Development of specific radiation therapy targeting hypoxic cells

缺氧细胞在肿瘤中的不均匀分布被认为是放疗和化疗耐药的主要决定因素。人们认为，如果肿瘤长期处于缺氧状态，由于血管内皮生长因子等因素的作用，其恶性程度在增殖或转移潜能方面会增加。在这里，我们开发了一种测量肿瘤缺氧状态的方法，其中缺氧细胞通过表征它们的缺氧细胞标记成像。然后，我们将该方法作为先前开发的31P-MRS和MRI方法的补充，开发出一种针对缺氧细胞的导弹治疗方法，利用64Cu和67Cu等核素标记的缺氧细胞标志物进行基于正电子的诊断，并通过将低氧靶向导弹治疗与抑制新生血管生成的分子靶向药物相结合，开发出一种新的癌症治疗方法。作为我们实验的一部分，我们植入了正常p53的SASneo细胞和p53异常的SASmp细胞。SASmp细胞比SASneo细胞增殖速度更快，坏死倾向更大。在小鼠尾静脉注射67-Cu-ATSM后，注射后1和24小时肝、肾、肺等实质器官的RI分布较高，相对于血浆的分布率分别为5.15、2.33和2.32。相比之下，在中枢神经系统的积累较低，分布率仅为0.67。RI积累在SASmp和SASneo之间没有差异。切除肿瘤放射自显像显示肿瘤周围有67-Cu-ATSM堆积。此外，注射治疗浓度的同位素后肿瘤生长的延迟率显示，SASneo细胞的生长抑制往往比SASmp细胞更大。

Hypoxic cells distributed unevenly through tumors are believed to be the primary determinants in resistance to radiation therapy and chemotherapy. It is thought that if tumors are left in a state of hypoxia for an extended period, their malignancy, in terms of proliferative or metastasizing potential, will increase due to vascular endothelial growth factor and other factors. Here, we developed a method for measuring the hypoxic state of tumors in which hypoxic cells are imaged via the hypoxic cell markers that characterize them. We then used this method as an addition to the previously developed 31P-MRS and MRI methods to develop a type of missile therapy targeting hypoxic cells, to conduct positron-based diagnosis using hypoxic cell markers labeled with nuclides such as 64Cu and 67Cu, and to develop a new method of cancer therapy through the combination of hypoxia-targeting missile therapy with a molecular-targeted drug that inhibits neoangiogenesis. As part of our experiments, we implanted SASneo cells with normal p53 and SASmp cells, which have an abnormality in p53. The SASmp cells showed a faster rate of proliferation and a greater tendency to necrotize than the SASneo cells. On injection of 67-Cu-ATSM into the caudal vein of these mice, distribution of RI at 1 and 24 hours after injection was relatively high in parenchymal organs such as the liver, kidneys, and lungs, with relative distribution rates to a plasma rate of 1 of 5.15, 2.33, and 2.32, respectively. In contrast, accumulation in the central nervous system was low, with a distribution rate of only 0.67. RI accumulation did not differ between SASmp and SASneo. Autoradiography of the excised tumors showed 67-Cu-ATSM accumulation in the peripheral portions of tumors. Further, the rate of delay in tumor growth following the injection of isotopes at therapeutic concentrations revealed that growth inhibition tended to be greater in SASneo cells than in SASmp cells.