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- All Subjects: Chemotherapy
- Creators: Blomquist, Mylan
- Creators: Clark, Caroline Marie
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
Description
Background: Esophageal adenocarcinoma (EAC) is one of the only malignancies whose incidence is rising in the United States. Current multidrug treatment for EAC has considerable toxic side effects that necessitate the development of less toxic, more specific target drugs. Recent large scale genomic analysis reveals that TP53 is the most frequently inactivated gene in EAC. One of the primary functions of TP53 and its gene product, the tumor suppressor p53, is in regulation of DNA repair in response to DNA damage. Inactivation of TP53 results in loss of the G1/S cell cycle checkpoint, and dependence on the G2/M checkpoint for DNA repair. Activity of cyclin-dependent kinase 1 (CDK1) is necessary for cells to exit the G2/M checkpoint and enter mitosis. Phosphorylation of CDK1 by the wee1 kinase inhibits CDK1 in response to DNA damage, allowing cells to maintain G2 arrest and repair the damaged DNA. Active in normal cells, wee1 kinase is critical in cancer cells to promote DNA repair and cell survival in response to DNA damage, particularly from commonly used DNA damaging therapies. AZD1775 is a small molecule inhibitor of wee1 kinase, currently under investigation in clinical trials. AZD1775 differentially targets cancer cells by blocking wee1 mediated inhibition of CDK1 and consequently preventing G2/M arrest in response to DNA damage. Combination of AZD1775 with DNA damaging agents is thought to push cancer cells with damaged DNA through to mitosis and initiate apoptosis instead of G2/M arrest and DNA repair. Based upon the incidence of TP53 mutation in EAC, we hypothesize that treatment with a DNA damaging agent in combination with AZD1775 will be as effective at eliciting DNA damage and cell death as the more toxic current standard of care, which is comprised of treatment with cisplatin, docetaxel, and radiation. Methods: p53 mutant EAC cell lines were dosed with cisplatin, AZD1775, and the combination of cisplatin and AZD1775, and then assayed for viability. Nude mice were implanted with p53 mutant patient derived xenograft esophageal adenocarcinoma tumors and randomized for treatment with AZD1775 alone, cisplatin and AZD1775, radiation and AZD1775, cisplatin, docetaxel, and radiation or vehicle (control). Tumor volume was measured over the five week treatment course. Results: In vitro and in vivo assays reveal a potent synergistic effect between AZD1775 and DNA damaging agents that is as efficacious as the standard of care therapy. The difference in AZD1775 sensitivity among TP53 mutant EAC cell lines indicates that TP53 alone may not be an adequate biomarker to assess for AZD1775- mediated toxicity.
ContributorsBlomquist, Mylan (Author) / Maley, Carlo (Thesis director) / Inge, Landon (Committee member) / Oberle, Eric (Committee member) / College of Letters and Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05