The broad, long-term goal of the proposed research career is to develop in silico models of deoxynucleotide metabolism that will facilitate drug and radiation dose time course optimizations in the treatment of mismatch repair defective (MMR-) malignancies. The five-year goal of this research plan is to build a model of ionizing radiation (IR) damage driven iododeoxyuridine (IdUrd) incorporation into the DNA of quiescent cells as a model of the quiescent state of tumor stem cells; IdUrd radiosensitization is proportional to IdUrd-DNA and MMR- cells retain IdUrd-DNA longer than MMR+ cells. Using isogenic RKO cell lines that differ only in MMR competence, a mathematical model of deoxynucleotide metabolism will be developed to predict which time courses of IdUrd, leucovorin, ralitrexed, and 5'-amino-5-deoxythymidine maximize differences in IdUrd-DNA between MMR- cells and MMR+ cells over some post IR time interval; predicting when this time interval occurs could then be used to time a second dose of IR to exploit the IdUrd-DNA differences. The hypothesis is that such a model of deoxynucleotide metabolism can indeed be built and experimentally validated. ? ? The Specific Aims of this research are: (1) to develop a literature-based mathematical model of the folate-purine-pyrimidine system and use it to form a baseline prediction of IdUrd incorporation into DNA; (2) to further develop this model incrementally through a continuous cycle of wet-lab experimental validations of theoretical predictions followed by dry-lab model modifications and new predictions, beginning with single agents and proceeding to more complicated multi-drug scenarios with increasing cycles; and (3) to develop an interface and rigid programming format that will allow automatic conversions of source implementations of deoxynucleotide metabolism in R (an open source, object-oriented statistical programming environment that carries the advantage of Bioconductor tools) to Systems Biology Markup Language. Achievement of Aim 3 will broaden public use of the current model. Achievement of all three Specific Aims will provide building blocks for subsequent translational cancer research studies. These studies will include Dr. Timothy J. Kinsella's chemoradiation studies of an IdUrd prodrug, IPdR, against MMR defective malignancies, and likely the studies of others, since the folate-purine-pyrimidine system holds a very central position in anti-cancer drug development. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Quantitative Research Career Development Award (K25)
Project #
5K25CA104791-04
Application #
7341113
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2005-02-02
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$144,585
Indirect Cost
Name
Case Western Reserve University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Radivoyevitch, Tomas; Saunthararajah, Yogen; Pink, John et al. (2012) dNTP Supply Gene Expression Patterns after P53 Loss. Cancers (Basel) 4:1212-24
Radivoyevitch, Tomas; Kunos, Charles A (2012) On model ensemble analyses of nonmonotonic data. Nucleosides Nucleotides Nucleic Acids 31:147-56
Radivoyevitch, T; Munch-Petersen, B; Wang, L et al. (2011) A mathematical model of human thymidine kinase 2 activity. Nucleosides Nucleotides Nucleic Acids 30:203-9
Radivoyevitch, T (2010) How to use the computing environment R to analyze ATP-induced ribonucleotide reductase R1 hexamerization data. Nucleosides Nucleotides Nucleic Acids 29:427-32
Feng, I Jung; Radivoyevitch, Tomas (2009) SNP-SNP interactions between dNTP supply enzymes and mismatch DNA repair in breast cancer. Proc Ohio Collab Conf Bioinform 2009:123-128
Radivoyevitch, Tomas (2009) Automated mass action model space generation and analysis methods for two-reactant combinatorially complex equilibriums: an analysis of ATP-induced ribonucleotide reductase R1 hexamerization data. Biol Direct 4:50
Radivoyevitch, Tomas (2009) Mass action models versus the Hill model: an analysis of tetrameric human thymidine kinase 1 positive cooperativity. Biol Direct 4:49
Azizi, F; Wan, Q; Radivoyevitch, T et al. (2008) A COMBINATORIAL MULTICOMPONENT PLUG MIXER FOR SYSTEMS CHEMISTRY. Micro Total Anal Syst 2008:1904-1906
Radivoyevitch, Tomas (2008) Equilibrium model selection: dTTP induced R1 dimerization. BMC Syst Biol 2:15
Radivoyevitch, Tomas; Loparo, Kenneth A; Jackson, Robert C et al. (2006) On systems and control approaches to therapeutic gain. BMC Cancer 6:104

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