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You searched for +publisher:"University of Tennessee Health Science Center" +contributor:("Clinton Stewart, Pharm.D."). Showing records 1 – 3 of 3 total matches.

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1. Elmeliegy, Mohamed. CNS Penetration of Tyrosine Kinase Inhibitors in Mouse Models.

Degree: PhD, Biomedical Sciences, 2012, University of Tennessee Health Science Center

For the past three decades, advances in the treatment of central nervous system (CNS) tumors such as malignant glioma have only been modest. One particular challenge facing treatment of brain tumors is the delivery of therapeutically effective concentrations of anti-cancer agents to the target site in the brain. The sanctuary of the brain is protected by several barrier systems such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). These barriers restrict the passage of anti-cancer drugs into the brain via several protective mechanisms. In the present study, we used cerebral microdialysis sampling, a technique for sampling unbound molecules in brain extracellular fluid (ECF) via semi-permeable probe, to assess the role of murine ATP Binding Cassette (ABC) transporters Bcrp1, P-gp, and Mrp4 in CNS penetration of molecularly targeted agents under investigation for treatment of malignant glioma. We choose the specific inhibitor of epidermal growth factor receptor (EGFR), erlotinib (TarcevaTM), and the specific inhibitor of platelet-derived growth factor receptor (PDGFR), crenolanib, as examples of tyrosine kinase inhibitors currently tested for treatment of malignant glioma. Given the poor microdialysis probe recovery of these lipophilic molecules, we enhanced their recovery by including an affinity-based trapping agent, 10% hydroxypropylbetacyclodextrin (HPBCD), in the perfusate. Using this technique, we studied erlotinib and its major metabolite, OSI-420, penetration in control and transporter-deficient mice. We showed that Bcrp1 is the main efflux transporter preventing erlotinib and OSI-420 penetration in mouse brain. Intracellular accumulation studies confirmed the role of BCRP in erlotinib and OSI-420 transport. We also characterized the role of solute carrier transporters in erlotinib and OSI-420 brain accumulation. Our data show that erlotinib and OSI-420 are substrates for members of the SLC22A family of uptake transporters, OAT3 and OCT2. We then sought to characterize the disposition of tyrosine kinase inhibitors in malignant glioma using cerebral microdialysis. We decided to use a transgenic mouse model that highly recapitulates several features of the human glioma including tumor histology and genetic profiles. However, the bregma commonly used as a reference point to place microdialysis cannula does not appear on images derived by magnetic resonance imaging (MRI), the imaging method used to identify the size and location of the spontaneously arising tumors. Thus, we realized that a new technique to implant the microdialysis guide cannula would be necessary. Using angiography studies of mouse brain vasculature and T2-weighted MRI, we identified the intersection of the midline suture and the rostral rhinal vein on the mouse brain surface as a reference point for implanting the microdialysis cannula. This point correlated with the intersection between the midline and the olfactory bulb/frontal lobe border visualized on T2- weighted MRI. Our method allowed for… Advisors/Committee Members: Clinton Stewart, Pharm.D..

Subjects/Keywords: CNS penetration; Crenolanib; Erlotinib; Microdialysis; Tyrosine Kinase Inhibitors; Medical Cell Biology; Medical Molecular Biology; Medical Sciences; Medicine and Health Sciences

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APA (6th Edition):

Elmeliegy, M. (2012). CNS Penetration of Tyrosine Kinase Inhibitors in Mouse Models. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/74

Chicago Manual of Style (16th Edition):

Elmeliegy, Mohamed. “CNS Penetration of Tyrosine Kinase Inhibitors in Mouse Models.” 2012. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed April 16, 2021. https://dc.uthsc.edu/dissertations/74.

MLA Handbook (7th Edition):

Elmeliegy, Mohamed. “CNS Penetration of Tyrosine Kinase Inhibitors in Mouse Models.” 2012. Web. 16 Apr 2021.

Vancouver:

Elmeliegy M. CNS Penetration of Tyrosine Kinase Inhibitors in Mouse Models. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2012. [cited 2021 Apr 16]. Available from: https://dc.uthsc.edu/dissertations/74.

