Medicine and Health Sciences Commons^™

Increasing The Efficacy Of Actinomycin D With Resveratrol In Aerodigestive Tract Cancers, Lukmon Morenikeji Raji

Theses, Dissertations and Capstones

Chemotherapy poses a significant challenge for cancer patients due to drug-associated toxicity, which often results from their effects on both healthy (normal) and cancerous cells. While various options aim to reduce toxicity and optimize beneficial effects, a comprehensive solution remains elusive. Cyclotherapy is one such approach developed to protect normal cells from the toxic effects of chemotherapy drugs. The basic principle underlying cyclotherapy is p53- dependent cell cycle arrest of normal cells while killing cancer cells via a p53-independent mechanism using a second drug. In our research, we investigated the inhibitory effects of a combination of two low-dose anticancer drugs, …

Bladder Tumor In A Young Leukemic Patient Cured By Chemotherapy: A Case Report, Mohamed Tebaa, Mamoutou Dit Mody, Sylla Mahamadou, Mohamed Amine Lakmichi

Health Sciences

Adult bladder tumor is estimated to be the 10th most common tumor worldwide. However, its incidence is much less common in children. It is a disease of the elderly that peaks in the sixth decade of life. Nevertheless, bladder tumors could also affect children, adolescents, and young adults with a prevalence of

Impact Of Clinical And Pharmacogenetic Variables On The Risk Of Fluoropyrimidine-Related Adverse Events Within Ontario, Theodore J. Wigle

Electronic Thesis and Dissertation Repository

Severe life-threatening adverse events are a major limitation of fluoropyrimidine chemotherapy, these events are disastrous for patients and costly to the healthcare system. Identifying patients at high risk for developing adverse events would allow for preventive dose reduction, improving patient outcomes and reducing healthcare cost. This thesis uses data pulled from provincial databases to quantify the adverse event burden of fluoropyrimidines in Ontario. We found that 31% of Ontario patients treated with fluoropyrimidine systemic chemotherapy developed a severe adverse event that requires acute medical care. Patients that required acute medical therapy were significantly costlier to the public system averaging an …

Lapatinib And Poziotinib Overcome Abcb1-Mediated Paclitaxel Resistance In Ovarian Cancer, J. Robert Mccorkle, Justin W. Gorski, Jinpeng Liu, Mckayla J. Riggs, Anthony B. Mcdowell Jr., Nan Lin, Chi Wang, Frederick R. Ueland, Jill M. Kolesar

Markey Cancer Center Faculty Publications

Conventional frontline treatment for ovarian cancer consists of successive chemotherapy cycles of paclitaxel and platinum. Despite the initial favorable responses for most patients, chemotherapy resistance frequently leads to recurrent or refractory disease. New treatment strategies that circumvent or prevent mechanisms of resistance are needed to improve ovarian cancer therapy. We established in vitro paclitaxel-resistant ovarian cancer cell line and organoid models. Gene expression differences in resistant and sensitive lines were analyzed by RNA sequencing. We manipulated candidate genes associated with paclitaxel resistance using siRNA or small molecule inhibitors, and then screened the cells for paclitaxel sensitivity using cell viability assays. …

Mithramycin And Analogs For Overcoming Cisplatin Resistance In Ovarian Cancer, David Schweer, J. Robert Mccorkle, Jurgen Rohr, Oleg V. Tsodikov, Frederick R. Ueland, Jill M. Kolesar

Obstetrics and Gynecology Faculty Publications

Ovarian cancer is a highly deadly malignancy in which recurrence is considered incurable. Resistance to platinum-based chemotherapy bodes a particularly abysmal prognosis, underscoring the need for novel therapeutic agents and strategies. The use of mithramycin, an antineoplastic antibiotic, has been previously limited by its narrow therapeutic window. Recent advances in semisynthetic methods have led to mithramycin analogs with improved pharmacological profiles. Mithramycin inhibits the activity of the transcription factor Sp1, which is closely linked with ovarian tumorigenesis and platinum-resistance. This article summarizes recent clinical developments related to mithramycin and postulates a role for the use of mithramycin, or its analog, …

Evaluation Of Benefits Associated With Chemotherapy Dose-Banding Practices, Alexis Mann Pharmd, Mba, Kyle Becker Pharmd, Mba, Bcop, Jesse Christman Pharmd, Bcop

Parkview Pharmacy Department

2021 ASHP Midyear Clinical Meeting / Virtual Meeting / Poster # 1130014

The objective of this study was to evaluate the benefit of applying a 10% rounding strategy with predetermined dose-bands to the current chemotherapy dosing policy at Parkview Health.

