Therapies targeting reductive/oxidative (redox) metabolism hold potential in cancers resistant to chemotherapy and radiation. A redox imaging marker would help identify cancers susceptible to redox-directed therapies. Copper(II)-diacetyl-bis(4-methylthiosemicarbazonato) (Cu-ATSM) is a PET tracer developed for hypoxia imaging that could potentially be used for this purpose. We aimed to demonstrate that Cu-ATSM signal is dependent on cellular redox state, irrespective of hypoxia. Methods: We investigated the relationship between ⁶⁴Cu-ATSM signal and redox state in human cervical and colon cancer cells. We altered redox state using drug strategies and single-gene mutations in isocitrate dehydrogenases (IDH1/2). Concentrations of reducing molecules were determined by spectrophotometry and liquid chromatography–mass spectrometry and compared with ⁶⁴Cu-ATSM signal in vitro. Mouse models of cervical cancer were used to evaluate the relationship between ⁶⁴Cu-ATSM signal and levels of reducing molecules in vivo, as well as to evaluate the change in ⁶⁴Cu-ATSM signal after redox-active drug treatment. Results: A correlation exists between baseline ⁶⁴Cu-ATSM signal and cellular concentration of glutathione, nicotinamide adenine dinucleotide phosphate (NADPH), and nicotinamide adenine dinucleotide (NADH). Altering NADH and NADPH metabolism using drug strategies and IDH1 mutations resulted in significant changes in ⁶⁴Cu-ATSM signal under normoxic conditions. Hypoxia likewise changed ⁶⁴Cu-ATSM signal, but treatment of hypoxic cells with redox-active drugs resulted in a more dramatic change than hypoxia alone. A significant difference in NADPH was seen between cervical tumor orthotopic implants in vivo, without a corresponding difference in ⁶⁴Cu-ATSM signal. After treatment with β-lapachone, there was a change in ⁶⁴Cu-ATSM signal in xenograft tumors smaller than 50 mg but not in larger tumors. Conclusion: ⁶⁴Cu-ATSM signal reflects redox state, and altering redox state impacts ⁶⁴Cu-ATSM metabolism. Our animal data suggest there are other modulating factors in vivo. These findings have implications for the use of ⁶⁴Cu-ATSM as a predictive marker for redox therapies, though further in vivo work is needed.

针对还原/氧化（氧化还原）代谢的疗法在抵抗化学疗法和放射线的癌症中具有潜力。氧化还原成像标记物将有助于鉴定易受氧化还原定向疗法治疗的癌症。铜（II）-二乙酰基-双（4-甲基硫代氨基甲磺酸钠）（Cu-ATSM）是开发用于缺氧成像的PET示踪剂，可潜在地用于此目的。我们旨在证明Cu-ATSM信号取决于细胞的氧化还原状态，而与低氧无关。方法：我们调查了^64个之间的关系人宫颈癌和结肠癌细胞中的Cu-ATSM信号和氧化还原状态。我们使用药物策略和异柠檬酸脱氢酶（IDH1 / 2）中的单基因突变来改变氧化还原状态。用分光光度法和液相色谱-质谱法测定还原分子的浓度，并与⁶⁴ Cu-ATSM信号进行体外比较。宫颈癌的小鼠模型用于评估⁶⁴ Cu-ATSM信号与体内还原分子水平之间的关系，以及评估氧化还原活性药物治疗后⁶⁴ Cu-ATSM信号的变化。结果：基线⁶⁴之间存在相关性谷胱甘肽，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）和烟酰胺腺嘌呤二核苷酸（NADH）的Cu-ATSM信号和细胞浓度。在常氧条件下，使用药物策略和IDH1突变改变NADH和NADPH代谢会导致⁶⁴ Cu-ATSM信号发生显着变化。缺氧同样会改变⁶⁴ Cu-ATSM信号，但是用氧化还原活性药物处理缺氧细胞会导致比单独的缺氧更为显着的变化。在体内宫颈肿瘤原位植入物之间观察到NADPH的显着差异，但在⁶⁴ Cu-ATSM信号中无相应差异。用β-拉帕酮治疗后，有^64例发生了变化小于50 mg的异种移植肿瘤中的Cu-ATSM信号，但较大的肿瘤中没有。结论： ⁶⁴ Cu-ATSM信号反映了氧化还原状态，而改变氧化还原状态会影响⁶⁴ Cu-ATSM的代谢。我们的动物数据表明体内还有其他调节因子。这些发现暗示了使用⁶⁴ Cu-ATSM作为氧化还原疗法的预测指标，尽管还需要进一步的体内工作。