Council of Science Editors:

Elmeliegy M. CNS Penetration of Tyrosine Kinase Inhibitors in Mouse Models. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2012. Available from: https://dc.uthsc.edu/dissertations/74

2. Shen, Jun. Factors Influencing Topotecan CNS Penetration in Mouse Models.

Degree: PhD, Interdisciplinary Program, 2008, University of Tennessee Health Science Center

Camptothecin analogs such as topotecan are currently tested in clinical trials for brain tumors. However the clinical outcome is far below the expectations, which are derived from the promising preclinical studies. This discrepancy could be partially attributed to the presence of two barrier systems in the brain, the blood brain barrier (BBB) and blood cerebrospinal fluid (CSF) barrier (BCB). Further investigations have demonstrated multiple ATP-binding cassette (ABC) transporters are present at the two barriers. Camptothecin analogs are well known substrates for several of the transporters. This work defined the role of two ABC transporters, Bcrp1 and P-gp in determination of topotecan CNS penetration in mouse models by using cerebral microdialysis. Microdialysis sampling of drugs in ventricular cerebrospinal fluid (vCSF) provides insight into drug penetration into the brain across the blood CSF barrier (BCB); however, this method has been reported primarily in larger animal species. The initial studies were designed to improve our existing surgical technique to implant a microdialysis cannula into the lateral ventricle to sample vCSF. The modifications done in these studies consisted of changes in the stereotaxic coordinates and insertion of the cannula at a 20° angle. Exact placement of the probe was confirmed using ultrasound (US), micro-computed tomography (CT), and histologic review of serial paraffin sections. Studies of topotecan CSF penetration in the FVB mouse using this modified approach determined that the vCSF to plasma AUC ratio of unbound topotecan lactone was greater than that previously reported using previous surgical technique. Results of studies from this lab have shown that topotecan has differential CNS penetration, and that vCSF topotecan penetration is greater than penetration into brain parenchymal extracellular fluid (ECF). We hypothesize Bcrp1 and P-gp together play a major role in regulation of topotecan CNS penetration. To further characterize the topotecan CNS transport mechanisms, topotecan penetration in two CNS compartments, vCSF and brain parenchymal ECF were determined in several knockout mouse models (Bcrp1(-/-), Mdr1a/b(-/-) and Bcrp1/Mdr1a/b(-/-) by adapting an intracerebral microdialysis technique. After an intravenous (i.v.) bolus dose of 4 mg/kg topotecan, unbound topotecan lactone vCSF penetration was defined by a vCSF to plasma area under the curve ratio (AUCu,vCSF/AUCu,plasma). The topotecan vCSF penetration (AUCu,ECF/AUCu,plasma) was significantly decreased in all three knockout models compared with wild type. The penetration into the brain parenchyma, defined by the ECF to plasma AUC ratio, was not changed in Bcrp1(-/-) but significantly increased in Bcrp1/Mdr1a/b(-/-). Pre-treatment with the EGFR tyrosine kinase inhibitor gefitinib (200 mg/kg) to inhibit Bcrp1 and P-gp transporters significantly decreased topotecan vCSF penetration but increased ECF penetration in FVB wild type. The topotecan lactone to carboxylate AUC ratio in vCSF (AUClactone,CSF/AUCcarboxylate,CSF)… Advisors/Committee Members: Clinton Stewart, Pharm.D..

Subjects/Keywords: Blood brain barrier; Blood CSF barrier; CNS; Topotecan; Pharmacokinetics; ABC-transporters; Microdialysis; Mouse tumor model; Medical Sciences; Medicine and Health Sciences; Neurosciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Shen, J. (2008). Factors Influencing Topotecan CNS Penetration in Mouse Models. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/241

Chicago Manual of Style (16th Edition):

Shen, Jun. “Factors Influencing Topotecan CNS Penetration in Mouse Models.” 2008. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed April 16, 2021. https://dc.uthsc.edu/dissertations/241.

MLA Handbook (7th Edition):

Shen, Jun. “Factors Influencing Topotecan CNS Penetration in Mouse Models.” 2008. Web. 16 Apr 2021.

Vancouver:

Shen J. Factors Influencing Topotecan CNS Penetration in Mouse Models. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2008. [cited 2021 Apr 16]. Available from: https://dc.uthsc.edu/dissertations/241.