Bypassing The Blood-Brain Barrier: A Physical And Pharmacological Approach For The Treatment Of Metastatic Brain Tumors, Samuel A. Sprowls

Graduate Theses, Dissertations, and Problem Reports

This dissertation (a) provided an in depth literature review of methods to disrupt the BBB/BTB and improve therapeutic distribution to brain tumors, (b) evaluated the use of azacitidine as a single agent therapy for the treatment of brain metastasis of breast cancer and a potential molecular mechanism by which brain tropic cells are sensitized to hypomethylating agents, (c) determined the impact cannabidiol has on P-glycoprotein mediated efflux at the blood-brain barrier and its potential for use as a single agent treatment for metastatic brain tumors, (d) developed a preclinical radiation therapy protocol for use in small animals and in vitro …

Ligand-Installed Polymeric Nanocarriers For Combination Chemotherapy, Xinyuan Xi

Theses & Dissertations

Combination chemotherapy remains the mainstay of cancer treatment because such strategy targets different cell signaling pathways to decrease the likelihood of developing protective mechanisms by cancer cells, thereby delaying the onset of recurrence and prolonging the survival. The co-delivery of binary drug combination via a single nanocarrier provides benefits in reducing dose-limiting toxicities, improving the pharmacokinetic properties of the cargo, spatial-temporal synchronization of drug exposure, and synergistic therapeutic effects. Rational design of such regimen is crucial for maximizing the therapeutic effects since only certain drug ratios exposed to the target might be synergistic while other ratios exert additive or even …

A Simulation Activity To Assess Student Pharmacists' Knowledge And Perceptions Of Oncology Pharmacy, Elizabeth Ledbetter, Scarlet Lau, Andrea Enterline, Bethany Sibbitt, Aleda Chen

Pharmacy Practice Faculty Publications

Objective. To assess the impact of an interactive activity on student pharmacists’ confidence in answering oncology-related questions and their perceptions of an oncology pharmacists’ roles in practice.

Methods. Two cohorts (2016 and 2017) of third-year student pharmacists completed a two-hour, interactive, four-station activity during the fourth week of an oncology module. Each station simulated a different oncology-related scenario that represented a specific practice settings. Pre- and post-activity surveys were administered to determine changes in students’ confidence levels and perceptions.

Results. Over the two years, 66 student pharmacists completed the pre- and post-activity survey instruments. In both cohorts, there was a …

Potential Drug- Drug Interactions Between Anti- Tumor Agents And Other Prescribed Medications In Lung Cancer Patients: A Retrospective Study, Mahadev Rao Dr

Manipal College of Pharmaceutical Sciences, Manipal Theses and Dissertations

Background: Cancer patients are more prone to drug interactions as multiple medications are administered concomitantly along with cytotoxic agents in addition with drugs targeted to treat underlying comorbidities, and these are poorly evaluated. In the challenging field of cancer where the number of patients diagnosed increases in a geometric manner, the difficulties faced by healthcare professionals to treat the patients poses a great deal of arduous task in designing an optimum therapeutic regimen. This study addresses the current dilemma and suggests to bring about a resolution to the existing problem. Objectives: The primary objective of this study is to characterize, …

Ramucirumab: A New Agent For Advanced Or Metastatic Gastric Junction Adenocarcinoma, Adam Smith, Rebecca Worden, Jessica Hoffert, Brendon Rasor, Hannah Stewart, David Koh

Pharmacy and Wellness Review

Ramucirumab (Cyramza®), approved April 21, 2014, is a vascular endothelial growth factor receptor 2 (VEGFR2) antagonist with a U.S. Food and Drug Administration (FDA) indication for the treatment of advanced or metastatic gastric/gastroesophageal junction adenocarcinoma. Gastric cancer is a prevalent cancer in the United States with a poor prognosis. The phase 3 trial, REGARD, shows that ramucirumab, when used within four months after the last dose of first-line chemotherapy or six months after the last dose of adjuvant chemotherapy, increases overall survival. Also, ramucirumab has been included in combination therapy, such as in the RAINBOW trial, which demonstrated its effectiveness …

Olanzapine For Chemotherapy-Induced Nausea And Vomiting, John B. Bossaer

John B. Bossaer

Excerpt: Navari and colleagues (July 14 issue)1 report on the use of olanzapine for the prevention of chemotherapy-induced nausea and vomiting.

