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Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040

Aimiuwu, Josephine Eki
http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Pharmacy.
Cancer, like most human diseases is complex and the therapeutic approaches available to treat this disease have limited efficacy. Therefore, combination studies of two or more anticancer drugs is expected to be essential in achieving a better therapeutic response in patients and may also provide a cure for drug-resistant cancers. Leukemia is a cancer of the blood, which results from an uncontrolled proliferation of white blood cells, thereby inhibiting its functions. Important insights into the pathogenesis of this disease have led to the development of a number of anti-leukemia drugs, including nucleoside analogs and new antisense compounds, that intervene at the level of disease progression. 5-Azacytidine and decitabine are hypomethylating agents recently approved by the U.S Food and Drug Administration for the treatment of Myelodysplastic Syndrome (MDS) and are also in clinical trials for the treatment of hematological malignancies, such as acute myeloid leukemia (AML). These drugs are approved based on their ability to induce DNA demethylation, resulting in reactivation of hypermethylation-associated silencing of tumor suppressor genes. Aracytidine (Ara-C) is another nucleoside drug, widely used as antimetabolite for the treatment of acute myelogenous leukemia. Antisense GTI-2040 is a 20-mer oligonucleotide inhibiting the expression of ribonucleotide reductase subunit M2 (RRM2) mRNA, an enzyme that has been found to be over-expressed in most cancers. In this dissertation, investigations on pharmacodynamic studies of nucleoside analogs in combination with GTI-2040 were carried out. It has been demonstrated that inhibition of cellular RR, which subsequently decreases deoxyribonucleotide triphosphate (dNTP) pools, could enhance the anti-tumor activity of subsequently administered nucleoside analogs. We have in our studies, provided both in vitro and in vivo evidences to support the novel combination treatment of antisense GTI-2040 and 5-azaC, leading to a synergistic effect. In addition, GTI-2040 decreases RRM2 levels, and most notably, we discovered that 5-azaC modulates RRM2 for the first time and this result makes RR a novel target for 5-azaC. In addition, the biomarkers involved in the development of 5-azaC and decitabine (DAC) resistances were assessed in order to elucidate the potential mechanisms that contribute to the induction of resistance in cancer cells. In a phase II evaluation of GTI-2040 in combination with Ara-C in patients with AML at The James Cancer Hospital and Research Institute at The Ohio State University, clinical pharmacokinetic of GTI-2040 and the in vitro-in vivo pharmacodynamic analysis with Ara-C was established to assist in the exploration of their pharmacokinetic-pharmacodynamic (PK-PD) correlations in relation to clinical response. Finally, our studies of GTI-2040, 5-AzaC, DAC and Ara-C provide valuable insights into their clinical development as a single agent or in combination with other drugs.
Kenneth Chan, PhD (Advisor)
Guido Marcucci, MD (Committee Member)
Robert Lee, PhD (Committee Member)
Robert Snapka, PhD (Committee Member)
277 p.
Pharmaceuticals
preclinical; clinical pharmacokinetics/pharmacodynamics; and drug development

Recommended Citations

Citations

  • Aimiuwu, J. E. (2011). Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882

    APA Style (7th edition)

  • Aimiuwu, Josephine. Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882.

    MLA Style (8th edition)

  • Aimiuwu, Josephine. "Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.