Council of Science Editors:

Shen J. Factors Influencing Topotecan CNS Penetration in Mouse Models. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2008. Available from: https://dc.uthsc.edu/dissertations/241

3. Turner, Patricia Kellie. The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan.

Degree: PhD, Pharmaceutical Sciences, 2007, University of Tennessee Health Science Center

High-risk neuroblastoma presents a significant therapeutic challenge because the 5-year survival rate remains less than 30% despite the use of surgery, multi-agent chemotherapy, radiation, and autologous bone marrow transplant. Novel therapeutic modalities are under development. The camptothecin analogs topotecan and irinotecan have been identified as successful cytotoxic agents. For topotecan, pharmacokinetically guided dosing to achieve a systemic exposure associated with preclinical anti-tumor activity in neuroblastoma xenograft models is feasible and has elicited favorable responses in children with high-risk neuroblastoma. However, some children with high-risk disease did not respond to the putatively effective topotecan systemic exposure. These children represent a subset of the disease intrinsically resistant to topotecan. Furthermore, mRNA expression of the adenosine triphosphate (ATP)-binding cassette (ABC) transporters P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1), which efflux many drugs used in neuroblastoma therapy, has been implicated in poor outcome in neuroblastoma. Therefore, the purpose of our studies was to determine the role of ABC transport protein expression in neuroblastoma resistance to the camptothecin analogs topotecan and irinotecan. Initially studies focused on determining the expression of ABC transporters for which the camptothecin analogs are substrates in neuroblastoma cell lines. By western blot analysis we demonstrated MRP4 and Pgp expression in neuroblastoma cell lines relatively resistant to topotecan (e.g., NB1691), but not in cell lines sensitive to topotecan (e.g., NB1643). In contrast, MRP1, MRP2, and breast cancer resistance protein (BCRP) expression did not discriminate between sensitive and resistant cell lines. To determine the functional contribution of both MRP4 and Pgp in neuroblastoma, we used RNA interference (RNAi) to silence MRP4 and Pgp expression in NB1691. Long term, stable expression of retroviral vector mediated short hairpin RNA (shRNA) reduced MRP4 and Pgp expression. Isogenic cell lines with reduced expression of MRP4 and Pgp exhibited an increase in sensitivity to both topotecan and SN-38, the active moiety of the prodrug irinotecan. In addition, we overexpressed MRP4 in NB1643, which resulted in increased topotecan resistance. The NB1691 cell lines with reduced MRP4 expression were subsequently transplanted as xenografts into severe combined immunodeficiency (SCID) mice to determine the effect of MRP4 expression on the in vivo response to topotecan. Unexpectedly, MRP4 silencing did not persist in vivo, and none of the xenograft models responded to topotecan. However, MRP4 expression was associated with failure to respond to topotecan, supporting the hypothesis that MRP4 mediates resistance to topotecan. Finally, we determined the ABC transporter expression profile in primary tumor specimens from patients with high-risk neuroblastoma who were treated with pharmacokinetically guided… Advisors/Committee Members: Clinton Stewart, Pharm.D..

Subjects/Keywords: Neuroblastoma; topotecan; irinotecan; ABC transporter; multidrug resistance; MRP4; Pgp; RNAi; shRNA; siRNA; immunohistochemistry; Amino Acids, Peptides, and Proteins; Chemicals and Drugs; Diseases; Medicinal and Pharmaceutical Chemistry; Medicine and Health Sciences; Neoplasms; Pharmaceutical Preparations; Pharmaceutics and Drug Design; Pharmacy and Pharmaceutical Sciences

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Turner, P. K. (2007). The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan. (Doctoral Dissertation). University of Tennessee Health Science Center. Retrieved from https://dc.uthsc.edu/dissertations/269

Chicago Manual of Style (16th Edition):

Turner, Patricia Kellie. “The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan.” 2007. Doctoral Dissertation, University of Tennessee Health Science Center. Accessed April 16, 2021. https://dc.uthsc.edu/dissertations/269.

MLA Handbook (7th Edition):

Turner, Patricia Kellie. “The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan.” 2007. Web. 16 Apr 2021.

Vancouver:

Turner PK. The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan. [Internet] [Doctoral dissertation]. University of Tennessee Health Science Center; 2007. [cited 2021 Apr 16]. Available from: https://dc.uthsc.edu/dissertations/269.

Council of Science Editors:

Turner PK. The Role of Multi-Drug Resistance Associated Protein 4 and P-glycoprotein in Resistance of Neuroblastoma to Topotecan and Irinotecan. [Doctoral Dissertation]. University of Tennessee Health Science Center; 2007. Available from: https://dc.uthsc.edu/dissertations/269

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