Translesion Synthesis Inhibitors As Anti-Cancer Adjuvant Agents, Kelly Allison Chan

University Scholar Projects

The translesion synthesis (TLS) pathway is a major mechanism through which cancer cells replicate past DNA lesions and promote chemoresistance. TLS allows cancers to survive genotoxic chemotherapy and increases the rate of mutation in tumors leading to drug-resistant cells. Cancer cells use a set of specialized low-fidelity TLS DNA polymerases to copy over lesions with Rev1 serving as a key scaffolding protein. Suppressing Rev1 activity sensitizes cancers to genotoxic chemotherapy and reduces the onset of chemoresistance by decreasing tumor mutation rate. Disruption of the Rev1/polζ-dependent TLS selective inhibitors has demonstrated the ability to sensitize cancer cells to platinating agents and …

Evaluating Itraconazole Analogues And Translesion Synthesis Inhibitors As Anti-Cancer Agents, Kelly Allison Chan

Honors Scholar Theses

My projects were to evaluate itraconazole (ITZ) analogues as anti-cancer hedgehog (Hh) and angiogenesis inhibitors, and translesion synthesis (TLS) inhibitors as anti-cancer agents. Itraconazole (ITZ) is a clinically effective triazole antifungal agent that has also been identified for its anti-cancer properties. As reported in the current literature, ITZ inhibits Gli1 transcription of the Hedgehog (Hh) signaling pathway and angiogenesis. However, the triazole moiety of ITZ has a detrimental side effect of inhibiting cytochrome P450 3A4 enzymes (CYP3A4). Thus, we have removed the triazole from the ITZ scaffold and develop a new series of ITZ analogues called des-triazole ITZ analogues. The …

Paclitaxel Enhances Oncolytic Potential Of Herpes Simplex Virus Type-1 In Cancer Cells, Misagh Naderi

LSU Master's Theses

Taxanes are spindle poisons that bind to and stabilize microtubules resulting in mitotic arrest. Herpes simplex Typ-1 (HSV-1) virions utilize the microtubular network for intracellular transport during both virus entry and virus egress from infected cells. It has been reported previously that taxanes may synergize with oncolytic herpes simplex viruses in the treatment of experimental prostate and breast tumors in mice. Other reports have indicated that taxanes may inhibit viral replication in infected cells. In this study the previously characterized Oncolytic Herpes Simplex Virus type 1 (OSVP), which was constructed in Kousoulas lab was used in conjugation with paclitaxel (taxol) …

Permeability Changes And Effect Of Chemotherapy In Brain Adjacent To Tumor In An Experimental Model Of Metastatic Brain Tumor From Breast Cancer, Afroz S. Mohammad, Chris E. Adkins, Neal Shah, Rawaa Aljammal, Jessica I. G. Griffith, Rachel M. Tallman, Katherine L. Jarrell, Paul R. Lockman

Faculty & Staff Scholarship

Abstract

Background: Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes.

Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle …

Evaluation Of A Drug Delivery System Based On Cyclodextrins For Cancer Therapy, Caroline Mendes

Doctoral

Due to the side-effects caused by regular chemotherapy, the development of drug delivery systems that can specifically target cancer cells and deliver the therapeutic dose is required. In this study, a folate-derivative of β-cyclodextrin has been studied as a vehicle for targeting folate receptors (FR) and delivering the chemotherapeutic drug methotrexate (MTX). FRs can be considered key cell membrane targets since they are commonly over-expressed in cancer cells and play an important role in cancer development and progression. Cyclodextrins (CDs) are cyclic oligosaccharides with a unique structure that allows them to form inclusion complexes with guest molecules, increasing their aqueous …

Synthesis Of 2,4,6-Substituted Pyrrolo[2,3-D]Pyrimidines As Potential Anticancer Agents, Si Yang

Electronic Theses and Dissertations

This thesis mainly focuses on the introduction of the background and work have been done in the areas of antifolates development, such as folate function, its three uptake mechanisms inside human cells, antifolates’ role in chemotherapy, et. al. In addition, the Structure-Activity-Relationship design rationale for the series of antifolates will also be discussed. Nevertheless, the details of synthesizing these pyrrolo[2,3-d]pyrimidines as potential antifolates have been described, including chemistry reviews on the pyrrolo[2,3-d]pyrimidine scaffold, and the challenges encountered and the solutions how to solve or improve in order to achieve better yield.

