PDF(Pubmed)
Abstract：
BACKGROUND: Ifosfamide is a major anti-cancer drug in children with well-known renal toxicity. Understanding the mechanisms underlying this toxicity could help identify children at increased risk of toxicity.
METHODS: The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified.
RESULTS: The 15 participants received a median total ifosfamide dose of 59 g/m2 (range: 24-102), given over a median of 7 cycles (range: 4-14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children.
CONCLUSIONS: Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.
METHODS: The IFOS01 study included children undergoing ifosfamide-based chemotherapy for Ewing sarcoma or rhabdomyosarcoma. A fully evaluation of renal function was performed during and after chemotherapy. Proton nuclear magnetic resonance (NMR) and conventional biochemistry were used to detect early signs of ifosfamide-induced tubulopathy. The enzymatic activity of aldehyde dehydrogenase (ALDH) was measured in the peripheral blood lymphocytes as a marker of ifosfamide-derived chloroacetaldehyde detoxification capacity. Plasma and urine concentrations of ifosfamide and dechloroethylated metabolites were quantified.
RESULTS: The 15 participants received a median total ifosfamide dose of 59 g/m2 (range: 24-102), given over a median of 7 cycles (range: 4-14). All children had acute proximal tubular toxicity during chemotherapy that was reversible post-cycle, seen with both conventional assays and NMR. After a median follow-up of 31 months, 8/13 children presented overall chronic toxicity among which 7 had decreased glomerular filtration rate. ALDH enzymatic activity showed high inter- and intra-individual variations across cycles, though overall activity looked lower in children who subsequently developed chronic nephrotoxicity. Concentrations of ifosfamide and metabolites were similar in all children.
CONCLUSIONS: Acute renal toxicity was frequent during chemotherapy and did not allow identification of children at risk for long-term toxicity. A role of ALDH in late renal dysfunction is possible so further exploration of its enzymatic activity and polymorphism should be encouraged to improve the understanding of ifosfamide-induced nephrotoxicity.
摘要：
背景：异环磷酰胺是具有众所周知的肾毒性的儿童的主要抗癌药物。了解这种毒性的潜在机制可以帮助识别毒性风险增加的儿童。
方法：IFOS01研究包括接受以异环磷酰胺为基础的Ewing肉瘤或横纹肌肉瘤化疗的儿童。在化疗期间和之后对肾功能进行了全面评估。质子核磁共振（NMR）和常规生物化学用于检测异环磷酰胺诱导的肾小管病的早期症状。在外周血淋巴细胞中测量醛脱氢酶（ALDH）的酶活性，作为异环磷酰胺衍生的氯乙醛解毒能力的标志。定量异环磷酰胺和去氯乙基化代谢物的血浆和尿液浓度。
结果：15名参与者接受的异环磷酰胺总剂量中位数为59g/m2（范围：24-102），在7个周期的中位数上给出（范围：4-14）。所有儿童在化疗期间都有急性近端肾小管毒性，这是可逆的，用常规测定法和NMR都可以看到。经过31个月的中位随访，8/13儿童呈现总体慢性毒性，其中7例肾小球滤过率降低。ALDH酶活性在整个循环中显示出很高的个体间和个体内差异，尽管随后出现慢性肾毒性的儿童的总体活动看起来较低。所有儿童的异环磷酰胺和代谢物浓度相似。
结论：急性肾毒性在化疗期间是常见的，并且不能确定有长期毒性风险的儿童。ALDH在晚期肾功能不全中的作用是可能的，因此应鼓励进一步探索其酶活性和多态性，以增进对异环磷酰胺诱导的肾毒性的理解。
方法：IFOS01研究包括接受以异环磷酰胺为基础的Ewing肉瘤或横纹肌肉瘤化疗的儿童。在化疗期间和之后对肾功能进行了全面评估。质子核磁共振（NMR）和常规生物化学用于检测异环磷酰胺诱导的肾小管病的早期症状。在外周血淋巴细胞中测量醛脱氢酶（ALDH）的酶活性，作为异环磷酰胺衍生的氯乙醛解毒能力的标志。定量异环磷酰胺和去氯乙基化代谢物的血浆和尿液浓度。
结果：15名参与者接受的异环磷酰胺总剂量中位数为59g/m2（范围：24-102），在7个周期的中位数上给出（范围：4-14）。所有儿童在化疗期间都有急性近端肾小管毒性，这是可逆的，用常规测定法和NMR都可以看到。经过31个月的中位随访，8/13儿童呈现总体慢性毒性，其中7例肾小球滤过率降低。ALDH酶活性在整个循环中显示出很高的个体间和个体内差异，尽管随后出现慢性肾毒性的儿童的总体活动看起来较低。所有儿童的异环磷酰胺和代谢物浓度相似。
结论：急性肾毒性在化疗期间是常见的，并且不能确定有长期毒性风险的儿童。ALDH在晚期肾功能不全中的作用是可能的，因此应鼓励进一步探索其酶活性和多态性，以增进对异环磷酰胺诱导的肾毒性的理解。
