The impact of cytidine metabolic pathways on cytarabine therapy of hematological malignancies and new diagnostic tools for their analysis

Cytidine deaminase (CDA) and deoxycytidine monophosphate deaminase (DCTD), deoxycytidine kinase (dCK), 5'-nucleotidase and human equilibrative nucleoside transporter (hENT1) participate in the regulation of cellular nucleotide and nucleoside pools and also in the metabolism of therapeutically significant nucleoside and nucleotide analogs including cytarabine that is commonly used for the treatment of diverse hematological malignancies. As the impact of these metabolic pathways on the results of treatment with cytarabine is not well described, the studies focused on the detailed description of their roles are necessary. Results of the project presented will contribute to the understanding of differences in the response of particular patients to cytarabine and other drugs based on cytidine analogs. Results of the presented project will also allow identification of new biomarkers and provide new diagnostic tools enabling to take the individuality of patient into account. The project presented is focused on i) the analysis of the variability of genes encoding CDA, DCTD, dCK, 5'-nucleotidase, hENT1 with respect to the course and the effectiveness of cytarabine-based treatment; ii)the analysis of the effect of the levels of cytidine deaminase activity in the cancer cells and blood plasma with respect to the course and the effectiveness of the treatment by cytarabine , and iii) the development of a new technology for the fast non-isotopic detection and quantification of DCTD activity in the cells and CDA activity in the cells and in solutions including the blood plasma.