p210（BCR-ABL）特异性酪氨酸激酶抑制剂的良好治疗指数；对定向分化和原始慢性粒细胞白血病祖细胞的活性。
Favorable therapeutic index of a p210(BCR-ABL)-specific tyrosine kinase inhibitor; activity on lineage-committed and primitive chronic myelogenous leukemia progenitors.
作者信息
Kasper B, Fruehauf S, Schiedlmeier B, Buchdunger E, Ho A D, Zeller W J
机构信息
German Cancer Research Center (DKFZ), Diagnostics and Experimental Therapy, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
出版信息
Cancer Chemother Pharmacol. 1999;44(5):433-8. doi: 10.1007/s002800051001.
PURPOSE
In order to assess the effect of the tyrosine kinase inhibitor CGP57148B on lineage-committed and primitive chronic myelogenous leukemia (CML) progenitor cells, peripheral blood progenitor cells (PBPC) mobilized in chronic phase CML were exposed to this compound in vitro.
METHODS
Both short-term (</=1 week) and long-term exposure (>/=2 weeks) to CGP57148B were investigated using suspension culture, semisolid (methylcellulose) assay or stroma-dependent long-term culture (LTC). The proportion of bcr/abl-positive progenitors was determined after direct plating [2 weeks in colony-forming cell (CFC) assay] as well as after 2 or 6 weeks LTC (LTC always followed by CFC replates).
RESULTS
Incubation of CML PBPC over 48 h in suspension culture with 100 microM CGP57148B reduced the proportion of bcr/abl-positive colonies to 4.4 +/- 4.3% (n = 5) after direct plating, 6.6 +/- 4.2% (n = 5) after 2 weeks LTC and 5 +/- 5.6% (n = 2) after 6 weeks LTC. At this dose, survival of drug-exposed normal PBPC was 53 +/- 4.2%, 51 +/- 2.8% and 54.5 +/- 4.9% (n = 2), respectively. Incubation with CGP57148B at a concentration of 10 microM over 1 week under LTC conditions reduced the number of bcr/abl-positive colonies to 11.8 +/- 6.1% (n = 5) after direct plating, 12 +/- 6.4% (n = 4) after 2 weeks LTC and 14.3 +/- 11.4% (n = 3) after 6 weeks LTC; survival of normal PBPC was 84.5 +/- 2.1%, 93 +/- 4.2% and 86 +/- 1.4% (n = 2), respectively. Following long-term exposure to CGP57148B at a concentration of 1 microM, the proportion of remaining bcr/abl-positive colonies was 35%, 9% and 25% of untreated CML samples after direct plating as well as after 2 and 6 weeks LTC, respectively. The respective values for 10 microM CGP57148B were 10%, 11% and 19%. Long-term exposure of normal progenitors to CGP57148B yielded a survival of 98%, 100% and 93% (1 microM) or 77%, 86% and 80% (10 microM), respectively.
CONCLUSION
The results support the use of CGP57148B either for short-term exposure in vitro (e.g. purging) or for continuous treatment of CML in vivo.
目的
为了评估酪氨酸激酶抑制剂CGP57148B对定向分化及原始慢性粒细胞白血病（CML）祖细胞的作用，将慢性期CML动员的外周血祖细胞（PBPC）在体外暴露于该化合物。
方法
使用悬浮培养、半固体（甲基纤维素）分析或基质依赖的长期培养（LTC）研究了对CGP57148B的短期（≤1周）和长期暴露（≥2周）。在直接接种后（集落形成细胞（CFC）分析中培养2周）以及2或6周LTC后（LTC后总是继以CFC再接种）测定bcr/abl阳性祖细胞的比例。
结果
在悬浮培养中用100μM CGP57148B孵育CML PBPC 48小时以上，直接接种后bcr/abl阳性集落的比例降至4.4±4.3%（n = 5），2周LTC后为6.6±4.2%（n = 5），6周LTC后为5±5.6%（n = 2）。在此剂量下，暴露于药物的正常PBPC的存活率分别为53±4.2%、51±2.8%和54.5±4.9%（n = 2）。在LTC条件下用10μM CGP57148B孵育1周以上，直接接种后bcr/abl阳性集落的数量降至11.8±6.1%（n = 5），2周LTC后为12±6.4%（n = 4），6周LTC后为14.3±11.4%（n = 3）；正常PBPC的存活率分别为84.5±2.1%、93±4.2%和86±1.4%（n = 2）。长期暴露于1μM CGP57148B后，直接接种以及2和6周LTC后，剩余bcr/abl阳性集落的比例分别为未处理CML样本的35%、9%和25%。10μM CGP57148B的相应值分别为10%、11%和19%。正常祖细胞长期暴露于CGP57148B后的存活率分别为98%、100%和93%（1μM）或77%、86%和80%（10μM）。
结论
结果支持将CGP57148B用于体外短期暴露（例如净化）或用于CML的体内持续治疗。
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