Lauterburg B H, Nguyen T, Hartmann B, Junker E, Küpfer A, Cerny T
Department of Clinical Pharmacology, University of Bern, Switzerland.
Cancer Chemother Pharmacol. 1994;35(2):132-6. doi: 10.1007/BF00686635.
The sulfhydryl status of cells, particularly the intracellular concentration of glutathione, is a critical determinant of the response of tumor and normal cells to cytostatic drugs. Recent data indicate that the administration of mercaptoethane sulfonate (mesna), which is often combined with ifosfamide, markedly decreases the circulating concentration of total cysteine and could thereby influence the response of the organism to the cytotoxic effects of chemotherapy. The aim of the present study was to assess the effects of the combination of ifosfamide/mesna on sulfhydryl and disulfide homeostasis in tumor patients. Ifosfamide was infused into 14 patients with advanced sarcoma for 5 days at a dose of 2.4-3.2 g/m2 per day together with mesna. The plasma concentrations of total mesna, cysteine, glutathione, and homocysteine were measured before and on days 1 and 6 of the first course of ifosfamide/mesna therapy and prior to the next course of chemotherapy, and the urinary excretion of cysteine and mesna was monitored daily using a high-performance liquid chromatography (HPLC) method. Ifosfamide/mesna resulted in a marked depletion of circulating total cysteine, i.e., cysteine, cystine, and cysteine mixed disulfides [from 245 +/- 36 to 50 +/- 14 nmol/ml (mean +/- 95% CI) on day 6], total glutathione (from 6.9 +/- 1.1 to 2.5 +/- 1.1 nmol/ml), and total homocysteine (from 12.3 +/- 2.1 to 1.4 +/- 1.1 nmol/ml). The values returned to baseline levels prior to the next course of chemotherapy. The urinary excretion of cysteine increased significantly from 0.28 to 1.82 mmol/day on the 1st day, whereupon it returned toward baseline. An average of 62% +/- 6% of the delivered dose of mesna was recovered in urine. The combination of ifosfamide/mesna results in depletion of circulating total cysteine, glutathione, and homocysteine. This marked derangement of sulfhydryl and disulfide homeostasis could modulate the efficacy and toxicity of ifosfamide/mesna therapy.
细胞的巯基状态，尤其是细胞内谷胱甘肽的浓度，是肿瘤细胞和正常细胞对细胞生长抑制药物反应的关键决定因素。最近的数据表明，常与异环磷酰胺联合使用的巯基乙烷磺酸盐（美司钠）的给药会显著降低循环中总半胱氨酸的浓度，从而可能影响机体对化疗细胞毒性作用的反应。本研究的目的是评估异环磷酰胺/美司钠联合用药对肿瘤患者巯基和二硫键稳态的影响。将异环磷酰胺以每天2.4 - 3.2 g/m²的剂量输注给14例晚期肉瘤患者，共5天，同时给予美司钠。在异环磷酰胺/美司钠治疗的第一个疗程的第1天、第6天以及下一个化疗疗程之前，测量血浆中总美司钠、半胱氨酸、谷胱甘肽和同型半胱氨酸的浓度，并使用高效液相色谱（HPLC）法每日监测尿液中半胱氨酸和美司钠的排泄情况。异环磷酰胺/美司钠导致循环中总半胱氨酸（即半胱氨酸、胱氨酸和半胱氨酸混合二硫键）显著减少[第6天时从245±36降至50±14 nmol/ml（平均值±95%可信区间）]、总谷胱甘肽（从6.9±1.1降至2.5±1.1 nmol/ml）以及总同型半胱氨酸（从12.3±2.1降至1.4±1.1 nmol/ml）。在下一个化疗疗程之前，这些值恢复到基线水平。尿液中半胱氨酸的排泄量在第1天从0.28 mmol/天显著增加至1.82 mmol/天，随后又恢复到基线水平。尿液中回收的美司钠平均占给药剂量的62%±6%。异环磷酰胺/美司钠联合用药导致循环中总半胱氨酸、谷胱甘肽和同型半胱氨酸减少。这种巯基和二硫键稳态的明显紊乱可能会调节异环磷酰胺/美司钠治疗的疗效和毒性。
