20 research outputs found
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A mechanistic study of how adenovirus infection alters the expression and function of hepatic cytochrome P450 3A
No full texttextRecombinant adenoviruses, commonly used in gene therapy and vaccine applications, compromise the expression and function of hepatic CYP3A for 14 days. When given with docetaxel (DTX), plasma clearance of DTX (3.38 ± 0.22 l/kg.h) was significantly lower than those given DTX alone (6.41 ± 1.10 l/kg.h). The area under the plasma concentration-time curve of DTX in rats given virus (2,987.37 ± 197.97 ng/ml.h) was significantly greater than those given drug alone (1,666.59 ± 317.04 ng/ml.h). The virus extended the half-life of DTX three-fold. This may explain why adenoviral vectors improve chemotherapy. PEGylation of the virus reduced interleukin-6 (IL-6), IL-12, tumor necrosis factor alpha (TNF-α), aspartate transaminase (AST) and lactate dehydrogenase (LDH) levels in mice and non-human primates. PEGylation dramatically reduced transduction efficiency of virus in the baboon liver and did not alter hepatic transgene expression in the mouse. Unmodified and PEGylated virus (3 x 1012 vp/kg) reduced hepatic CYP3A4 protein by 60% and 40%, respectively 96 hours after virus administration. Catalytic activity was decreased by 55% and 45% with respect to an untreated control by the native and PEGylated viruses respectively. This suggests that changes in hepatic CYP3A during infection is not entirely due to the immune response and these observed effects most likely occur in humans. The effects of adenovirus on hepatic CYP3A expression and function in mice, however, resolved at a faster rate than that in baboons. HC-04 cells are a suitable in vitro model to study virus infection and hepatic CYP3A function. A panel of adenoviruses inhibited CYP3A catalytic activity and induced changes in expression and distribution of retinoid X receptor alpha (RXRα), pregnane X receptor (PXR) and constitutive androstane (CAR) receptors. Virus (1.5 x 1011 vp) inhibited CYP3A in the mouse. When the ability of the virus to bind to integrins was removed, changes in CYP were not detected. Treatment with a RGD peptide, that binds to integrins, reduced CYP3A activity in a manner similar to the virus. Silencing of β3 and β5 integrins also resolved changes in CYP3A activity during infection, suggesting that simple engagement of integrin receptors can initiate changes in CYP3A.Pharmaceutical Science
อิริโนทีแคน ในมุมมองเภสัชพันธุศาสตร์ Irinotecan: Pharmacogenetic Perspective
No full textอิริโนทีแคนเป็นยาเคมีบำบัดที่ใช้ในการรักษามะเร็งหลายชนิด ได้แก่ มะเร็งลำไส้ใหญ่และทวารหนัก มะเร็งปอด มะเร็งตับอ่อน ยามีลักษณะเป็น prodrug ที่ต้องผ่านกระบวนการไฮโดรไลซิสล์ (hydrolysis) เป็น 7-ethyl-10-hydroxy-camptothecin (SN-38) ซึ่งเป็นสารที่มีฤทธิ์ทางเภสัชวิทยา และถูกเปลี่ยนแปลงผ่านกระบวนการ glucuronidation ซึ่งจะถูกกำจัดออกจากร่างกายผ่านทางน้ำดีเป็นหลัก ยาออกฤทธิ์โดยการยับยั้งการทำงานของเอนไซม์ topoisomerase I ผลข้างเคียงที่สำคัญคืออาการท้องเสียถ่ายเหลวและภาวะเม็ดเลือดขาวต่ำ ด้วยภาวะพหุสัณฐานทางพันธุกรรมของกลุ่มยีนที่เกี่ยวข้องกับเภสัชจลนศาสตร์ของยา เช่น SLCO1B1, UGT1A, CYP3A และ ABC ส่งผลให้การตอบสนองต่อยาและอาการไม่พึงประสงค์ของผู้ป่วยแต่ละรายแตกต่างกัน โดยเฉพาะอย่างยิ่ง UGT1A1*28 และ UGT1A1*6 ซึ่งส่งผลให้อาการท้องเสียถ่ายเหลวและภาวะเม็ดเลือดขาวต่ำเกิดได้มากขึ้น ดังนั้นการตรวจคัดกรองทางพันธุศาสตร์จึงมีความสำคัญ ทั้งนี้จะต้องคำนึงถึงค่าใช้จ่ายและประสิทธิผลในการตรวจคัดกรอง บทความนี้จึงมีวัตถุประสงค์ในการทบทวนวรรณกรรมที่เกี่ยวข้องกับยาอิริโนทีแคนในมุมมองด้านเภสัชพันธุศาสตร์ เพื่อให้บุคลากรทางการแพทย์นำไปประยุกต์ใช้ในการดูแลผู้ป่วยที่ได้รับยาอิริโนทีแคนได้อย่างเหมาะสม คำสำคัญ: