Hagenbeek A, Martens A C
Eur J Cancer Clin Oncol. 1982 Aug;18(8):763-9. doi: 10.1016/0277-5379(82)90075-x.
In view of its application in patients with acute leukemia prior to bone marrow transplantation, the toxicity and efficacy of high-dose cyclophosphamide treatment were evaluated in a rat model for human acute myelocytic leukemia (BNML). The LD50 in leukemic rats proved to be lower than that in normal rats (100 vs 164 mg/kg respectively). With dosages above 120 mg/kg, bone marrow transplantation was required to overcome irreversible aplasia. Additional causes of death were lung-, bladder- and intestinal tract hemorrhages (160-200 mg/kg) or acute cardiopulmonary failure (250-300 mg/kg). In leukemic rats, excessive leukemic cell kill leading to tumor cell embolism was another contributing factor. In this respect, treatment of late-stage leukemia proved invariably fatal. In leukemic rats, the highest therapeutic index was achieved with 100 mg/kg. Depending on the stage of disease, a 5-8.5 log leukemic cell kill was achieved. An increased proliferation rate of residual leukemic cells after cyclophosphamide treatment appeared likely. Finally, the present data are extrapolated to the current treatment of human acute myelocytic leukemia in complete remission with high-dose cyclophosphamide in combination with supralethal total-body irradiation.
鉴于高剂量环磷酰胺在骨髓移植前急性白血病患者中的应用，我们在人类急性髓细胞白血病大鼠模型（BNML）中评估了其毒性和疗效。白血病大鼠的半数致死剂量低于正常大鼠（分别为100和164毫克/千克）。剂量超过120毫克/千克时，需要进行骨髓移植以克服不可逆的再生障碍。其他死亡原因包括肺、膀胱和肠道出血（160 - 200毫克/千克）或急性心肺衰竭（250 - 300毫克/千克）。在白血病大鼠中，白血病细胞过度杀伤导致肿瘤细胞栓塞是另一个促成因素。在这方面，晚期白血病的治疗被证明总是致命的。在白血病大鼠中，100毫克/千克的剂量达到了最高治疗指数。根据疾病阶段，实现了5 - 8.5个对数级的白血病细胞杀伤。环磷酰胺治疗后残留白血病细胞的增殖率似乎有所增加。最后，将目前的数据外推至当前高剂量环磷酰胺联合超致死剂量全身照射治疗完全缓解的人类急性髓细胞白血病的情况。
