Tumor cells—even if nonauxotrophic—are often highly sensitive to arginine deficiency. We hypothesized that arginine deprivation therapy (ADT) if combined with irradiation could be a new treatment strategy for glioblastoma (GBM) patients because systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle in vitro study was performed with ADT being mimicked by application of recombinant human arginase or arginine-free diets. ADT inhibited two-dimensional (2-D) growth and cell-cycle progression, and reduced growth recovery after completion of treatment in four different GBM cell line models. Cells were less susceptible to ADT alone in the presence of citrulline and in a three-dimensional (3-D) environment. Migration and 3-D invasion were not unfavorably affected. However, ADT caused a significant radiosensitization that was more pronounced in a GBM cell model with p53 loss of function as compared with its p53-wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase or argininosuccinate lyase protein expression and not abrogated by the presence of citrulline. The radiosensitizing potential was maintained or even more distinguishable in a 3-D environment as verified in p53-knockdown and p53-wildtype U87-MG cells via a 60-day spheroid control probability assay. Although the underlying mechanism is still ambiguous, the observation of ADT-induced radiosensitization is of great clinical interest, in particular for patients with GBM showing high radioresistance and/or p53 loss of function. Mol Cancer Ther; 17(2); 393–406. ©2017 AACR. See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

中文翻译：

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精氨酸剥夺疗法：通过放射增敏根除胶质母细胞瘤细胞的推定策略

肿瘤细胞——即使是非营养缺陷型的——通常对精氨酸缺乏高度敏感。我们假设精氨酸剥夺疗法 (ADT) 如果与辐射相结合，可能成为胶质母细胞瘤 (GBM) 患者的新治疗策略，因为全身性 ADT 不受局部渗透和扩散限制的影响。通过应用重组人精氨酸酶或无精氨酸饮食模拟 ADT，进行了一项体外原理验证研究。在四种不同的 GBM 细胞系模型中，ADT 抑制二维 (2-D) 生长和细胞周期进程，并降低治疗完成后的生长恢复。在瓜氨酸存在的情况下和三维 (3-D) 环境中，细胞对单独的 ADT 不太敏感。迁移和 3-D 入侵没有受到不利影响。然而，ADT 引起显着的放射增敏作用，与 p53 野生型对应物相比，在具有 p53 功能丧失的 GBM 细胞模型中更为明显。协同作用不依赖于碱性和诱导的精氨琥珀酸合酶或精氨琥珀酸裂解酶蛋白表达，并且不会因瓜氨酸的存在而消除。通过 60 天球体控制概率测定在 p53 敲低和 p53 野生型 U87-MG 细胞中验证了放射致敏潜力在 3-D 环境中保持或什至更可区分。尽管潜在机制仍然不明确，但观察 ADT 诱导的放射增敏具有重要的临床意义，特别是对于显示高放射抗性和/或 p53 功能丧失的 GBM 患者。摩尔癌症治疗; 17(2); 393-406。©2017 AACR。