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Modulation of Classical Multidrug Resistance and Drug Resistance in General
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
In contrast to these trials, several studies of MDR modulation in AML have been negative. The Cancer and Leukemia Group B performed a trial of valspodar (PSC-833) combined with daunorubicin, cytarabine, and etoposide in patients with newly diagnosed AML aged 60 and above (111). The trial was halted early because of excess early mortality in the valspodar arm (44% versus 20% in controls), illustrating the problem of drug interactions with cyclosporin drugs and chemotherapies. Despite the higher early death rate, there was a trend in favor of the experimental arm for leukemia-free survival (5 vs. 14 months, p = 0.07). A French trial of quinine in primary AML for patients 65 years and younger, combined with idarubicin and cytarabine, was negative for OS, but reported an improved CR rate for the P-gp positive subset (48% vs. 83%, p = 0.01) (112). The Eastern Cooperative Oncology Group (ECOG) performed a trial of valspodar combined with mitoxantrone, etoposide, and cytarabine, in patients with refractory or relapsed leukemia aged 15 to 70 years, which was negative for all clinical outcomes (113). Novartis sponsored a trial of valspodar, daunorubicin, and cytarabine in patients aged 60 years and above with previously untreated AML, which was also negative for all clinical outcomes (114). Both this trial and the ECOG trial confirmed that P-gp expression was a significant adverse prognostic factor. Therefore, it is likely that other, co-expressed resistance mechanisms mitigated any clinical benefit for MDR modulation in these trials of valspodar. Finally, the Pediatric Oncology Group performed a trial of high-dose cyclosporine with induction therapy in children with AML (115). The negative results of this trial are not surprising, considering fewer than 15% of these pediatric AML specimens expressed P-gp. These trials are summarized in Table 3 (111–115).
Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Mohammad Feyzizadeh, Ashkan Barfar, Zeinab Nouri, Muhammad Sarfraz, Parvin Zakeri-Milani, Hadi Valizadeh
A phase III clinical trial revealed that the addition of the potent MDR-inhibitor compound, valspodar, to vincristine, doxorubicin, and dexamethasone in patients with recurring multiple myeloma failed to provide prolonged survival. Additionally, the patients co-administered with valspodar exhibited more toxicity compared with vincristine, doxorubicin, and dexamethasone alone [61].
Do differences in cell lines and methods used for calculation of IC50 values influence categorisation of drugs as P-glycoprotein substrates and inhibitors?
Published in Xenobiotica, 2022
Donna A. Volpe, Abhay Joshi, Vikram Arya
Data was collected for 30 drugs having a known positive or negative clinical interaction with digoxin, generating 691 in vitro IC50 values with at least two cell lines and two calculation methods. The number of data points for a drug ranged from 79 (for verapamil) to 3 (for atorvastatin, linagliptin, and pantoprazole). Twelve of the drugs were inhibitory in vivo with 331 IC50 data points (48%) and the remaining 18 drugs were not inhibitory in vivo with 360 data points (52%). Caco-2 was the most common cell line with 411 (59%) of the IC50 values followed by LLC-PK1-MDR1 and MDCK-MDR1 with 148 (21%) and 132 (19%), respectively. The use of different calculation methods was more evenly distributed among NSF (274, 40%), Papp,BL-AP (224, 32%), and ER (193, 28%). Supplemental file 2 summarises the in vitro data collected for the inhibitory drugs. There was variability in the overall geometric mean IC50 values for the 30 drugs which ranged from 76.02 µM for pantoprazole to 0.18 µM for valspodar. Eighteen drugs had geometric mean IC50 values less than 20 µM. There was no pattern in rank order for the geometric mean of IC50 values for the drugs based on a cell line or calculation method. Based on the calculation method, the lowest geometric mean IC50 values were from ER in 23 of the 30 drugs (77%). The lowest geometric mean IC50 values were in Caco-2 cells in 22 of the 30 drugs (73%). Valspodar was the most potent inhibitor in Caco-2 and LLC-PK1-MDR1 cells (no data available in MDCK cells), while itraconazole was the most potent in MDCK-MDR1 cells (Table 3). Valspodar had the lowest IC50 values across all three calculation methods (Table 3). There was no pattern in the rank order of IC50 values for the drugs based on either the cell line or calculation method (rank order data not shown). Over two-thirds of the drugs had their lowest geometric mean IC50 values in Caco-2 cells and with the ER calculation method for 80% of all the drugs.
In vitro drug–drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes
Published in Xenobiotica, 2018
Nancy Chen, Donghui Cui, Qing Wang, Zhiming Wen, Richard D. Finkelman, Devin Welty
The corrected efflux ratios of budesonide (2 μM) for P-gp and BCRP were 26.9 and 1.61, respectively (Table 2). The P-gp inhibitor valspodar caused a decrease in the efflux ratio from 26.9 to 0.0874 (>50%) (Table 2). The BCRP inhibitor Ko143 caused a decrease in the efflux ratio from 1.61 to 1.21 (<50%) (Table 2).