Laing Rachel E, Walter Martin A, Campbell Dean O, Herschman Harvey R, Satyamurthy Nagichettiar, Phelps Michael E, Czernin Johannes, Witte Owen N, Radu Caius G
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2847-52. doi: 10.1073/pnas.0812890106. Epub 2009 Feb 5.
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)F-labeled 1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine] ([(18)F]FAC), a PET probe recently developed by our group. We show that [(18)F]FAC is a DCK substrate with an affinity similar to that of dFdC. In vitro, accumulation of [(18)F]FAC in murine and human leukemia cell lines is critically dependent on DCK activity and correlates with dFdC sensitivity. In mice, [(18)F]FAC accumulates selectively in DCK-positive vs. DCK-negative tumors, and [(18)F]FAC microPET scans can predict responses to dFdC. We suggest that [(18)F]FAC PET might be useful for guiding treatment decisions in certain cancers by enabling individualized chemotherapy.
吉西他滨（2'，2'-二氟脱氧胞苷，dFdC）和阿糖胞苷（阿糖胞嘧啶，ara-C）是一类用于癌症化疗的核苷类似物。作为前药给药后，dFdC和ara-C穿过细胞膜，并通过内源性核苷激酶催化的连续磷酸化步骤转化为细胞毒性衍生物。脱氧胞苷激酶（DCK）控制着dFdC和ara-C激活级联反应中的限速步骤。DCK活性在个体之间以及不同肿瘤类型之间存在显著差异，并且是肿瘤对这些前药反应的关键决定因素。目前测量DCK表达和活性的检测方法需要活检样本，并且容易出现采样误差。能够检测全身肿瘤病变中DCK活性的非侵入性方法可以规避这些限制。在这里，我们展示了一种通过使用正电子发射断层扫描（PET）和（18）F标记的1-（2'-脱氧-2'-氟阿拉伯呋喃糖基）胞嘧啶[（18）F]FAC来体内检测DCK活性的方法，[（18）F]FAC是我们团队最近开发的一种PET探针。我们表明[（18）F]FAC是一种DCK底物，其亲和力与dFdC相似。在体外，[（18）F]FAC在小鼠和人类白血病细胞系中的积累严重依赖于DCK活性，并且与dFdC敏感性相关。在小鼠中，[（18）F]FAC选择性地在DCK阳性肿瘤与DCK阴性肿瘤中积累，并且[（18）F]FAC微型PET扫描可以预测对dFdC的反应。我们认为[（18）F]FAC PET可能通过实现个体化化疗来指导某些癌症的治疗决策。