อิริโนทีแคน, เภสัชพันธุศาสตร์, พหุสัณฐานIrinotecan is a chemotherapeutic drug used in many cancers, including colorectal cancer, lung cancer, and pancreatic cancer. It is a prodrug that is hydrolyzed into 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite, which is further metabolized by glucuronidation and excreted mainly into the biliary system. Its primary mechanism is inhibiting topoisomerase I. There are many adverse effects including diarrhea and neutropenia. There are many genetic polymorphisms of enzymes and transporters involved in pharmacokinetics of irinotecan such as SLCO1B1, UGT1A, CYP3A, and ABC, leading to individual variability in drug efficacy and adverse effects. It is known that UGT1A1*28 and UGT1A1*6 polymorphisms could increase risk of diarrhea and neutropenia. Thus, pharmacogenetics screening test may be necessary for patients receiving irinotecan. However, cost-effectiveness should also be considered. This article aims to present a review of the scientific literature on genetic polymorphisms associated with pharmacologic profile of irinotecan for healthcare personnel applications. Keywords: irinotecan, pharmacogenetics, polymorphis
PEGylated Adenoviruses: From Mice to Monkeys
No full textCovalent modification with polyethylene glycol (PEG), a non-toxic polymer used in food, cosmetic and pharmaceutical preparations for over 60 years, can profoundly influence the pharmacokinetic, pharmacologic and toxciologic profile of protein and peptide-based therapeutics. This review summarizes the history of PEGylation and PEG chemistry and highlights the value of this technology in the context of the design and development of recombinant viruses for gene transfer, vaccination and diagnostic purposes. Specific emphasis is placed on the application of this technology to the adenovirus, the most potent viral vector with the most highly characterized toxicity profile to date, in several animal models
Combining vitamin B<sub>12</sub> and cisplatin-loaded porous silica nanoparticles via coordination: a facile approach to prepare a targeted drug delivery system
No full textIn this work, a novel drug delivery system for targeted therapy is developed based on noncovalent interactions.</p
Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations
No full textEpidermal growth factor receptor (EGFR) is the key molecular target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC treatment. In the present study, mansonone G (MG), a naturally occurring quinone-containing compound, and its semi-synthetic ether derivatives were subjected to investigate the anticancer effects on human NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) exhibits the potent cytotoxic effect on both A549 (IC50 of 8.54 μM) and H1975 (IC50 of 4.21 μM) NSCLC cell lines with low toxicity against PCS201-010 normal fibroblast cells (IC50 of 21.16 μM). Western blotting and flow cytometric analyses revealed that MG3 induces a caspase-dependent apoptosis mechanism through: (i) inhibition of p-STAT3 and p-Akt without affecting upstream p-EGFR and (ii) activation of p-Erk. The 500-ns molecular dynamics simulations and the molecular mechanics combined with generalized Born surface area (MM/GBSA)-based binding free energy calculations suggested that MG3 could possibly interact with STAT3 SH2 domain and ATP-binding pocket of Akt. According to principal component analysis, the binding of MG3 toward STAT3 and Akt dramatically altered the conformation of proteins, especially the residues in the active site, stabilizing MG3 mainly through van der Waals interactions
Panduratin A from Boesenbergia rotunda Effectively Inhibits EGFR/STAT3/Akt Signaling Pathways, Inducing Apoptosis in NSCLC Cells with Wild-Type and T790M Mutations in EGFR
