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All Subjects: Chemotherapy
Creators: Baker, Laurie
Creators: Clark, Caroline Marie

DIRECTED ENZYME PRODRUG THERAPY: THE SYNTHESIS OF A Β-GLUCURONIDE LINKER AND ITS COUPLING WITH Z-IODOCOMBSTATIN

Description

The purpose of this project is to explore the benefit of using prodrugs in chemotherapy, as well as to explain the concept of angiogenesis and the importance of this process to tumor development. Angiogenesis is the formation of new blood capillaries that are necessary for the survival of a tumor, as a tumor cannot grow larger than 1-2 mm3 without developing its own blood supply. Vascular disrupting agents, such as iodocombstatin, a derivative of combretastatin, can be used to effectively cut off the blood supply to a growing neoplasm, effectively inhibiting the supply of oxygen and nutrients needed for cell division Thus, VDAs have a very important implication in terms of the future of chemotherapy. A prodrug, defined as an agent that is inactive in the body until metabolized to yield the drug itself, was synthesized by combining iodocombstatin with a β-glucuronide linker. The prodrug is theoretically hydrolyzed in the body to afford the active drug by β-glucuronidase, an enzyme that is produced five times as much by cancer cells as by normal cells. This effectively creates a “magic-bullet” form of chemotherapy, known as Direct Enzyme Prodrug Therapy (DEPT).

ContributorsClark, Caroline Marie (Author) / Pettit, George Robert (Thesis director) / Melody, Noeleen (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)

Created2015-05

Characterizing the Mechanism of Action of a Potential Targeted Therapy, Triptolide, in Small Cell Carcinoma of the Ovary

Description

Small cell carcinoma of the ovary (SCCOHT) is a rare ovarian cancer affecting young women and characterized by mutation in SMARCA4 and silencing of SMARCA2, two tumor suppressors that function as ATPases in the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. SCCOHT patients face a 5-year survival rate of only 26%, but recently we have identified sensitivity of SCCOHT models to a natural product, triptolide. This study aims to ascertain the mechanism of action of triptolide. Previous SCCOHT epigenetic drug research has shown that some drugs reverse SMARCA2 epigenetic silencing to inhibit tumor growth, therefore it is hypothesized that triptolide acts the same and restores SWI/SNF function. Cells treated with triptolide have no change in SMARCA2 expression, suggesting that re-expression of epigenetically silenced tumor suppressor gene does not underlie its mechanism of action. Growth rates following triptolide treatment were observed in the presence and absence of SMARCA4, but no difference in sensitivity was observed. Thus, it is not likely that triptolide acts by restoring SWI/SNF. Others have observed that triptolide acts on xeroderma pigmentosa type B protein (XPB), a component of super-enhancers, which are DNA regions with high levels of transcription that regulate genes responsible for cell identity and oncogenes driving tumorigenesis. Both SCCOHT-1 and BIN67 cell lines treated with triptolide displayed lower expression of the super-enhancer associated MYC oncogene compared to untreated cells, supporting the theory that triptolide could be inhibiting super-enhancers regulating oncogenes.. A western blot confirmed reduced protein levels of RNA polymerase II and bromodomain 4 (BRD4), two essential components found at high levels at super-enhancers, in BIN67 cells treated with triptolide. ChIP-sequencing of Histone H3 Lysine-27 Acetylation (H3K27ac) marks in BIN67 and SCCOHT-1 cell lines identified super-enhancers in SCCOHT using tools CREAM and ROSE, which were mapped to neighboring genes associated genes and compared with the COSMIC database to identify oncogenes, of which the top 11 were examined by qRT-PCR to ascertain whether triptolide reduces their expression. It has been found that 6 out of 11 of the oncogenes examined (SALL4, MYC, SGK1, HIST1H3B, HMGA2, and CALR) decreased in expression when treated with triptolide. Thus, there is reason to believe that triptolide’s mechanism of action is via inhibition of super-enhancers that regulate oncogene expression.

ContributorsViloria, Nicolle Angela (Author) / Lake, Douglas (Thesis director) / Hendricks, William (Committee member) / Lang, Jessica (Committee member) / School of Life Sciences (Contributor) / School of Human Evolution & Social Change (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)

Created2020-05

Controlling Chemotherapy-Induced Nausea and Vomiting Through Guideline Adherence

Description

Background:
Thirty to fifty percent of cancer patients undergoing chemotherapy will experience
chemotherapy induced nausea and or vomiting (CINV) despite the use of antiemetic prophylaxis Uncontrollable CINV can lead to complications that add extra stress to patients, increase in healthcare costs, and utilization of resources. CINV can lead to chemotherapy dose reductions, treatment delays, chemotherapy changes, or discontinuation of treatment. Guidelines exist to better prevent and treat CINV. Evidence supports the use of guidelines to prevent CINV, however patients still suffer from CINV often due to a lack of guideline adherence.

Objectives:
The purpose of this project was to increase CINV guideline adherence by increasing knowledge of antiemetic guidelines utilizing an educational intervention for providers and nurses at an outpatient oncology office.

Methods:
A brief educational intervention on CINV and recommended NCCN guidelines was
conducted with providers and nurse (n=6) at an oncology practice in Southwestern United States. An evaluation to assess change in knowledge was performed using a pre and post test format. Statistical analysis was performed using descriptive statistics, McNemar tests and Wicoxan Signed Rank Test.

Findings:
There was a significant effect on knowledge of NCCN antiemetic guidelines (Z=-1.89, p=0.059, mean 2.5) post intervention. There also was a significant impact on likelihood to use guidelines in practice (Z=-1.89, p=0.059, mean 2.5). Increasing awareness and likelihood to CHEMOTHERAPY INDUCED NAUSEA AND VOMITING 3 follow recommended guidelines may improve CINV symptoms in patients undergoing chemotherapy and improve the treatment outcomes for these patients.

ContributorsBarbosa, Jennifer (Author) / Baker, Laurie (Thesis advisor)

Created2018-04-29