Date of Award

5-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Duane D. Miller, Ph.D.

Committee

Terreia S. Jones, Pharm.D. Ram I. Mahato, Ph.D. Peter J. McKinnon, Ph.D. Lawrence M. Pfeffer, Ph.D. Zhaohui Wu, M.D., Ph.D.

Keywords

Astrocytes, Brain, Dexamethasone, Glioma, Therapy, Thiopurines

Abstract

Glioma is a brain tumor that arises from glial cells or glial progenitor cells, and represents 80% of malignant brain tumor incidence in the United States. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor malignancy with fewer than 8% of patients with GBM surviving for 3 years. Over the past 10 years, despite improvement in diagnosis and therapies for cancer, the survival rate for high-grade glioma patients remains unchanged. The main focus of this dissertation is to investigate two therapeutic agents that are related to increase tumor resistance or increase secondary tumor incidence, which might play a role in poor prognosis and outcome for glioma. There are several studies, which show that corticosteroid treatment increases tumor resistance to chemo- and radiotherapy. Corticosteroids are mainstay drugs for managing peritumoral edema. Therefore, we investigated the effect of corticosteroids in a PDGF driven glioma mouse model. We found that corticosteroid treatment decreases tumor cell proliferation without inducing cell death as shown by a significant decrease in PCNA and Ki67 but not in cleaved caspase-3 staining. Decreased tumor cell growth could compromise the responsiveness of tumor cells to chemotherapy and/or radio-therapy, because cancer therapeutics often target rapidly growing cells. In addition, we found that corticosteroids decrease tumorassociated microglial cells proliferation. Furthermore, in vitro and in vivo studies revealed a shift in microglial cells to less pro-tumor phenotype as evidenced by decreasing MMP9 and IL-1ra expression. However, we did not find an association between the decrease in tumor proliferation and the shift in microglia phenotype. In addition, the use of thiopurine drugs in leukemia treatment was associated with the development of secondary cancers including glioma. Therefore, we investigated the cytotoxic effects of thiopurine drugs in primary astroglial cultures. Thiopurine drugs are commonly used to treat cancer, autoimmune disorders, and transplantation. However, thiopurines and their metabolites can be inactivated by the thiopurine methyltransferase (TPMT) enzyme. We found that a low TPMT phenotype predicted significantly higher sensitivity to the cytotoxic action of thiopurines than did a high TPMT phenotype. Thiopurines induced significantly more cell death and DNA damage in primary astrocytes and human glioma cells with low TPMT versus high TPMT. It is possible that the DNA damage caused by low TPMT function can ultimately contribute to transformative events over time. Finally, we assessed the anticancer activity of 2 classes of novel small molecules; tetrahydroisoquinoline (THIQ) and chromenes. These molecules were screened in vitro to find the most potent anticancer derivatives that exhibited the least toxicity on normal stromal cells. EDL-360 (5-10 µM) and SP-6-27 (IC50 = 7-21 nM) were the most potent analogs of THIQ and chromene in glioma cells, respectively, and low cytotoxic action was observed in normal astrocytes. Furthermore, theses compounds induced a partial regression in glioma tumor engraftment.

DOI

10.21007/etd.cghs.2014.0007

Comments

One year embargo expired May 2015.

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