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Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress

Abstract: Nucleotide deficiency causes replication stress (RS) and DNA damage in dividing cells. How nucleotide metabolism is regulated in vivo to prevent these deleterious effects remains unknown. In this study, we investigate a functional link between nucleotide deficiency, RS, and the nucleoside salvage pathway (NSP) enzymes deoxycytidine kinase (dCK) and thymidine kinase (TK1). We show […]

Stratification of Nucleoside Analog Chemotherapy Using 1-(2′-Deoxy-2′-18F-Fluoro-β-D-Arabinofuranosyl)Cytosine and 1-(2′-Deoxy-2′-18F-Fluoro-β-L-Arabinofuranosyl)-5-Methylcytosine PET

Abstract: The ability to measure tumor determinants of response to nucleoside analog (NA) chemotherapy agents such as gemcitabine and related compounds could significantly affect the management of several types of cancer. Previously we showed that the accumulation in tumors of the new PET tracer 1-(2′-deoxy-2′-18F-fluoro-β-D-arabinofuranosyl)cytosine (18F-FAC) is predictive of responses to gemcitabine. 18F-FAC retention in […]

Novel Positron Emission Tomography Probes Specific for Deoxycytidine Kinase

Abstract: Deoxycytidine kinase (dCK) is a rate-limiting enzyme in the deoxyribonucleoside salvage pathway and a critical determinant of therapeutic activity for several nucleoside analog pro-drugs. We have previously reported the development of 18F-FAC, (1-(2′-deoxy-2′-18F-fluoro-β-D-arabinofuranosyl) cytosine), a new probe for PET imaging of dCK activity in immune disorders and certain cancers. The objective of the current […]

Requirement for deoxycytidine kinase in T and B lymphocyte development

Abstract: Deoxycytidine kinase (dCK) is a rate-limiting enzyme in deoxyribonucleoside salvage, a metabolic pathway that recycles products of DNA degradation. dCK phosphorylates and therefore activates nucleoside analog prodrugs frequently used in cancer, autoimmunity, and viral infections. In contrast to its well established therapeutic relevance, the biological function of dCK remains enigmatic. Highest levels of dCK […]

Molecular imaging of lymphoid organs and immune activation using positron emission tomography with a new 18F-labeled 2′-deoxycytidine analog

Abstract: Monitoring immune function using molecular imaging could significantly impact the diagnosis and treatment evaluation of immunological disorders and therapeutic immune responses. Positron Emission Tomography (PET) is a molecular imaging modality with applications in cancer and other diseases. PET studies of immune function have been limited by a lack of specialized probes. We identified [18F]FAC […]

Noninvasive prediction of tumor responses to gemcitabine using positron emission tomography

Abstract: Gemcitabine (2′,2′-difluorodeoxycytidine, dFdC) and cytosine arabinoside (cytarabine, ara-C) represent a class of nucleoside analogs used in cancer chemotherapy. Administered as prodrugs, dFdC and ara-C are transported across cell membranes and are converted to cytotoxic derivatives through consecutive phosphorylation steps catalyzed by endogenous nucleoside kinases. Deoxycytidine kinase (DCK) controls the rate-limiting step in the activation […]