el-Beltagi H M, Martens A C, Lelieveld P, Haroun E A, Hagenbeek A
Department of Hemato-Oncology TNO, Erasmus University Rotterdam, The Netherlands.
Cancer Res. 1993 Jul 1;53(13):3008-14.
Acetyldinaline [CI-994; GOE 5549; PD 123 654; 4-acetylamino-N-(2'-aminophenyl)-benzamide] is the acetylated derivative form of the original compound Dinaline (GOE 1734; PD 104 208). The efficacy and toxicity of Acetyldinaline for remission-induction treatment of leukemia were evaluated and compared with those observed in previous studies of Dinaline in the Brown Norway acute myelocytic leukemia, as a preclinical model for human acute myelocytic leukemia. There were three treatment groups. Leukemic animals received either 1 or 2 courses of 5 daily p.o. administrations of Acetyldinaline with a "full dose" of 23.7 mg/kg once daily (first group), a twice daily "half dose" of 11.85 mg/kg with an interval of 8 h (second group), or a "half dose" of 11.85 mg/kg once daily (third group). The drug-free interval between the 2 courses was 2 or 9 days. With repeated daily p.o. administrations of 23.7 mg/kg either in a single daily dose or a split daily dose of 2 x 11.85 mg/kg for 1 course, at least an 8-log leukemic cell kill was achieved. In contrast, with these treatment schedules, less than a 1-log cell kill of normal pluripotent hemopoietic stem cells (CFU-S) in the femoral bone marrow was found. Split daily dose treatment was more effective resulting in 37.5% cures, while no cures were observed with the single daily treatment for one course. Treatment with single daily dose of 23.7 mg/kg or a split daily dose of 2 x 11.85 mg/kg for 2 courses, with either a 2- or 9-day interval in between, resulted in lethal toxicity in most of rats. This result was comparable with that previously observed after equimolar doses of Dinaline (20 mg/kg). The half-dose once daily treatment with Acetyldinaline (11.85 mg/kg) for 1 or 2 cycles resulted in about a 4.5 or > 8-log leukemic cell kill, respectively. Toxic side effects, i.e., damage to the gastro-intestinal tract and hemorrhages in the lungs, were more pronounced with full dose either in the single or the split daily dose regimen. No significant toxicity was observed at the half-dose treatment once daily. In conclusion, the impressive differential activity against leukemic cells and normal stem cells observed in this relevant rat model for human acute myelocytic leukemia warrants the introduction of this compound in clinical phase I/II studies.
乙酰二苯胺[CI-994；GOE 5549；PD 123 654；4-乙酰氨基-N-(2'-氨基苯基)-苯甲酰胺]是原始化合物二苯胺（GOE 1734；PD 104 208）的乙酰化衍生物形式。作为人类急性髓细胞白血病的临床前模型，在棕色挪威大鼠急性髓细胞白血病中，评估了乙酰二苯胺用于白血病诱导缓解治疗的疗效和毒性，并与先前二苯胺研究中观察到的疗效和毒性进行了比较。有三个治疗组。白血病动物接受1或2个疗程的治疗，每个疗程口服乙酰二苯胺5天，第一组每天一次“全剂量”23.7 mg/kg（一次给药），第二组每天两次“半剂量”11.85 mg/kg，间隔8小时，第三组每天一次“半剂量”11.85 mg/kg。两个疗程之间的停药间隔为2天或9天。对于1个疗程，每天重复口服23.7 mg/kg，无论是单次给药还是分成2×11.85 mg/kg的分次给药，至少可使白血病细胞减少8个对数级。相比之下，按照这些治疗方案，在股骨骨髓中发现正常多能造血干细胞（CFU-S）的细胞减少不到1个对数级。分次给药治疗更有效，治愈率为37.5%，而单次给药1个疗程未观察到治愈情况。对于2个疗程，每天单次剂量23.7 mg/kg或分成2×11.85 mg/kg的分次给药，中间间隔2天或9天，大多数大鼠出现致命毒性。这一结果与先前等摩尔剂量二苯胺（20 mg/kg）后观察到的结果相当。乙酰二苯胺每天一次半剂量（11.85 mg/kg）治疗1或2个周期，分别导致白血病细胞减少约4.5个或>8个对数级。毒性副作用，即胃肠道损伤和肺部出血，在单次或分次全剂量给药方案中更为明显。每天一次半剂量治疗未观察到明显毒性。总之，在这个与人类急性髓细胞白血病相关的大鼠模型中观察到的对白血病细胞和正常干细胞的显著差异活性，值得将该化合物引入临床I/II期研究。
