PDF(Pubmed)
Abstract：
Radiation therapy (RT) remains a common treatment for cancer patients worldwide, despite the development of targeted biological compounds and immunotherapeutic drugs. The challenge in RT lies in delivering a lethal dose to the cancerous site while sparing the surrounding healthy tissues. Low linear energy transfer (low-LET) and high linear energy transfer (high-LET) radiations have distinct effects on cells. High-LET radiation, such as alpha particles, induces clustered DNA double-strand breaks (DSBs), potentially inducing cell death more effectively. However, due to limited range, alpha-particle therapies have been restricted. In human cancer, mutations in TP53 (encoding for the p53 tumor suppressor) are the most common genetic alteration. It was previously reported that cells carrying wild-type (WT) p53 exhibit accelerated senescence and significant rates of apoptosis in response to RT, whereas cells harboring mutant p53 (mutp53) do not. This study investigated the combination of the alpha-emitting atoms RT based on internal Radium-224 (224Ra) sources and systemic APR-246 (a p53 reactivating compound) to treat tumors with mutant p53. Cellular models of colorectal cancer (CRC) or pancreatic ductal adenocarcinoma (PDAC) harboring mutant p53, were exposed to alpha particles, and tumor xenografts with mutant p53 were treated using 224Ra source and APR-246. Effects on cell survival and tumor growth, were assessed. The spread of alpha emitters in tumors was also evaluated as well as the spatial distribution of apoptosis within the treated tumors. We show that mutant p53 cancer cells exhibit radio-sensitivity to alpha particles in vitro and to alpha-particles-based RT in vivo. APR-246 treatment enhanced sensitivity to alpha radiation, leading to reduced tumor growth and increased rates of tumor eradication. Combining alpha-particles-based RT with p53 restoration via APR-246 triggered cell death, resulting in improved therapeutic outcomes. Further preclinical and clinical studies are needed to provide a promising approach for improving treatment outcomes in patients with mutant p53 tumors.
摘要：
放射治疗（RT）仍然是全球癌症患者的常用治疗方法，尽管开发了靶向生物化合物和免疫治疗药物。RT的挑战在于向癌变部位提供致死剂量，同时保留周围的健康组织。低线性能量转移(低LET)和高线性能量转移(高LET)辐射对细胞具有不同的影响。高LET辐射,比如α粒子，诱导成簇的DNA双链断裂（DSB），可能更有效地诱导细胞死亡。然而,由于范围有限，α粒子疗法受到限制。在人类癌症中，TP53（编码p53肿瘤抑制因子）的突变是最常见的遗传改变。先前报道，携带野生型（WT）p53的细胞表现出加速的衰老和显着的凋亡率，而带有突变型p53（mutp53）的细胞则没有。这项研究调查了基于内部镭224（224Ra）来源的α发射原子RT和全身性APR-246（p53再激活化合物）的组合，以治疗突变p53的肿瘤。带有突变型p53的结直肠癌（CRC）或胰腺导管腺癌（PDAC）的细胞模型暴露于α颗粒，使用224Ra来源和APR-246处理具有突变型p53的肿瘤异种移植物。对细胞存活和肿瘤生长的影响，被评估。还评估了α发射体在肿瘤中的扩散以及在治疗的肿瘤内凋亡的空间分布。我们表明，突变型p53癌细胞在体外对α粒子和体内基于α粒子的RT表现出放射敏感性。APR-246治疗增强了对α辐射的敏感性，导致肿瘤生长减少和肿瘤根除率增加。结合基于α-粒子的RT与p53恢复通过APR-246触发的细胞死亡，改善治疗结果。需要进一步的临床前和临床研究来提供一种有希望的方法来改善突变型p53肿瘤患者的治疗结果。
