Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark.
Institute for Inflammation Research, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark.
Int J Mol Sci. 2024 Sep 4;25(17):9582. doi: 10.3390/ijms25179582.
The treatment of childhood cancer is challenged by toxic side effects mainly due to chemotherapy-induced organ damage and infections, which are accompanied by severe systemic inflammation. Insulin-like growth factor I (IGF-I) is a key regulating factor in tissue repair. This study investigated associations between the circulating IGF-I levels and chemotherapy-related toxicity in pediatric acute lymphoblastic leukemia (ALL). In this prospective study, we included 114 patients (age: 1-17 years) with newly diagnosed ALL treated according to The Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2013 and 2018. The patients' plasma levels of IGF-I, and the primary binding protein, IGFBP-3, were measured weekly during the first six weeks of treatment, including the induction therapy. The patients' systemic inflammation was monitored by their C-reactive protein (CRP) and interleukin (IL)-6 levels and their intestinal epithelial damage by their plasma citrulline levels. IGF-I and IGFBP-3 were converted into sex-and age-adjusted standard deviation scores (SDS) using 1621 healthy children as reference. At ALL diagnosis, IGF-I levels were decreased (median (quartiles): -1.2 SDS (-1.9 to -0.5), = 0.001), but increased significantly following the initiation of chemotherapy, peaking on day 8 (0.0 SDS (from -0.8 to 0.7), < 0.001). This increase correlated with the levels of CRP (rho = 0.37, < 0.001) and IL-6 (rho = 0.39, = 0.03) on day 15, when these markers reached maximum levels. A larger IGF-I increase from day 1 to 15 correlated with a slower recovery rate of the intestinal damage marker citrulline from day 15 to 29 (rho = -0.28, = 0.01). Likewise, IGFBP-3 was reduced at diagnosis, followed by an increase after treatment initiation, and was highly correlated with same-day IGF-I levels. This study demonstrates a chemotherapy-induced increase in IGF-I, with a response that appears to reflect the severity of tissue damage and systemic inflammation, preceding CRP and IL-6 increases. IGF-I may have potential as an early reactive biomarker for acute toxicity in patients with ALL.
儿童癌症的治疗受到毒性副作用的挑战，主要是由于化疗引起的器官损伤和感染，同时伴有严重的全身炎症。胰岛素样生长因子 I（IGF-I）是组织修复的关键调节因子。本研究调查了循环 IGF-I 水平与儿科急性淋巴细胞白血病（ALL）化疗相关毒性之间的关系。在这项前瞻性研究中，我们纳入了 114 名（年龄：1-17 岁）新诊断为 ALL 的患者，他们根据北欧儿科血液学和肿瘤学学会（NOPHO）ALL2008 方案于 2013 年至 2018 年接受治疗。在治疗的前六周内，包括诱导治疗期间，每周测量患者的 IGF-I 及其主要结合蛋白 IGFBP-3 的血浆水平。通过 C 反应蛋白（CRP）和白细胞介素（IL）-6 水平监测患者的全身炎症，通过血浆瓜氨酸水平监测患者的肠上皮损伤。使用 1621 名健康儿童作为参考，将 IGF-I 和 IGFBP-3 转换为性别和年龄调整后的标准差评分（SDS）。在 ALL 诊断时，IGF-I 水平降低（中位数（四分位数）：-1.2 SDS（-1.9 至-0.5）， = 0.001），但在化疗开始后显著升高，在第 8 天达到峰值（0.0 SDS（从-0.8 至 0.7）， < 0.001）。这种增加与第 15 天 CRP（rho = 0.37， < 0.001）和 IL-6（rho = 0.39， = 0.03）的水平相关，此时这些标志物达到最高水平。第 1 天至第 15 天 IGF-I 增加幅度较大与第 15 天至第 29 天肠损伤标志物瓜氨酸恢复速度较慢相关（rho = -0.28， = 0.01）。同样，IGFBP-3 在诊断时降低，随后在治疗开始后增加，并且与同日 IGF-I 水平高度相关。这项研究表明，IGF-I 会受到化疗诱导而增加，其反应似乎反映了组织损伤和全身炎症的严重程度，先于 CRP 和 IL-6 的增加。IGF-I 可能作为 ALL 患者急性毒性的早期反应性生物标志物具有潜力。
