamentous virus scaffolds for the immobilization of functional proteins. The merger of the virus and SAM‐Au protected microspheres not only provides exceptionlly dense antibody loading, but also resembles biological cellular structures that enhance ligand‐receptor interactions. Site‐specific biotinylation of filamenous viruses allows formation of free‐standing virus threads (>1.0 × 1010) on streptavidin‐modified SAM‐Au microspheres. The augmented yield of antibody loading, due to the increased surface to volume ratio, on virus‐modified Au microspheres is confirmed by measuring fluorescence intensities. The bead‐based immunoassays for the detection of cardiac marker proteins exhibit increased sensitivity of virus‐Au microspheres, as low as 20 pg mL−1 of cardiac troponin I in serum, and extremely low non‐specific adsorption when compared with bare polymer beads. This increased sensitivity due to filamentous morphology and SAM‐Au layer demonstrates the feasibility of merging viruses with non‐biological materials to yield biomimetic tools for the enhanced bead‐based immunoassays.

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

“…However, three patients (Patients #7, 9, and 11) who had no residual plasma doxorubicin prior to their second cycle, all consistently had 50% reduction in total doxorubicin clearance in cycle 2 supporting the conclusion that this finding was not an estimation artefact from the residual drug. Therefore, the reduction in total doxorubicin clearance with the addition of valspodar in cycle 2 was likely a result of a pharmacokinetic interaction, similar to that seen in other models where the clearance of single agent cytotoxic agents such as etoposide, doxorubicin, paclitaxel, and vinblastine was significantly reduced by valspodar administration (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). An influence of repeated administrations of PEG-LD on this interaction could not be assessed, as all patients received valspodar in combination with PEG-LD after cycle 1.…”

“…Clinical trials in solid tumour malignancies using the P-glycoprotein modulator, valspodar, combined with single agent etoposide, doxorubicin, paclitaxel, or vinblastine have required dose reductions of the antineoplastic agents (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). These dose reductions are necessary in order to reduce toxicity due to the decreased clearance and increased AUC of these agents when given in combination with valspodar.…”

“…One such agent, valspodar (PSC 833), a cyclosporine D analogue, reverses P-glycoprotein-mediated resistance in vitro at concentrations of 1000 ng ml À1 (Twentyman and Bleehen, 1991). In phase 1 studies, combinations of valspodar with single agent etoposide, doxorubicin, paclitaxel, or vinblastine are feasible with toxicities consisting of reversible cerebellar ataxia, myelosuppression, and hyperbilirubinemia (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). Responses and disease stabilisation have been noted in patients with carcinomas of the ovary, lung, and kidney (Fracasso et al, 2000;Bates et al, 2001;Chico et al, 2001).…”

“…Valspodar has been shown to decrease the clearance of etoposide, doxorubicin, paclitaxel, and vinblastine, and these interactions have necessitated dose reductions of the anticancer agents when given as single agents in combination with valspodar (Boote et al, 1996;Giaccone et al, 1997;Fracasso et al, 2000;Bates et al, 2001Bates et al, , 2004Chico et al, 2001;Minami et al, 2001). Liposomal encapsulated anticancer agents may be better suited to combination therapy with valspodar therapy, as one such agent, liposomal doxorubicin, appears to have minimal pharmacokinetic interactions with valspodar in mice, in comparison to free doxorubicin (Krishna and Mayer, 1997;Krishna et al, 2000).…”

Imaging recognition of inhibition of multidrug resistance in human breast cancer xenografts using 99mTc-labeled sestamibi and tetrofosmin

“…Examples of modulators include verapamil, cyclosporin A, GG918 (elacridar) and PSC833 (valspodar). PSC833 is a cyclosporine derivative that lacks immunosuppressive and nephrotoxic effects and has been reported to be a powerful MDR modulator in animal studies and clinical trials [8][9][10][11][12][13][14]. It was also conceived that PSC833 could inhibit the development of cancer by compromising Pgp function [15].…”