Aboagye E O, Artemov D, Senter P D, Bhujwalla Z M
The Johns Hopkins University School of Medicine, Department of Radiology, Baltimore, Maryland 21205, USA.
Cancer Res. 1998 Sep 15;58(18):4075-8.
The monitoring of antibody-directed enzyme-prodrug therapies requires evaluation of drug activation within the tissues of interest. We have demonstrated the feasibility of noninvasive magnetic resonance spectroscopy and spectroscopic imaging (chemical shift imaging) to detect activation of the prodrug 5-fluorocytosine (5-FCyt) to the cytotoxic species 5-fluorouracil (5-FU) by monoclonal antibody-cytosine deaminase (CD) conjugates. In vitro, L6-CD but not 1F5-CD selectively metabolized 5-FCyt to 5-FU on H2981 human lung adenocarcinoma cells because of the presence and absence of cell surface L6 and CD20 antigens, respectively. After pretreatment of H2981 tumor-bearing mice with L6-CD, in vivo metabolism of 5-FCyt to 5-FU within the tumors was detected by 19F magnetic resonance spectroscopy; the chemical shift separation between 5-FCyt and 5-FU resonances was approximately 1.2 ppm. 5-FU levels were 50-100% of 5-FCyt levels in tumors 10-60 min after 5-FCyt administration. Whole body 19F chemical shift imaging (6 x 6 mm in-plane resolution) of tumor-bearing mice demonstrated the highest signal intensity of 5-FU within the tumor region. This study supports further development of noninvasive magnetic resonance methods for preclinical and clinical monitoring of CD enzyme-prodrug therapies.
抗体导向酶-前药疗法的监测需要评估目标组织内的药物激活情况。我们已经证明了无创磁共振波谱和波谱成像（化学位移成像）检测单克隆抗体-胞嘧啶脱氨酶（CD）偶联物将前药5-氟胞嘧啶（5-FCyt）激活为细胞毒性物质5-氟尿嘧啶（5-FU）的可行性。在体外，由于分别存在和不存在细胞表面L6和CD20抗原，L6-CD而非1F5-CD在H2981人肺腺癌细胞上选择性地将5-FCyt代谢为5-FU。在用L6-CD预处理荷H2981肿瘤小鼠后，通过19F磁共振波谱检测到肿瘤内5-FCyt向5-FU的体内代谢；5-FCyt和5-FU共振之间的化学位移分离约为1.2 ppm。在给予5-FCyt后10 - 60分钟，肿瘤内5-FU水平为5-FCyt水平的50 - 100%。荷瘤小鼠的全身19F化学位移成像（面内分辨率为6×6 mm）显示肿瘤区域内5-FU的信号强度最高。本研究支持进一步开发用于CD酶-前药疗法临床前和临床监测的无创磁共振方法。
