60Cu-ATSM in Cancer of the Uterine Cervix

Tumor uptake of copper(II)-diacetyl-bis(N4-methylthiosemicarbazone) (copper-ATSM), a hypoxia-targeting radiopharmaceutical, assessed by PET has been found to correlate with prognosis in several human cancers. Wide clinical utility of this tracer will require its labeling with a copper radionuclide having a longer half-life than the 60Cu used in studies to date. The purpose of this work was to obtain the requisite preclinical data for copperATSM to file an investigational new drug application, followed by a crossover comparison of PET image quality and tumor uptake with 60Cu-ATSM and 64Cu-ATSM in women with cancer of the uterine cervix. Methods: The preclinical toxicology and pharmacology of a copper-ATSM formulation was examined using standard in vitro and in vivo assays, as well as 14-d toxicity studies in both rats and rabbits. For the clinical test–retest imaging study, 10 patients with cervical carcinoma underwent PET on separate days with 60Cu-ATSM and 64Cu-ATSM. Image quality was assessed qualitatively, and the tumor-to-muscle activity ratio was measured for each tracer. Results: The toxicology and pharmacology data demonstrated that the formulation has an appropriate margin of safety for clinical use. In the patient study, we found that the image quality with 64Cu-ATSM was better than that with 60Cu-ATSM because of lower noise. In addition, we found that the pattern and magnitude of tumor uptake of 60CuATSM and 64Cu-ATSM on studies separated by 1–9 d were similar. Conclusion: 64Cu-ATSM appears to be a safe radiopharmaceutical that can be used to obtain high-quality images of tumor hypoxia in human cancers.

正电子发射断层扫描（PET）评估发现，一种靶向缺氧的放射性药物——二乙酰基-双（N4 -甲基氨基硫脲）铜（II）（Cu - ATSM）在肿瘤中的摄取与几种人类癌症的预后相关。这种示踪剂若要在临床上广泛应用，就需要用一种半衰期比迄今为止研究中使用的\(^{60}Cu\)更长的铜放射性核素进行标记。本研究的目的是获取Cu - ATSM必要的临床前数据以提交研究性新药申请，随后在宫颈癌女性患者中对\(^{60}Cu - ATSM\)和\(^{64}Cu - ATSM\)的PET图像质量和肿瘤摄取进行交叉比较。 方法：采用标准的体外和体内试验以及对大鼠和兔子进行14天的毒性研究，检测一种Cu - ATSM制剂的临床前毒理学和药理学特性。在临床试验 - 再测试成像研究中，10名宫颈癌患者在不同日期分别接受\(^{60}Cu - ATSM\)和\(^{64}Cu - ATSM\)的PET检查。对图像质量进行定性评估，并测量每种示踪剂的肿瘤 - 肌肉活性比。 结果：毒理学和药理学数据表明，该制剂具有适合临床使用的安全边际。在患者研究中，我们发现由于\(^{64}Cu - ATSM\)噪声更低，其图像质量优于\(^{60}Cu - ATSM\)。此外，我们发现间隔1 - 9天的研究中\(^{60}Cu - ATSM\)和\(^{64}Cu - ATSM\)的肿瘤摄取模式和程度相似。 结论：\(^{64}Cu - ATSM\)似乎是一种安全的放射性药物，可用于获取人类癌症肿瘤缺氧的高质量图像。