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dc.contributor.advisorMitra, Ashim K., 1954-eng
dc.contributor.authorVadlapatla, Ramya Krishnaeng
dc.date.issued2014-08-28eng
dc.date.submitted2014 Springeng
dc.descriptionTitle from PDF of title page, viewed on July 15, 2015eng
dc.descriptionDissertation advisor: Ashim K. Mitraeng
dc.descriptionVitaeng
dc.descriptionIncludes bibliographic references (pages 195-222)eng
dc.descriptionThesis (Ph.D.)--School of Pharmacy and Department of Chemistry. University of Missouri--Kansas City, 2014eng
dc.description.abstractMultidrug resistance (MDR), a clinical outcome characterized by subtherapeutic intracellular drug concentration, is one of the predominant factors limiting effective cancer chemotherapy. Several possible mechanisms and molecular alterations have been implicated in the development of MDR, including activation of efflux transporters and metabolizing enzymes in response to therapeutic agents. Therefore, the primary objective of my dissertation project is to develop strategies for overcoming drug resistance in cancer chemotherapy. Human adenocarcinoma cells (LS-180) were treated for 72 hours with vinblastine alone and in the presence of ritonavir. The expression of efflux transporters (MDR1 and MRP2), metabolizing enzyme (CYP3A4) and nuclear hormone receptor (PXR) was induced in response to vinblastine. This overexpression was completely neutralized when cells were cotreated with ritonavir. Uptake of [3H] lopinavir and Vivid™ assay further confirmed the functional activity of transcribed genes upon cotreatment. Reduced cell proliferation, migration and increased apoptosis of cancer cells were further indicative of enhanced activity of chemotherapeutics (doxorubicin, paclitaxel, tamoxifen and vinblastine) in the presence of ritonavir. Combination therapy of anticancer drug with ritonavir may overcome drug resistance by neutralizing overexpression of efflux transporters and metabolizing enzymes. Hypoxia leading to neovascularization has also been implicated in the development of MDR and ocular neovascular diseases. Despite introduction of novel therapeutics, treatment of retinal disorders remains challenging, possibly due to complex nature of hypoxia signaling. This study demonstrates for the first time that hypoxic conditions may alter expression of efflux and influx transporters in retinal pigment epithelial (RPE) cells. These findings suggest that hypoxia may further alter disposition of ophthalmic drugs. Inhibiting this signaling mechanism with an already approved therapeutic molecule may have promising antiangiogenic role with fewer side effects. Our studies (quantitative PCR, immunoblot analysis, ELISA and angiogenic assay) have demonstrated that ritonavir inhibits the expression of hypoxia-inducible factor-1α (HIF-1α) mediated vascular endothelial growth factor (VEGF) expression in RPE cells probably via inhibition of PI3K/AKT pathway. This inhibition may reduce retinal neovascularization. These findings shed new light on the possibility of incorporating ritonavir in the treatment regimen of ocular angiogenic diseases. Although many inhibitors of HIF-1α are in clinical trials, additional benefit of using ritonavir is that it has been given to HIV patients with relatively low toxicity. The process of traditional drug development could be fast tracked since ritonavir is clinically approved for human use. However, further preclinical and clinical experiments are necessary to determine the repositioning of ritonavir in the treatment of ocular neovascular diseaseseng
dc.description.tableofcontentsMechanisms of drug resistance in cancer chemotherapy: Coordinated role and regulation of efflux transporters and metabolizing enzymes -- Differential effect of MDR1 and MRP2 in cellular translocation of gemifloxacin -- PXR mediated induction of efflux transporters by fluoroquinolones: a possible mechanism for development of multidrug resistance -- Rotonavir: a novel therapeutic for overcoming drug resistance in cancer chemotherapy -- Hypoxia-inducible factor 1 (HIF-1): a potential target intervention in ocular neovascular diseases -- Molecular expression and functional activity of efflux and influx transporters in hypoxia induced retinal pigment epithelial cells -- Ritonavir inhibits HIF-1a mediated VEGF expression in retinal pigment epithelial cells -- Summary and recommendations -- Appendixeng
dc.format.extentvxiii, 223 pageseng
dc.identifier.urihttp://hdl.handle.net/10355/43710eng
dc.subject.lcshMultidrug resistanceeng
dc.subject.lcshCancer -- Chemotherapyeng
dc.subject.lcshDrug resistance in cancer cellseng
dc.subject.lcshEye -- Diseases -- Treatmenteng
dc.subject.lcshAntiretroviral agentseng
dc.subject.otherDissertation -- University of Missouri--Kansas City -- Pharmacyeng
dc.subject.otherDissertation -- University of Missouri--Kansas City -- Chemistryeng
dc.titleRitonavir - A Novel Multidrug Resistance Modulator in Cancer Chemotherapy and Ocular Neovascular Diseaseseng
dc.typeThesiseng
thesis.degree.disciplinePharmaceutical Sciences (UMKC)eng
thesis.degree.disciplineChemistry (UMKC)
thesis.degree.grantorUniversity of Missouri--Kansas Cityeng
thesis.degree.levelDoctoraleng
thesis.degree.levelPh.D.eng


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