P-glycoprotein (MDR1/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) limit brain accumulation of the FLT3 inhibitor quizartinib in mice

Publication date: Available online 12 December 2018Source: International Journal of PharmaceuticsAuthor(s): Jing Wang, Changpei Gan, Irene A. Retmana, Rolf W. Sparidans, Wenlong Li, Maria C. Lebre, Jos H. Beijnen, Alfred H. SchinkelAbstractQuizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33-51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research

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Authors: Zhou S, Wei J, Wang Y, Liu X Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. Despite clinical advances, the survival rate of patients with HCC remains low, as most patients are diagnosed with HCC when they are already at the advanced stage. Certain circular RNAs (circRNAs) are closely associated with the development of liver cancer. In the present study, a circRNA array was performed to screen differentially expressed circRNAs in HCC tissues. The further analysis focused on the newly identified circRNA_101237, the host gene of which, cyclin-dependent kin...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
Authors: Li L, Zheng Y, Zheng Q, Jiang J Abstract The present study aimed to investigate the antiproliferative effect of embryonic stem cell-conditioned medium (ESC-CM) on the mouse liver cancer Hepa1-6 cells in vitro. Furthermore, in order to elucidate the underlying molecular mechanism, the microRNAs (miRNAs) in ESC-CM associated with the inhibition of Hepa1-6 proliferation were identified. Following the co-culture of ESC-CM and Hepa1-6 in Transwell chambers, the proliferation, cell cycle, apoptosis and associated protein expression were determined in Hepal-6 cells. Moreover, miRNA array analysis was employed to ...
Source: Experimental and Therapeutic Medicine - Category: General Medicine Tags: Exp Ther Med Source Type: research
In spite of the recent approval of new promising targeted therapies, the clinical outcome of patients with acute myeloid leukemia (AML) remains suboptimal, prompting the search for additional and synergistic therapeutic rationales. It is increasingly evident that the bone marrow immune environment of AML patients is profoundly altered, contributing to the severity of the disease but also providing several windows of opportunity to prompt or rewire a proficient antitumor immune surveillance. In this Review, we present current evidence on immune defects in AML, discuss the challenges with selective targeting of AML cells, an...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
Bacteria in some tumors may hinder cancer treatments. (read more)
Source: Environmental Factor - NIEHS Newsletter - Category: Environmental Health Source Type: news
Publication date: Available online 31 March 2020Source: Actas Urológicas Españolas (English Edition)Author(s): D. Nieblas-Toscano, A.J. Arenas-Bonilla, J.F. Flores-Martín, F. Gutiérrez-Tejero, C. Velarde-Muñoz, C.I. Ramos-Alaminos, M.C. Salas-Moreno, R. Galisteo-Moya, J. Moreno-Jiménez
Source: Actas Urologicas Espanolas - Category: Urology & Nephrology Source Type: research
This report provides an in-depth look at public drug program spending in Canada, using the Canadian Institute for Health Information's (CIHI) National Prescription Drug Utilization Information System. Public drug program spending does not include spending on drugs dispensed in hospitals or on those funded through cancer agencies and other special programs. Public drug program spending increased by 6.8% in 2018, compared to an increase of 5.3% in 2017. The growth in 2018 was largely because of the introduction of Ontario Health Insurance Plan+ (OHIP+), which extended drug coverage to all Ontario residents age 24 years or y...
Source: Healthcare Quarterly - Category: International Medicine & Public Health Source Type: research
This article analyzes data on 28 indicators prioritized over these years and demonstrates that 25 have shown sustained improvement over time. The performance management approach, lessons learned and gaps in knowledge are described to inform future research and practice.
Source: Healthcare Quarterly - Category: International Medicine & Public Health Source Type: research
Publication date: Available online 31 March 2020Source: Preventive MedicineAuthor(s): Dean Connolly, Xan Hughes, Alison Berner
Source: Preventive Medicine - Category: International Medicine & Public Health Source Type: research
This study assessed the utility and safety of robot-assisted ISR by comparing groups of patients who underwent low anterior resection (LAR) with or without ISR and ISR extent.MethodsThis study enrolled 897 patients who underwent curative LAR between 2010 and 2017. Patients were divided into those who did (ISR+) and did not (ISR −) undergo ISR, with the former group subdivided by ISR extent (partial, subtotal, and total). Tumor recurrence and survival were compared in the two groups by one-to-one nearest neighbor matching (218 patients each).ResultsRobot-assisted ISR was performed via an entirely transabdominal approa...
Source: Surgical Endoscopy - Category: Surgery Source Type: research
In conclusion, e-As4S4 holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment. Introduction Metastasis is the leading cause of breast cancer mortality, which has been one major challenge in clinical treatment (1). In particular, triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors (ER), progesterone receptors (PR) and HER2 receptors, which is one of the most aggressive types of breast cancers, marked by high rates of relapse, visceral metastases and early death (2, 3). The...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
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