el-Beltagi H M, Martens A C, Haroun E A, Hagenbeek A
Institute of Applied Radiobiology and Immunology TNO, Rijswijk, The Netherlands.
Leukemia. 1993 Aug;7(8):1275-80.
The cytostatic drug acetyldinaline [ACD, CI-994, 4-acetylamine-N-(2-aminophenyl)-benzamide] shows an extreme antileukemic effect in the Brown Norway (BN) rate model for acute myelocytic leukemia (BNML) with only minor toxicity for normal pluripotent hemopoietic stem cells. So far, the mode of action is unknown. A resistant subline (BNML/ACD-R) was developed in vivo in the BNML model. Leukemic rats received repeated oral administrations of ACD. When the leukemia relapsed after initial remission-induction with ACD, the cells were transferred to new recipients which were again treated. In total, the animals received 247 oral administrations of ACD (33 x 2 mg/kg per day and 214 x 5 mg/kg per day) before full resistance was reached. The cell line was transferred 17 times in total. Treatment of the final resistant cell line with therapeutically highly active doses of 23.7 mg/kg per day and 11.85 mg/kg per day ACD for 5 days, that resulted in an increase of life span (ILS) of 57 and 18 days, respectively, when applied to the sensitive parent BNML line (BNML/S), resulted in only 10 and 3 days ILS, respectively. These results indicate that a significant degree of resistance has been achieved, which can be overcome partially by increasing the dose of ACD. Whether the development of a resistant subpopulation of the BNML is a result of acquired resistance or whether a naturally resistant subpopulation has been selected out after prolonged treatment with ACD remains to be established. The currently available resistant subline BNML/ACD-R now offers the possibility for further studies on the mechanism of action of ACD.
细胞生长抑制药物乙酰二苯胺[ACD，CI - 994，4 - 乙酰氨基 - N -（2 - 氨基苯基）- 苯甲酰胺]在急性髓细胞白血病（BNML）的布朗挪威（BN）大鼠模型中显示出极强的抗白血病作用，而对正常多能造血干细胞仅有轻微毒性。到目前为止，其作用方式尚不清楚。在BNML模型中体内培育出了一个耐药亚系（BNML/ACD - R）。白血病大鼠接受了ACD的重复口服给药。当用ACD诱导初始缓解后白血病复发时，将细胞转移至新的受体动物并再次进行治疗。在达到完全耐药之前，动物总共接受了247次ACD口服给药（33次每日2 mg/kg和214次每日5 mg/kg）。该细胞系总共传代了17次。用治疗活性高的剂量每日23.7 mg/kg和11.85 mg/kg的ACD对最终的耐药细胞系进行5天治疗，当应用于敏感的亲本BNML系（BNML/S）时分别使寿命延长（ILS）57天和18天，而应用于耐药细胞系时仅分别使ILS延长10天和3天。这些结果表明已产生了显著程度的耐药性，增加ACD剂量可部分克服这种耐药性。BNML耐药亚群的产生是获得性耐药的结果，还是在用ACD长期治疗后选出了一个天然耐药亚群，仍有待确定。目前可用的耐药亚系BNML/ACD - R为进一步研究ACD的作用机制提供了可能性。
