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 cascade of dFdC and ara-C. DCK activity varies significantly among individuals and across different tumor types and is a critical determinant of tumor responses to these prodrugs. Current assays to measure DCK expression and activity require biopsy samples and are prone to sampling errors. Noninvasive methods that can detect DCK activity in tumor lesions throughout the body could circumvent these limitations. Here, we demonstrate an approach to detecting DCK activity in vivo by using positron emission tomography (PET) and 18

Requirement for deoxycytidine kinase in T and B lymphocyte development

“…We employed two biochemical assays to validate our gene targeting strategy. These assays used radiolabeled 1-(2′-deoxy-2′-fluoroarabinofuranosyl) cytosine (FAC), a high-affinity substrate for dCK that closely resembles the endogenous dCK substrate deoxycytidine (17,18). We first performed an in vitro dCK kinase assay on bone marrow and spleen cell lysates.…”

A novel radiochemical approach to 1‐(2'‐deoxy‐2'‐[18F]fluoro‐β‐d‐arabinofuranosyl)cytosine (18F‐FAC)

“…Table 1. Calculated electron density Ω of selected cytidine (4)(5)(6)(7)(8) and uridine derivatives (9-11).…”

“…[3] Especially in highgrade tumours it appears to be more powerful in predicting treatment response and survival than 18 F-FDG, as measured by standard uptake values of 18 F-FLT directly corresponding to cell proliferation shown by the Ki-67 proliferation index. [4] Cytidine-based radiotracers for PET imaging such as 18 F-FAC (1, Figure 1) and 1-(2´-deoxy-2´-[ 18 F]fluoroarabinofuranosyl)-5-methylcytosine ( 18 F-FMAC, 2, Figure 1) have been previously shown to be successful as predictors of response for nucleoside analogue based treatment of cancer [5,6] as well as local immune activation in mouse models. [7] As such, 18 F-FAC has been used for response prediction to the widely used chemotherapy drug gemcitabine.…”

“…[7] As such, 18 F-FAC has been used for response prediction to the widely used chemotherapy drug gemcitabine. [5] Gemcitabine is frequently used for (combination) chemotherapy of a number of solid tumors such as pancreatic, non-small lung, breast and bladder cancer. Importantly, gemcitabine efficacy is compromised by poor cellular uptake by nucleoside transporters, variable activity of the essential deoxycytidine kinase (dCK) activating enzyme, and rapid deactivating metabolism by cytidine deaminase (CDA).…”

“…Calculated electron density Ω of selected cytidine (4)(5)(6)(7)(8) and uridine derivatives (9)(10)(11) [a] Quantum chemically calculated net charge at the 2-carbonyl oxygen. …”