Baranowska-Kortylewicz Janina, Sharp John G, McGuire Timothy R, Joshi Shantharam, Coulter Don W
Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Department of Genetics Cell Biology & Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Cancer Biother Radiopharm. 2020 Aug;35(6):418-424. doi: 10.1089/cbr.2019.3112. Epub 2020 Feb 19.
Osteosarcoma (OST) is the most common bone tumor in children and adolescents with a second peak of incidence in elderly adults usually diagnosed as secondary tumors in Paget's disease or irradiated bone. Subjects with metastatic disease or whose disease relapses after the initial therapy have a poor prognosis. Moreover, multifocal OST contains tumor-initiating cells that are resistant to chemotherapy. The use of aggressive therapies in an attempt to eradicate these cells can have long-term negative consequences in these vulnerable patient populations. Th-labeled molecular probes based on ligands to OST-associated receptors such as IGF-1R (insulin-like growth factor receptor 1), HER2 (human epidermal growth factor receptor 2), and PSMA (prostate-specific membrane antigen) are expected to detect and treat osseous and nonosseous sites of multifocal OST. Published reports indicate that Th has limited myelotoxicity, can be stably chelated to its carriers and, as it decays at targeted sites, Th produces Ra that is subsequently incorporated into the areas of increased osteoblastic activity, that is, osseous metastatic lesions. Linear energy transfer of α particles emitted by Th and its daughter Ra is within the range of the optimum relative biological effectiveness. The radiotoxicity of α particles is virtually independent of the phase in the cell cycle, oxygenation, and the dose rate. For these reasons, even resistant OST cells remain susceptible to killing by high-energy α particles, which can also kill adjacent quiescent OST cells or cells with low expression of targeted receptors. Systemic side effects are minimized by the limited range of these intense radiations. Quantitative single-photon emission computed tomography of Th and Ra is feasible. Additionally, the availability of radionuclide pairs, for example, Zr for positron emission tomography and Th for therapy, establish a strong basis for the theranostic use of Th in the individualized treatment of multifocal OST.
骨肉瘤（OST）是儿童和青少年中最常见的骨肿瘤，在老年人中发病率有第二个高峰，通常被诊断为佩吉特病或放疗后骨的继发性肿瘤。患有转移性疾病或初始治疗后疾病复发的患者预后较差。此外，多灶性骨肉瘤含有对化疗耐药的肿瘤起始细胞。试图根除这些细胞而采用的激进疗法可能会对这些脆弱的患者群体产生长期负面影响。基于与骨肉瘤相关受体（如胰岛素样生长因子受体1（IGF-1R）、人表皮生长因子受体2（HER2）和前列腺特异性膜抗原（PSMA））配体的钍标记分子探针有望检测和治疗多灶性骨肉瘤的骨和非骨部位。已发表的报告表明，钍的骨髓毒性有限，可以稳定地螯合到其载体上，并且当它在靶向部位衰变时，钍会产生镭，随后镭会被整合到成骨活性增加的区域，即骨转移病变部位。钍及其子体镭发射的α粒子的线能量转移在最佳相对生物效应范围内。α粒子的放射毒性实际上与细胞周期阶段、氧合作用和剂量率无关。由于这些原因，即使是耐药的骨肉瘤细胞仍然容易被高能α粒子杀死，高能α粒子也可以杀死相邻的静止骨肉瘤细胞或靶向受体低表达的细胞。这些强烈辐射的有限射程将全身副作用降至最低。钍和镭的定量单光子发射计算机断层扫描是可行的。此外，放射性核素对的可用性，例如用于正电子发射断层扫描的锆和用于治疗的钍，为钍在多灶性骨肉瘤个体化治疗中的诊疗应用奠定了坚实基础。