Olanzapine For Chemotherapy-Induced Nausea And Vomiting, John B. Bossaer

ETSU Faculty Works

Excerpt: Navari and colleagues (July 14 issue)1 report on the use of olanzapine for the prevention of chemotherapy-induced nausea and vomiting.

A Systematic Review Of The Cost-Effectiveness Of Chemotherapy Regimens, Chelsea R. Manion, Eric Blizzard, Emily Bruce, Hannah Chittenden, David Fisher, Lia G. Hickinbotham, Abigail Moon, Nicholas Rudy, Aleda Chen, Kristi Coe

The Research and Scholarship Symposium (2013-2019)

Background: The rising cost of chemotherapy dramatically increases the burden on healthcare and presents new challenges in achieving optimal patient outcomes. New treatments, in general, are more specialized but show minor progress in regards to efficacy. Accordingly, the threat of overpaying for chemotherapy regimens has increased. There is a need for a comprehensive review to compile relevant studies in order to inform clinician decisions on the basis of cost-effectiveness and quality of life.

Objectives: The objective of this project is to assess the cost-effectiveness of anticancer medications with a special focus on the quality of life of patients undergoing chemotherapy, …

Overcoming Cancer Multidrug Resistance Through Inhibition Of Microparticles, Sora Vysotski, Rivka Winzelberg, Mariana Babayeva

Touro College of Pharmacy (New York) Publications and Research

One of the main obstacles to success of chemotherapy agents is the development of cancer resistance. Cancer multidrug resistance (MDR) is thought to arise from over-expression of efflux transporters on cancer cells’ plasma membranes. Recently, microparticles (MP) were found to play a major role in mediating the resistance to antineoplastic agents. Microparticles can confer MDR phenotype to cancer cells though 3 complimentary pathways: 1) Intercellular transfer of P-gp and MRP1; 2) Intercellular transfer of regulatory nucleic acids that ensure acquisition of MDR phenotype; and 3) Internal sequestration of anticancer drugs to reduce the amount of free active drug. Compounds that …

Overcoming Innate And Acquired Therapy Resistance By Targeting Dna Repair In Human Cancer Cells, Mateusz Rytelewski

Electronic Thesis and Dissertation Repository

Genomic instability and a high mutation rate lead to heterogeneity in human tumors. Mathematical modelling predicts that these characteristics promote acquired resistance to cytotoxic and targeted therapies, by increasing the likelihood that resistant subpopulations exist at the start of treatment (and promoting the accumulation of de novo resistance mutations during treatment). As a result, genome plasticity promotes increased fitness on the population level, but individual tumor cells must nonetheless maintain a level of DNA integrity that allows for continued survival, particularly in the context of DNA-damaging therapy (which DNA repair counteracts). Thus, DNA repair proteins are a source of innate …

A Systematic Review Of The Cost-Effectiveness Of Chemotherapy Regimens, Nicholas Rudy, Hannah Chittenden, David Fisher, Abigail Moon, Lia G. Hickinbotham, Emily Bruce, Eric Blizzard, Aleda Chen, Chelsea Manion

Pharmacy and Nursing Student Research and Evidence-Based Medicine Poster Session

Background

The rising cost of chemotherapy dramatically increases the burden on healthcare and presents new challenges in achieving optimal patient outcomes. New treatments, in general, are more specialized but show minor progress in regards to efficacy. Accordingly, the threat of overpaying for chemotherapy regimens has increased. There is a need for a comprehensive review to compile relevant studies in order to inform clinician decisions on the basis of cost-effectiveness and quality of life.

Objectives

Therefore, the aim of this project is to assess the cost-effectiveness of anticancer medications with a special focus on the quality of life of patients undergoing …

An In Vitro Assessment Of Liposomal Topotecan Simulating Metronomic Chemotherapy In Combination With Radiation In Tumor-Endothelial Spheroids, Amar Jyoti, Kyle Daniel Fugit, Pallavi Sethi, Ronald C. Mcgarry, Bradley D. Anderson, Meenakshi Upreti

Pharmaceutical Sciences Faculty Publications

Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors. Extended release of TPT from liposomal formulations also has the potential to mimic metronomic therapies with fewer treatments. Here we investigate potential toxicities of equivalent doses of free and actively loaded liposomal TPT (LTPT) and compare …

Drug-Induced Cardiotoxicity Of Oncological Agents: Monitoring Parameters, Prevention, And Future Chemotherapy, Sarah Nguyen, Mary Nguyen, Laura Tsu

Pharmacy Faculty Articles and Research

The goal of this article is to educate pharmacists of the impact of cardiotoxicity on chemotherapy regimens including key cancer agents, monitoring parameters, prevention, and the future of chemotherapy.

