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

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

Bibliographic Details
Main Author: Aimiuwu, Josephine Eki
Language:English
Published: The Ohio State University / OhioLINK 2011
Subjects:
Pharmaceuticals
preclinical
clinical pharmacokinetics/pharmacodynamics
and drug development
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu12928518822021-08-03T06:01:15Z Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040 Aimiuwu, Josephine Eki Pharmaceuticals preclinical clinical pharmacokinetics/pharmacodynamics and drug development 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. 2011-01-10 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882 http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Pharmaceuticals
preclinical
clinical pharmacokinetics/pharmacodynamics
and drug development
spellingShingle Pharmaceuticals
preclinical
clinical pharmacokinetics/pharmacodynamics
and drug development
Aimiuwu, Josephine Eki
Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040
author Aimiuwu, Josephine Eki
author_facet Aimiuwu, Josephine Eki
author_sort Aimiuwu, Josephine Eki
title Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040
title_short Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040
title_full Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040
title_fullStr Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040
title_full_unstemmed Modulation of Pharmacologic Effects of 5-Azacytidine by Ribonucleotide Reductase Antisense GTI-2040
title_sort modulation of pharmacologic effects of 5-azacytidine by ribonucleotide reductase antisense gti-2040
publisher The Ohio State University / OhioLINK
publishDate 2011
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1292851882
work_keys_str_mv AT aimiuwujosephineeki modulationofpharmacologiceffectsof5azacytidinebyribonucleotidereductaseantisensegti2040
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