The central goal of this proposal is to develop hypotheses for optimized administration of drug combinations for the therapy of acute myelogenous leukemia (AML) based on in vitro pharmacological, biochemical, and molecular studies. Subsequently, protocols will be designed to evaluate the pharmacokinetic and pharmacodynamic predictions of these hypotheses and for clinical response. Because ara-C is important for the therapy of AML, attempts will be directed toward enhancing its efficacy by biochemical modulation strategies, dosing and scheduling, and by combination of other effective antileukemic drugs. Pilot studies conducted under R03 CA53311 have demonstrated that fludarabine infusion increased the rate of ara-CTP accumulation nearly 2-fold in leukemia blasts over that after ara-C alone in the same patient. Clinically, the combination of these two agents resulted in better response rates than our previous treatments. In the present proposal we plan to extend that work by investigating the mechanism of potentiation of ara-CTP metabolism by fludarabine and by studying the molecular action of these two analogue triphosphates to understand the synergistic cytotoxicity. We have amended the protocol based on the pharmacology studies and will investigate the cellular pharmacokinetics and pharmacodynamics to seek correlations with clinical response. Additionally, we will implement a new protocol: combination of ara-C and fludarabine with a DNA damaging agent, mitoxantrone. Pharmacokinetics of ara-CTP accumulation in leukemic blasts will be analyzed to evaluate the modulatory action of fludarabine and mitoxantrone. Studies will be performed to analyze the DNA damage introduced in vivo into unlabeled leukemia cells from patients receiving mitoxantrone therapy. Biochemical studies of the interaction of these agents for ara-CTP metabolism and for DNA damage in vitro in leukemic blasts isolated from the same patient will be conducted to complement and extend in vivo investigations. Correlations will be sought between these studies to determine the prognostic significance of modulation of ara-CTP metabolism. Knowledge gained from these investigations will be used to optimize scheduling of drugs for the existing protocol and to design and evaluate new treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA057629-01
Application #
3201977
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1992-09-15
Project End
1995-08-31
Budget Start
1992-09-15
Budget End
1993-08-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Lamba, Jatinder K; Crews, Kristine R; Pounds, Stanley B et al. (2011) Identification of predictive markers of cytarabine response in AML by integrative analysis of gene-expression profiles with multiple phenotypes. Pharmacogenomics 12:327-39
Zhang, Honghao; Gogada, Raghu; Yadav, Neelu et al. (2011) Defective molecular timer in the absence of nucleotides leads to inefficient caspase activation. PLoS One 6:e16379
Balakrishnan, Kumudha; Burger, Jan A; Wierda, William G et al. (2009) AT-101 induces apoptosis in CLL B cells and overcomes stromal cell-mediated Mcl-1 induction and drug resistance. Blood 113:149-53
Guo, Yanping; Köck, Kathleen; Ritter, Christoph A et al. (2009) Expression of ABCC-type nucleotide exporters in blasts of adult acute myeloid leukemia: relation to long-term survival. Clin Cancer Res 15:1762-9
Chen, Lisa S; Nowak, Billie J; Ayres, Mary L et al. (2009) Inhibition of ATP synthase by chlorinated adenosine analogue. Biochem Pharmacol 78:583-91
Cervantes-Gomez, Fabiola; Nimmanapalli, Ramadevi; Gandhi, Varsha (2009) Transcription inhibition of heat shock proteins: a strategy for combination of 17-allylamino-17-demethoxygeldanamycin and actinomycin d. Cancer Res 69:3947-54
Chen, Lisa S; Redkar, Sanjeev; Bearss, David et al. (2009) Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood 114:4150-7
Gandhi, Varsha; Tam, Constantine; O'Brien, Susan et al. (2008) Phase I trial of nelarabine in indolent leukemias. J Clin Oncol 26:1098-105
Faderl, Stefan; Gandhi, Varsha; Kantarjian, Hagop M (2008) Potential role of novel nucleoside analogs in the treatment of acute myeloid leukemia. Curr Opin Hematol 15:101-7
Chen, Lisa S; Plunkett, William; Gandhi, Varsha (2008) Polyadenylation inhibition by the triphosphates of deoxyadenosine analogues. Leuk Res 32:1573-81

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