A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors

Planting, A. S. T.; Sonneveld, Pieter; Gaast, Ate van der; Sparreboom, Alex; Burg, M.E.L. van der; Luyten, Gregorius P M; Leeuw, K. De; Boer-Dennert, M. de; Wissel, Paul; Jewell, Roxanne C.; Paul, Elaine; Purvis, Norman; Verweij, Jaap

doi:10.1007/s00280-004-0854-6

Cited by 91 publications

(62 citation statements)

References 29 publications

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“…Elacridar inhibited ABCG2 as well as ABCB1 and has been used in preclinical and clinical settings (38,39). Elacridar can also significantly increase plasma pharmacokinetics and brain distribution of several drugs, including dasatinib (40), gefitinib (41), and sunitinib (42).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

Sugano

Seike

Noro

et al. 2015

Molecular Cancer Therapeutics

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Patients with non-small cell lung cancer (NSCLC) EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFR-TKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFR-TKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA-665752-resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosphorylation of MET. EBC-1R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial-mesenchymal transition (EMT). The level of miR-138 that targeted ABCB1 was decreased in EBC-1R cells. ABCB1 siRNA and the ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse resistance to PHA-665752 in EBC-1R cells. Our study demonstrated that ABCB1 overexpression, which was associated with CSC properties and EMT, was involved in the acquired resistance to MET inhibitors. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitors.

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Section: Discussionmentioning

confidence: 99%

Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

Sugano

Seike

Noro

et al. 2015

Molecular Cancer Therapeutics

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“…In situ single-pass jejunal perfusion and portal vein-cannulated rats were used as study systems to exclude or minimize the confounding influence of first-pass hepatic metabolism. (Planting et al, 2005), and product information is provided by Cayman Chemical (Ann Arbor, MI; www.caymanchem.com), respectively. Midazolam (MDZ) (Versed, 5 mg/ml; Roche Laboratories) was purchased through the Rutgers University Health Center Pharmacy.…”

Section: Saquinavir [Sqv (N-tert-butyl-decahydro-2-[2(r)-hydroxy-4-pmentioning

confidence: 99%

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Usansky¹,

Hu²,

Sinko³

2008

Drug Metab Dispos

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ABSTRACT:The objective of this investigation was to differentiate the roles of P-glycoprotein (Pgp), multidrug resistance-associated protein 2 (Mrp2), and CYP3A on saquinavir ( -(((3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl) ((3-(dimethylamino-3-oxopropyl)thio)methyl)-thio) propanoic acid (MK571)], and/or CYP3A (midazolam). Plasma concentrations of SQV and related metabolites were analyzed by liquid chromatography-tandem mass spectrometry. When given alone, SQV absorption was extremely low both in situ (F a ‫؍‬ 0.07%) and in vivo [C max ‫؍‬ 0.068 g/ml; area under the curve (AUC) ‫؍‬ 6.8 g ⅐ min/ml]. Coadministration of GF120918 boosted SQV absorption by more than 20-fold with decreased variation in AUCs (percent coefficient of variation ‫؍‬ 30% versus 100%). In contrast, coadministration of MK571 or midazolam increased SQV absorption only 2-to 3-fold without improving the variation in AUCs. SQV oral absorption was not further improved when it was given with GF120918 and midazolam or with GF120918 and MK571. The current results provide, for the first time, direct and explicit evidence that the low oral absorption of SQV is controlled by a secretory transporter, Pgp, and not by limited passive diffusion owing to its poor physicochemical properties. Pgp-mediated transport is also responsible for the highly variable oral bioavailability of SQV. In contrast, intestinal Mrp2 and intestinal CYP3A appear to play minor roles in SQV oral bioavailability. Given the differential and complex roles of Pgp and CYP3A in SQV oral absorption, the optimization of AIDS boosting regimens requires careful consideration to avoid therapylimiting drug-drug transporter and enzyme interactions.

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“…We also studied the reversal effects of two of the latestdeveloped potent inhibitors of human Pgp known to interact with its TMDs, namely, zosuquidar (LY335979) (8,9) and elacridar (GF120918) (20,40). In contrast to other modulators of mammalian Pgp, both compounds were quite active in reversing DNM resistance in the MDR Leishmania line, elacridar being more toxic for the parental wild-type line (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This interaction at the TMDs, however, does not seem to lead to transport of the compound. We also analyzed the reversing effect of some new modulators of human Pgp that are known to interact with its TMDs and not to be transported (8,9,20,40). While conventional Pgp inhibitors such as verapamil, cyclosporine, and quinidine were not very efficient at reversing the resistance phenotype in Leishmania (35), we show here that the latestdeveloped modulators zosuquidar (LY335979) and elacridar (GF120918) constitute new classes of promising reversal agents in these parasites.…”

Section: Discussionmentioning

confidence: 99%

“…Preliminary structure-activity relationships have allowed us to design a new, potent flavonoid derivative with high affinity for the cytosolic NBDs. As modulators directed to the TMDs, we have used one of the most potent sesquiterpenes described, named C-3 (38), and we have also studied the effects of two of the most promising, latestdeveloped modulators of human Pgp, zosuquidar (LY335979) (8,9) and elacridar (GF120918) (20,40), currently used in clinical trials. The results show that this combinatorial strategy efficiently overcomes parasite miltefosine resistance by inhibiting drug efflux without any cytotoxicity in the parental nonresistant Leishmania line and in different mammalian cell lines.…”

mentioning

confidence: 99%

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Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

Pérez‐Victoria

Cortés-Selva

Parodi-Talice

et al. 2006

Antimicrob Agents Chemother

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Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-␤-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

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A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors

Cited by 91 publications

References 29 publications

Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

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