Berrigan M J, Marinello A J, Pavelic Z, Williams C J, Struck R F, Gurtoo H L
Cancer Res. 1982 Sep;42(9):3688-95.
One of the serious toxicities of cyclophosphamide chemotherapy is urotoxicity. In addition to causing leukopenia, high-dose cyclophosphamide caused both depression of hepatic microsomal enzyme activities and extensive urinary bladder damage, suggesting that a common biochemical mechanism may be responsible for both of these effects. Administration of 180 or 200 mg cyclophosphamide per kg to Wistar rats caused 41 to 67% decrease in aryl hydrocarbon hydroxylase activity, a 21 to 54% decrease in aminopyrine demethylase activity, and a 34 to 40% decrease in cytochrome P-450 content. This dose of cyclophosphamide also caused hematuria as well as necrosis and edema in the urinary bladder. Administration of N-acetylcysteine or sodium-2-mercaptoethane sulfonate (mesnum) with cyclophosphamide, while not protecting against leukopenia, protected against the enzymatic inactivation and urotoxicity. The biochemical basis of these observations is discussed. The results suggest that a common metabolite of cyclophosphamide, most probably acrolein, is responsible for both of these undesirable effects of cyclophosphamide therapy. Use of combinations including cyclophosphamide and an appropriate thiol may increase the therapeutic index of this drug.
环磷酰胺化疗的严重毒性之一是泌尿毒性。除了导致白细胞减少外，高剂量环磷酰胺还会引起肝微粒体酶活性降低以及广泛的膀胱损伤，这表明可能存在一种共同的生化机制导致这两种效应。给Wistar大鼠每千克体重注射180或200毫克环磷酰胺，会导致芳烃羟化酶活性降低41%至67%，氨基比林脱甲基酶活性降低21%至54%，细胞色素P - 450含量降低34%至40%。这个剂量的环磷酰胺还会导致血尿以及膀胱坏死和水肿。与环磷酰胺同时给予N - 乙酰半胱氨酸或2 - 巯基乙烷磺酸钠（美司钠），虽然不能预防白细胞减少，但能预防酶失活和泌尿毒性。本文讨论了这些观察结果的生化基础。结果表明，环磷酰胺的一种共同代谢产物，很可能是丙烯醛，是环磷酰胺治疗的这两种不良效应的原因。使用包括环磷酰胺和适当硫醇的联合用药可能会提高这种药物的治疗指数。
