Neoplasms Commons^™

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

Dual Pi3k/Mtor Inhibition With Bez235 Augments The Therapeutic Efficacy Of Doxorubicin In Cancer Without Influencing Cardiac Function, David E. Durrant

Theses and Dissertations

Cancer continues to be a leading cause death in the United States despite improved treatments. Cancerous lesions form after acquiring oncogenic driver mutations or losing tumor suppressor function in normal cells. Traditional therapies have included use of genotoxic substances that take advantage of the increased growth rate and loss of tumor suppressor function to cause cell death. One such drug is the anthracycline antibiotic doxorubicin (DOX). DOX interchelates into DNA and disrupts transcriptional machinery while also poisoning topoisomerase II. This results in single and double stranded DNA breaks, which if severe enough leads to either necrotic or apoptotic cell death. …

Radiosensitization Of Head & Neck Carcinoma Cells By Linifanib, A Receptor Tyrosine Kinase Inhibitor, Heng-Wei Hsu

Loma Linda University Electronic Theses, Dissertations & Projects

Tumor angiogenesis is a hallmark of advanced cancers and promotes invasion and metastasis. Over 90% of head and neck squamous cell carcinomas (HNSCC) express angiogenic factors such as vascular endothelial growth factor (VEGF). Since radiotherapy is one of the most commonly used treatments for HNSCC, it is imperative to identify the interactions between antiangiogenic therapy and radiotherapy, and to develop combination therapy to improve clinical outcome. The mechanisms between antiangiogenic agents and ionizing radiation are complicated and involve many interactions between the vasculature, tumor stroma and tumor cells. The proliferation and metastasis of tumor cells rely on angiogenesis/blood vessel formation. …

The Protumorigenic Role Of Caspase-8 In Neuroblastoma, Devin Drew Twitchell

Theses and Dissertations (ETD)

Neuroblastoma (NB), the most common extracranial solid tumor in children, accounts for 15% of cancer-related deaths in pediatric patients. Caspase-8 (casp8), a proapoptotic protein, is silenced in approximately, 50-70% of neuroblastoma patient samples. Loss of casp8 has been suggested to increase NB metastasis and correlated, in some studies, with advanced-stage NB. Furthermore, decreased casp8 expression may facilitate neuroblastoma tumorigenesis by protecting cells from cell death mediated by either integrins or chemotherapeutics. Paradoxically, casp8 expression is maintained in 30-50% of NB patient samples giving rise to the possibility that casp8 may provide selective advantages for NB tumorigenesis. Caspase-8 is shown to …

Differential Effects Of Micrornas On Glioblastoma Growth And Migration, Duane Jeansonne, Marco Pacifici, Adam Lassak, Krzysztof Reiss, Giuseppe Russo, Jovanny Zabaleta, Francesca Peruzzi

School of Medicine Faculty Publications

Glioblastoma multiforme is characterized by rapid proliferation, aggressive metastatic potential, and resistance to radio- and chemotherapy. The matricellular protein CYR61 regulates cellular proliferation and migration and is highly expressed in Glioblastomas. MicroRNAs are 22-nucleotides long RNAs that regulate gene expression post-transcriptionally. Here, we utilized the LN229 glioblastoma cell line and found that CYR61 is a target of miR-136, miR-155, and miR-634. Over-expression of miR-136 and miR-634 miRNAs negatively affected proliferation, but not migration, while expression of miR-155 reduced migration but did not affect the proliferation of LN229 cells. Investigation of the molecular mechanisms affected by expression of miR-634 revealed an …

The Role Of The Yxxφ Motif In Cd82 Trafficking And Function, Mekel Marie Richardson

Theses and Dissertations (ETD)

CD82, a tetraspanin, is a tumor metastasis suppressor. Tetraspanins are membrane spanning proteins that play critical roles in diverse biological and pathological processes, e.g., the regulation of cancer metastasis. CD82 is ubiquitously expressed in various types of tissues, but its expression becomes down-regulated or lost in a majority of metastatic tumors. It inhibits tumor metastasis without affecting primary tumor growth. Cancer patients whose tumors contain CD82 exhibit minimal metastasis. We know that CD82 functions as a tumor metastasis suppressor but the mechanism by which this occurs is largely unknown. CD82 can be found on the plasma membrane as well as …