Honokiol Enhances Paclitaxel Efficacy In Multi-Drug Resistant Human Cancer Model Through The Induction Of Apoptosis, Xu Wang, Jonathan J. Beitler, Hong Wang, Michael J. Lee, Wen Huang, Lydia Koenig, Sreenivas Nannapaneni, Arm R. Amin, Michael Bonner, Hyung Ju C. Shin, Zhuo Georgia Chen, Jack L. Arbiser, Dong M. Shin

Pharmaceutical Science and Research

Resistance to chemotherapy remains a major obstacle in cancer therapy. This study aimed to evaluate the molecular mechanism and efficacy of honokiol in inducing apoptosis and enhancing paclitaxel chemotherapy in pre-clinical multi-drug resistant (MDR) cancer models, including lineage-derived human MDR (KB-8-5, KB-C1, KB-V1) and their parental drug sensitive KB-3-1 cancer cell lines. In vitro analyses demonstrated that honokiol effectively inhibited proliferation in KB-3-1 cells and the MDR derivatives (IC₅₀ ranging 3.35±0.13 µg/ml to 2.77±0.22 µg/ml), despite their significant differences in response to paclitaxel (IC₅₀ ranging 1.66±0.09 ng/ml to 6560.9±439.52 ng/ml). Honokiol induced mitochondria-dependent and death receptor-mediated apoptosis in …

Polymer Micelles For Tunable Drug Release And Enhanced Antitumor Efficacy, Andrei G. Ponta

Theses and Dissertations--Pharmacy

Cancer remains a leading cause of death in the United States. The most common treatment options include chemotherapy, but poor solubility, adverse side effects and differential drug sensitivity hamper clinical applications. Current chemotherapy generally aims to deliver drugs at the limit of toxicity, assuming that higher dosage increases efficacy, with little attention paid to potential benefits of tunable release. Growing evidence suggests that releasing drugs at a constant rate will be as effective as a single bolus dose. To test this hypothesis, it is critical to develop drug delivery systems that fine-tune drug release and elucidate the impact of tunable …

Chemotherapy: The Physiological Cost Of A Cure, Megan Ellis

A with Honors Projects

This project focuses on the common long term side effects of cancer treatments, apart from cure. In addition to physiological function changes, it focuses on the chemical composition of chemotherapy drugs.

Influence Of Oncotype Dx® On Chemotherapy Prescribing In Early Stage Breast Cancer Patients: A Claims-Based Evaluation Of Utilization In The Real World, Kenneth Neil Kennedy

Theses and Dissertations--Pharmacy

The decision for adjuvant therapy in women with early stage breast cancer (ESBC) has historically been guided by the presence or absence of specific biological markers (hormone and HER2 receptors), age, and extent of nodal involvement. Oncotype DX® is a validated assay that quantifies protein expression that can predict the risk of cancer recurrence. This study evaluates if the use of Oncotype DX® impacts chemotherapy prescribing in ESBC. This retrospective, cohort study identified patients with ESBC from a large commercially insured population from January 2007 through June 2009. Patients were identified as having ESBC by utilizing procedure and diagnosis codes …

Impaired Clearance Of Methotrexate In Organic Anion Transporter 3 (Slc22a8) Knockout Mice: A Gender Specific Impact Of Reduced Folates, Adam L. Vanwert, Douglas H. Sweet

Pharmaceutics Publications

Purpose

To elucidate the role of the renal basolateral transporter, Oat3, in the disposition of methotrexate.

Materials and Methods

Chinese hamster ovary cells expressing mouse Oat3 were used to determine kinetics and specificity of inhibition of methotrexate transport. Methotrexate clearance was then examined in vivo in wildtype and Oat3 knockout mice.

Results

NSAIDs, ß-lactams, and uremic toxins inhibited mOat3-mediated methotrexate uptake by 70–100%, while folate, leucovorin, and 5-methyltetrahydrofolate inhibited transport by 25–50%. A Km of 60.6±9.3 μM for methotrexate transport was determined. Oat3 knockout mice exhibited reduced methotrexate-to-inulin clearance ratios versus wildtype. Male wildtype mice, but not knockouts or …