scholarly journals P‐glycoprotein (MDR1/ABCB1) controls brain accumulation and intestinal disposition of the novel TGF‐β signaling pathway inhibitor galunisertib

2019 ◽  
Vol 146 (6) ◽  
pp. 1631-1642 ◽  
Author(s):  
Wenlong Li ◽  
Matthijs Tibben ◽  
Yaogeng Wang ◽  
Maria C. Lebre ◽  
Hilde Rosing ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
The Novel ◽  
P Glycoprotein

scholarly journals Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

2012 ◽  
Vol 32 (6) ◽  
pp. 559-566 ◽  
Author(s):  
Yan Xu ◽  
Feng Zhi ◽  
Guangming Xu ◽  
Xiaolei Tang ◽  
Sheng Lu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Antitumour Activity ◽  
Multidrug Resistant ◽  
The Novel ◽  
Mice Model ◽  
P Glycoprotein ◽  
Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

An open-label, pharmacokinetic study to determine the bioavailability, safety and tolerability of single dose oral docetaxel in metastatic prostate cancer (mPC) patients treated with IV docetaxel.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5050-5050
Author(s):  
Christopher G. C. A. Jackson ◽  
Yen-chuan Ou ◽  
Meng En ◽  
Tsu-Yi Chao ◽  
Noelyn Anne Hung ◽  
...  
Keyword(s):  
New Combination ◽  
Absolute Bioavailability ◽  
The Novel ◽  
Open Label ◽  
Serious Adverse Events ◽  
P Glycoprotein ◽  
Docetaxel Treatment ◽  
Dose Oral ◽  
Improve Patient ◽  
Clinical Trial Information

5050 Background: Docetaxel has poor oral bioavailability in part due to extrusion by intestinal p-glycoprotein. To improve IV solubility, it is fomulated with the nonionic surfactant polysorbate 80, requiring steroid premedication to manage hypersensitivity type reactions. Oral administration has the potential to improve tolerability, reduce day-stay utilization and improve patient convenience and allows investigation of alternative dosing schedules. Oradoxel is a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). Methods: Patients with mPC receiving IV docetaxel were enrolled in 3 cohorts with a dose escalation schedule of Oradoxel 75 mg/m2 in Cohort 1, 150 mg/m2 in Cohort 2, 300mg/m2 in Cohort 3. Oradoxel was given 3 weeks before or after IV docetaxel treatment. Intensive PK samples were taken on days 1-5 for Oradoxel and days 1-4 for IV docetaxel. Dose limiting toxicity (DLT) or serious adverse events (SAE) were assessed per CTCAE v4.03. Results: 3 evaluable patients in each Cohort were studied. No DLT, MTD, or drug-related SAE were observed. PK parameters of Oradoxel vs IV docetaxel are summarized in the table below. Mean absolute bioavailability of Oradoxel was 15.9% (range 8-25%). PK became non linear at 300mg/m2. Conclusions: Oradoxel was well tolerated. Based on the results of this and related studies, Oradoxel 300mg/m2 in divided doses is being further evaluated in phase 2 studies. Clinical trial information: 12616000983404. [Table: see text]

scholarly journals P-glycoprotein-dependent resistance of cancer cells toward the extrinsic TRAIL apoptosis signaling pathway

2013 ◽  
Vol 86 (5) ◽  
pp. 584-596 ◽  
Author(s):  
Hanan Galski ◽  
Tamar Oved-Gelber ◽  
Masha Simanovsky ◽  
Philip Lazarovici ◽  
Michael M. Gottesman ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Signaling Pathway ◽  
P Glycoprotein
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