Discovery Of Dihydroartemisinin And Dasatinib Drug Combination To Cure Pooroutcome Bcr-Abl+ Acute Lymphoblastic Leukemia, Harpreet Singh

Theses and Dissertations (ETD)

Oncogenic signaling by the Philadelphia chromosome-encoded BCR-ABL fusion kinase initiates and drives both Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myelogenous leukemia (CML). Food and Drug Administration (FDA)- approved BCR-ABL-specific kinase inhibitors (BCR-ABL–KIs) imatinib, dasatinib and nilotinib induce prolonged remissions in CML but poor leukemia-reduction and relapse-control in Ph+ ALL. The relative primary BCR-ABL–KI-resistance in Ph+ ALL patients carrying predominantly BCR-ABLWT disease cannot be attributed to drug-resistant BCR-ABL mutations (BCR-ABLMUTANTS), and remains poorly understood.

We established a cell-based platform to evaluate the modulation of anti-Ph+ ALL activity of drugs by both tumor-extrinsic cytokines normally present in the leukemia …

Chemosensitization Of Hepatocellular Carcinoma To Gemcitabine By Non-Invasive Radiofrequency Field-Induced Hyperthermia, Mustafa Raoof

Dissertations and Theses (Open Access)

Gemcitabine is a potent nucleoside analogue against solid tumors however drug resistance rapidly emerges. Removal of gemcitabine incorporated in the DNA by repair mechanisms could potentially contribute to resistance in chemo-refractory solid tumors. In this study, we evaluated homologous recombination repair of gemcitabine-stalled replication forks as a potential mechanism contributing to resistance. We also studied the effect of hyperthermia on homologous recombination pathway to explain the previously reported synergy between gemcitabine and hyperthermia. We found that hyperthermia degrades and inhibits localization of Mre11 to gemcitabine-stalled replication forks. Furthermore, gemcitabine-treated cells that were also treated with hyperthermia demonstrate a prolonged passage …

Self-Reported Exercise And Risk Of Osteoporosis In Prostate Cancer Patients Receiving Androgen Deprivation Therapy, Lori J. Mennen-Winchell

Loma Linda University Electronic Theses, Dissertations & Projects

Prostate cancer is stimulated to grow in response to testosterone. Androgen deprivation therapy (ADT) leads to chemical castration and suppression of prostate cancer cell production. Testosterone levels less then 300ng/ml decreases bone mineral density and could result in osteoporosis. Studies have shown that during the first year of ADT, fracture risk, mainly in hips and spine increases about 50%. In men, 40% of hip fractures result in death. Exercise may reduce the risk of osteoporosis and thus contribute to the prevention of hip and other fractures. There is limited data regarding whether exercise is associated with a reduced risk of …

A Survey Of Oxidative Paracatalytic Reactions Catalyzed By Enzymes That Generate Carbanionic Intermediates: Implications For Ros Production, Cancer Etiology, And Neurodegenerative Diseases, Victoria Bunik, John Schloss, John T. Pinto, Natalia Dudareva, Arthur J L Cooper

NYMC Faculty Publications

Enzymes that generate carbanionic intermediates often catalyze paracatalytic reactions with O2 and other electrophiles not considered “normal” reactants. For example, pyridoxal 5′-phosphate (PLP)—containing pig kidney dopa decarboxylase oxidizes dopamine with molecular O2 to 3,4-dihydroxyphenylacetaldehyde at about 1% of the rate at which it catalyzes nonoxidative dopa decarboxylation. The mutant Y332F enzyme, however, catalyzes stoichiometric conversion of dopa to 3,4-dihydroxyphenylacetaldehyde, suggesting that even minor structural changes may alter or initiate paracatalytic reactions catalyzed by certain enzymes. Carbanions generated by several thiamine diphosphate (ThDP)—dependent enzymes react with different electrophiles, transforming some xenobiotics and endogenous compounds into potentially biologically hazardous products. The detrimental …

