期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 15, 页码 4027-4032出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1524212113
关键词
nucleotide metabolism; deoxycytidine kinase; PET imaging; cancer
资金
- UCLA Scholars in Oncologic Molecular Imaging program (National Cancer Institute Award) [R25 CA098010]
- In Vivo Cellular and Molecular Imaging Center National Cancer Institute [P50 CA086306]
- National Cancer Institute [R01 CA187678]
- US Department of Energy, Office of Science [DE-SC0012353]
- Jonsson Comprehensive Cancer Center Foundation/UCLA Impact Grant
Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[F-18]Clofarabine; 2-chloro-2'-deoxy-2'-[F-18]fluoro-9-beta-D-arabinofuranosyl-adenine ([F-18]CFA) and 2'-deoxy-2'-[F-18]fluoro-9-beta-D-arabinofuranosylguanine ([F-18]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme. We demonstrate that, in the tracer concentration range used for PET imaging, [F-18]CFA is primarily a substrate for dCK, with minimal cross-reactivity. In contrast, [F-18]F-AraG is a better substrate for dGK than for dCK. [F-18]CFA accumulation in leukemia cells correlated with dCK expression and was abrogated by treatment with a dCK inhibitor. Although [F-18]CFA uptake was reduced by deoxycytidine (dC) competition, this inhibition required high dC concentrations present in murine, but not human, plasma. Expression of cytidine deaminase, a dC-catabolizing enzyme, in leukemia cells both in cell culture and in mice reduced the competition between dC and [F-18]CFA, leading to increased dCK-dependent probe accumulation. First-in-human, to our knowledge, [F-18]CFA PET/CT studies showed probe accumulation in tissues with high dCK expression: e.g., hematopoietic bone marrow and secondary lymphoid organs. The selectivity of [F-18]CFA for dCK and its favorable biodistribution in humans justify further studies to validate [F-18]CFA PET as a new cancer biomarker for treatment stratification and monitoring.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据