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Pharmacokinetic-Pharmacodynamic Studies Of 5-Azacytidine In Combination With Gti-2040

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2008, Doctor of Philosophy, Ohio State University, Pharmacy.
Leukemia is the most common blood cancer and is characterized by the increased expansion of abnormal blood cells. Important insights into the pathogenesis of this disease have led to the development of a number of anti-leukemia drugs including nucleoside analogues, such as 5-azacytidine (5-AzaC), decitabine and aracytidine, and ribonucleotide reductase inhibitor such as GTI-2040. 5-Azacytidine and decitabine are hypomethylating agents that induce DNA demethylation, resulting in reactivation of hypermethylation-associated silencing of tumor suppressor genes. GTI-2040 is a 20-mer oligonucleotide inhibiting the expression of ribonucleotide reductase subunit 2 mRNA, an enzyme that has been found to be over-expressed in most cancers. Aracytidine is widely used as important cytostatic drug in the treatment for acute myelogenous leukemia. In order to support the mechanistic studies and potential combination treatment of these anti-cancer drugs, a non-radioactive, sensitive and specific LC-MS/MS method has been developed to quantify intracellular NTP and dNTP pools in cell matrices. A significant decrease in dCTP and dATP levels has been observed following GTI-2040 treatment in human leukemia MV411 cells. More importantly, GTI-2040 was found to down-regulate R2 mRNA and protein levels in a dose dependent manner. In order to evaluate the combination treatment effect of GTI-2040 and aracytidine, a sensitive HPLC method has been developed to determine the intracellular aracytidine triphosphate (Ara-CTP) level. A significant increase in intracellular Ara-CTP level has been observed after pretreatment of GTI-2040 in vitro. Further pharmacokinetics / pharmacodynamics (PK/PD) modeling and simulation of GTI-2040 and aracytidine in the cell exhibited the increase of intracellular Ara-CTP level by >2 fold. In order to characterize pharmacokinetic profile of 5-azacytidine in patients with hematologic malignancies, a simple, non-radioactive, sensitive and specific high-performance HPLC-MS/MS method has also been developed to quantify 5-AzaC in human plasma. A further transporter study revealed that the transport of 5-AzaC into cell may involve the human equilibrative nucleoside transporter 1 (hENT1). The pharmacokinetics of decitabine was well characterized by a two-compartment model. Body surface area was identified as a covariate with total systemic clearance in population pharmacokinetic studies of decitabine in leukemia patients. These results provide valuable insights in clinical development of GTI-2040, 5-AzaC, aracytidine and decitabine as a single agent or in combination with other drugs.
Kenneth Chan, PhD (Advisor)
Guido Marcucci, PhD (Committee Member)
Duxin Sun, PhD (Committee Member)
Robert Snapka, PhD (Committee Member)
278 p.

Recommended Citations

Citations

  • Chen, P. (2008). Pharmacokinetic-Pharmacodynamic Studies Of 5-Azacytidine In Combination With Gti-2040 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1221854928

    APA Style (7th edition)

  • Chen, Ping. Pharmacokinetic-Pharmacodynamic Studies Of 5-Azacytidine In Combination With Gti-2040. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1221854928.

    MLA Style (8th edition)

  • Chen, Ping. "Pharmacokinetic-Pharmacodynamic Studies Of 5-Azacytidine In Combination With Gti-2040." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1221854928

    Chicago Manual of Style (17th edition)