Manipulation Of The Moloney Murine Leukemia Virus Envelope Protein In An Effort To Develop Directly And Indirectly Targeted Retroviral Vectors For Use In Human Gene Therapy, Geneva M. Vasser

Theses and Dissertations (ETD)

Highly effective, targeted therapies against cancer would revolutionize the way people recover from this devastating illness. Gone would be the lingering side effects of the current non-specific treatments and in their place would be faster recovery times, better quality of life both during and after treatment, and less ambiguity about whether or not treatment was effective. This concept will elude modern medicine until treatments can be tailored to the patient's individual and unique disease. This concept of a transient, targeted, and tailored vehicle aimed at cancer cells lends itself to the use of replication deficient retroviral gene therapy vectors with …

Novel Binding Domains Mediate Binding Of Hpv 16 E6 To Fadd And Procaspase 8, Sandy S. Tungteakkhun

Loma Linda University Electronic Theses, Dissertations & Projects

To evade the host response to infection, viruses have developed means to survive and propagate. HPV 16, a causative agent of cervical cancer and of some cases of oropharyngeal cancers, is one example. We have reported that the early viral protein E6 binds to proteins necessary for propagation of the apoptotic signal following receptor/ligand interactions, such as those mediated by FADD DED and procaspase 8 DED. E6 expression leads to the dose-dependent accelerated degradation of FADD and the protection of E6-expressing cells from Fas-induced apoptosis. Surprisingly, the splice isoforms of E6, E6_large and E6*, affect the stability of procaspase …

The Role Of Multi-Drug Resistance Associated Protein 4 And P-Glycoprotein In Resistance Of Neuroblastoma To Topotecan And Irinotecan, Patricia Kellie Turner

Theses and Dissertations (ETD)

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 …

The Potential Role Of Ledgf/P75 In Prostate Cancer, Tracy Ruth Daniels

Loma Linda University Electronic Theses, Dissertations & Projects

The serum autoantibody repertoire from cancer patients is currently being exploited for the identification of tumor associated antigens (TAA) and the design of TAA arrays. Such arrays would facilitate autoantibody profiling and potentially aid in the serological diagnosis and prognosis of tumors. The goal of this study was to identify and characterize prostate-specific TAA. We observed that while the general frequency and titers of autoantibodies in PCa patients were relatively similar to those in matched controls, significant differences could be detected between the two groups in the autoantibody response to the lens epithelial-derived growth factor p75 (LEDGF/p75). LEDGF/p75 is a …

The Relationship Between Tamoxifen And Depressive Symptoms In Women With Breast Cancer, Terry Marie Lynn

Loma Linda University Electronic Theses, Dissertations & Projects

The purpose of this study was to determine whether women with breast cancer and the presence of the drug tamoxifen, are more severely depressed than women with breast cancer and the absence of tamoxifen. Average Beck Depression Inventory (BDI) scores did not differ between the two sub-groups; however, two significant group differences were found. First, 10 women in the tamoxifen group had scores of zero (versus 4 in the absence of prescribed tamoxifen group). Research has shown that scores of zero do not always reflect an absence of depression. Second, the most severely depressed women (BDI scores in the 25 …

Relationship Between Dietary Intake And Reproductive Hormones In Premenopausal Vegetarian And Nonvegetarian Seventh-Day Adventist Women, Joan M. Spuehler

Loma Linda University Electronic Theses, Dissertations & Projects

There is evidence that specific nutrients may modify hormonal balance and contribute to breast cancer etiology. To investigate the relationship between dietary nutrients and plasma reproductive hormones and to determine hormone-nutrient interrelationships, we measured plasma estrogens, androgens. progesterone and prolactin levels in 10 premenopausal Seventh-day Adventist (SDA) vegetarian and 10 premenopausal SDA nonvegetarian women. Over three days in each of three consecutive months. diet records and fasting midluteal blood samples were collected. The nonvegetarians consumed significantly more protein, total and saturated fats, oleic and linoleic acids, and cholesterol than did the vegetarians. Hormonal status of the two groups did not …