No full textNon-small cell lung cancer (NSCLC) is a challenging disease, with the epidermal growth factor receptor (EGFR) being a key target for new, effective treatments crucial for the signaling pathways regulating cancer cell survival. Targeting EGFR-mediated signaling offers promising strategies to improve NSCLC therapies, particularly in overcoming resistance in EGFR-mutant lung cancer. In this study, we investigated the anticancer effects of panduratin A, a naturally occurring flavonoid from Boesenbergia rotunda, on human NSCLC cell lines expressing both wild-type EGFR (A549) and mutant EGFR (H1975) using in vitro experiments and molecular docking approaches. Cytotoxicity screening revealed that panduratin A exhibits potent effects on both A549 (IC50 of 6.03 ± 0.21 µg/mL) and H1975 (IC50 of 5.58 ± 0.15 µg/mL) cell lines while demonstrating low toxicity to normal MRC5 lung cells (12.96 ± 0.36 µg/mL). Furthermore, western blotting and flow cytometric analyses indicated that panduratin A induces apoptosis by inhibiting p-EGFR and its downstream effectors, p-STAT3 and p-Akt, in lung cancer cells. Additionally, the docking study showed lower binding energy between panduratin A and the target proteins, comparable to that of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). The ADMET prediction also highlighted panduratin A’s exceptional drug-like properties. This study concludes that panduratin A shows significant promise as an anti-lung cancer candidate for NSCLC, offering an economical and effective strategy
Molecular and macromolecular alterations of recombinant adenoviral vectors do not resolve changes in hepatic drug metabolism during infection
No full textAbstract In this report we test the hypothesis that long-term virus-induced alterations in CYP occur from changes initiated by the virus that may not be related to the immune response. Enzyme activity, protein expression and mRNA of CYP3A2, a correlate of human CYP3A4, and CYP2C11, responsive to inflammatory mediators, were assessed 0.25, 1, 4, and 14 days after administration of several different recombinant adenoviruses at a dose of 5.7 × 1012 virus particles (vp)/kg to male Sprague Dawley rats. Wild type adenovirus, containing all viral genes, suppressed CYP3A2 and 2C11 activity by 37% and 39%, respectively within six hours. Levels fell to 67% (CYP3A2) and 79% (CYP2C11) of control by 14 days (p ≤ 0.01). Helper-dependent adenovirus, with all viral genes removed, suppressed CYP3A2 (43%) and CYP2C11 (55%) within six hours. CYP3A2 remained significantly suppressed (47%, 14 days, p ≤ 0.01) while CYP2C11 returned to baseline at this time. CYP3A2 and 2C11 were reduced by 45 and 42% respectively 6 hours after treatment with PEGylated adenovirus, which has a low immunological profile (p ≤ 0.05). CYP3A2 remained suppressed (34%, p ≤ 0.05) for 14 days while CYP2C11 recovered. Inactivated virus suppressed CYP3A2 activity by 25–50% for 14 days (p ≤ 0.05). CYP2C11 was affected similar manner but recovered by day 14. Microarray and in vitro studies suggest that changes in cellular signaling pathways initiated early in virus infection contribute to changes in CYP.</p
Grade 7 students’ normative decision making in science learning about global warming through science technology and society (STS) approach
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Anti-inflammatory effects of moxifloxacin and levofloxacin on cadmium-activated human astrocytes: Inhibition of proinflammatory cytokine release, TLR4/STAT3, and ERK/NF-κB signaling pathway
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