Wagner T, Zink M, Schwieder G
J Cancer Res Clin Oncol. 1987;113(2):160-5. doi: 10.1007/BF00391439.
Presumably the coadministration of the uroprotector mesna in cyclophosphamide treatment does not influence the systemic activity of its activated metabolite. This was newly investigated in a mouse model. The LD50 values of i.p. administered mafosfamide, a derivative of act. CP, were increased by the simultaneous i.p. administration of mesna (mafosfamide: mesna 1:2 on a molar weight basis) from 590 mg/kg to 750 mg/kg, and after i.v. injection of cytostatic and thiol from 505 mg/kg to 810 mg/kg. Administration of 2 X molar cysteine i.v. or i.p. to mafosfamide-treated animals was even more effective against its lethal toxicity (LD50 i.p. 1800 mg/kg and i.v. 1130 mg/kg). Bone marrow toxicity (severe leukocytopenia) was partially abolished by both thiols. Also the therapeutic efficacy of act. CP against L1210 leukemia in DBA2 mice was reduced by 50% in the presence of cysteine and of mesna. Compared with mesna the higher detoxification effect of cysteine is attributed to its longer half-life (t1/2 20 min vs 12 min of mesna) and presumably an accumulation of cysteine in some cell systems (distribution coefficient 1.20 ml/g vs 0.68 ml/g of mesna). Nevertheless, our study clearly demonstrates a distinct systemic deactivation of act. CP by mesna, which might be of clinical relevance.
据推测，在环磷酰胺治疗中联合使用尿路保护剂美司钠并不影响其活化代谢产物的全身活性。这一点在小鼠模型中得到了新的研究。腹腔注射美法仑（活性环磷酰胺的衍生物）的半数致死量（LD50）值，在同时腹腔注射美司钠（按摩尔重量计美法仑：美司钠为1:2）时，从590毫克/千克增加到750毫克/千克，静脉注射细胞抑制剂和硫醇后，从505毫克/千克增加到810毫克/千克。给接受美法仑治疗的动物静脉或腹腔注射2倍摩尔量的半胱氨酸，对其致死毒性的对抗作用甚至更有效（腹腔注射LD50为1800毫克/千克，静脉注射为1130毫克/千克）。两种硫醇都部分消除了骨髓毒性（严重白细胞减少）。在存在半胱氨酸和美司钠的情况下，活性环磷酰胺对DBA2小鼠L1210白血病的治疗效果也降低了50%。与美司钠相比，半胱氨酸更高的解毒效果归因于其更长的半衰期（半胱氨酸为20分钟，美司钠为12分钟），并且可能是由于半胱氨酸在某些细胞系统中的蓄积（分布系数为1.20毫升/克，而美司钠为0.68毫升/克）。然而，我们的研究清楚地表明美司钠对活性环磷酰胺有明显的全身失活作用，这可能具有临床相关性。
