Phase I Study of Infusional Paclitaxel in Combination With the P-Glycoprotein Antagonist PSC 833

Chico, Isagani; Kang, Min H.; Bergan, Raymond C.; Abraham, Jame; Bakke, Susan; Meadows, Beverly; Rutt, Ann; Robey, Robert W.; Choyke, Peter L.; Mj, Merino; Goldspiel, Barry R.; Smith, Tom; Steinberg, Seth M.; Figg, William D.; Fojo, Tito; Bates, Susan E.

doi:10.1200/jco.2001.19.3.832

Cited by 85 publications

(52 citation statements)

References 23 publications

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“…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.…”

Section: Discussionsupporting

confidence: 60%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Fracasso¹,

Blum²,

K.³

et al. 2005

Br J Cancer

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Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20 -25 mg m À2 intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m À2 and escalated in an accelerated titration design to 25 mg m À2 . Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m À2 . The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10 -73) ml h À1 m À2 in cycle 1 to 18 (3 -37) ml h À1 m À2 with the addition of valspodar in cycle 2 (P ¼ 0.009). Treatment with PEG-LD 25 mg m À2 in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Fracasso¹,

Blum²,

K.³

et al. 2005

Br J Cancer

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“…Although many efforts have been made to overcome the MDR cancer, limited successful therapeutic regimens and antineoplastic agents have been applied. [4][5][6][7][8][9] The MDR of cancer cells results from many factors; one of the most important reasons is the reduction of drug accumulation caused by the superfamily of adenosine triphosphate (ATP)-binding cassette proteins, such as the P-glycoprotein (P-gp), MDR-associated protein (MRP), and breast cancer resistance protein (BCRP).…”

Section: Introductionmentioning

confidence: 99%

Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance

Dong

Yan

Wang

et al. 2016

IJN

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In this study, a type of multifunctional mixed micelles were prepared by a novel biodegradable amphiphilic polymer (MPEG-SS-2SA) and a multidrug resistance (MDR) reversal agent ( d -α-tocopheryl polyethylene glycol succinate, TPGS). The mixed micelles could achieve rapid intracellular drug release and reversal of MDR. First, the amphiphilic polymer, MPEG-SS-2SA, was synthesized through disulfide bonds between poly (ethylene glycol) monomethyl ether (MPEG) and stearic acid (SA). The structure of the obtained polymer was similar to poly (ethylene glycol)-phosphatidylethanolamine (PEG-PE). Then the mixed micelles, MPEG-SS-2SA/TPGS, were prepared by MPEG-SS-2SA and TPGS through the thin film hydration method and loaded paclitaxel (PTX) as the model drug. The in vitro release study revealed that the mixed micelles could rapidly release PTX within 24 h under a reductive environment because of the breaking of disulfide bonds. In cell experiments, the mixed micelles significantly inhibited the activity of mitochondrial respiratory complex II, also reduced the mitochondrial membrane potential, and the content of adenosine triphosphate, thus effectively inhibiting the efflux of PTX from cells. Moreover, in the confocal laser scanning microscopy, cellular uptake and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assays, the MPEG-SS-2SA/TPGS micelles achieved faster release and more uptake of PTX in Michigan Cancer Foundation-7/PTX cells and showed better antitumor effects as compared with the insensitive control. In conclusion, the biodegradable mixed micelles, MPEG-SS-2SA/TPGS, could be potential vehicles for delivering hydrophobic chemotherapeutic drugs in MDR cancer therapy.

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

Bates

Kang

Meadows

et al. 2001

Cancer

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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.

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Phase I Study of Infusional Paclitaxel in Combination With the P-Glycoprotein Antagonist PSC 833

Cited by 85 publications

References 23 publications

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

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

Biodegradable mixed MPEG-SS-2SA/TPGS micelles for triggered intracellular release of paclitaxel and reversing multidrug resistance

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

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