In vitro cytotoxicity of aplidin and crossresistance with other cytotoxic drugs in childhood leukemic and normal bone marrow and blood samples:: a rational basis for clinical development
In vitro cytotoxicity of aplidin and crossresistance with other cytotoxic drugs in childhood leukemic and normal bone marrow and blood samples:: a rational basis for clinical development
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DOI：
10.1038/sj.leu.2402972
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发表时间：
2003-07-01
期刊：
影响因子：
11.4
通讯作者：
Kaspers, GJL
中科院分区：
文献类型：
--
作者：
Bresters, D;Broekhuizen, AJF;Kaspers, GJL
为探讨阿普利定作为细胞毒剂治疗儿童白血病的可能性，采用四甲基偶氮唑盐比色法检测了72例不同类型白血病患儿和72例健康儿童的骨髓和外周血。此外，我们还将这些结果与其他细胞毒药物进行了比较。Aplidin在体外纳摩尔浓度下具有细胞毒性，且呈剂量依赖关系。用于预防阿普利定所致肌毒性的临床研究中的L-卡尼汀在体外对阿普利定的细胞毒性无影响。Aplidin对初治和复发的急性淋巴细胞白血病(ALL)或初治的ALL和初治的急性髓系白血病进行比较，其体外细胞毒作用无差异。然而，正常骨髓(n=19)和外周血(n=13)细胞对阿普利定的耐受性高于白血病细胞(中位数分别是白血病细胞的2~7倍，P=0.001和4~11倍，P<；0.0001)。在白血病标本中，除与2‘，2’-二氟脱氧胞苷有相关趋势(Rho=0.71，P=0.02)外，与其他细胞毒药物无明显交叉耐药。在正常的骨髓样本中，发现了与表鬼臼毒素的显著交叉耐药性，这不容易用目前已知的阿普利丁的作用机制来解释。综上所述，我们发现阿普利定在体外对儿童白血病细胞具有选择性细胞毒作用，与其他已知的细胞毒药物普遍缺乏交叉耐药性，值得临床研究。
To determine the potential of aplidin as a cytotoxic agent in pediatric leukemia, we tested bone marrow ( BM) and peripheral blood (PB) samples (n = 72) of children with different types of leukemia and healthy children in the methyl-thiazol-tetrazolium assay. Also, we compared these results with other cytotoxic drugs. Aplidin was cytotoxic in vitro at nanomolar concentrations, in a dose-dependent fashion. L-carnitine, that is applied in clinical studies to prevent myotoxicity caused by aplidin, had no effect on aplidin cytotoxicity in vitro. Aplidin cytotoxicity in vitro was not different when initial and relapsed acute lymphoblastic leukemia ( ALL) or initial ALL and initial acute myeloid leukemia were compared. However, normal BM (n = 19) and PB (n = 13) cells were more resistant to aplidin than leukemic cells ( median two- to seven-fold, P = 0.001 and median four- to 11-fold, P < 0.0001, respectively). In leukemia samples, no significant crossresistance between aplidin and other cytotoxic drugs was found, except for a trend for correlation with 2',2'-difluorodeoxycytidine (rho = 0.71, P = 0.02). In normal BM samples, significant crossresistance with the epipodophyllotoxins was found, which is not readily explained by the currently known mechanisms of action of aplidin. In conclusion, we show that aplidin has selective cytotoxicity in vitro towards childhood leukemia cells and generally lacks crossresistance with other known cytotoxic drugs, which warrants clinical studies.