Development of specific radiation therapy targeting hypoxic cells

低氧细胞在肿瘤中分布不均被认为是抵抗放射治疗和化疗的主要决定因素。人们认为，如果肿瘤长时间处于缺氧状态，其恶性程度，就其增殖或转移潜能而言，会由于血管内皮生长因子等因素而增加。在这里，我们开发了一种方法来测量肿瘤的缺氧状态，其中缺氧细胞通过表征它们的缺氧细胞标志物进行成像。然后，我们利用这种方法作为先前开发的31P-MRS和MRI方法的补充，开发了一种针对缺氧细胞的靶向治疗，使用标记有核素如64Cu和67Cu的缺氧细胞标记物进行基于正电子的诊断，并通过将缺氧靶向治疗与抑制新生血管的分子靶向药物相结合来开发一种新的癌症治疗方法。作为我们实验的一部分，我们将正常的P53和SASMP细胞植入SASneo细胞，这两个细胞在P53中存在异常。SASMP细胞较SASneo细胞表现出更快的增殖速度和更大的坏死率。在这些小鼠尾静脉注射67-Cu-ATSM后，RI在肝、肾、肺等实质器官中的分布较高，相对分布比率分别为5.15、2.33和2.32。相比之下，在中枢神经系统的蓄积较低，分布率仅为0.67。SRI积累在SASMP和SASneo之间没有差异。切除的肿瘤放射自显影显示67-Cu-ATSM聚集在肿瘤周围。此外，注射治疗浓度的同位素后肿瘤生长的延迟率表明，SASneo细胞的生长抑制往往比SASMP细胞的生长抑制更大。

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.