Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts
Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino)ethyl]amino]geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts
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DOI：
10.1007/s00280-004-0865-3
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发表时间：
2005-01-01
影响因子：
3
通讯作者：
Egorin, MJ
中科院分区：
文献类型：
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作者：
Eiseman, JL;Lan, J;Egorin, MJ
目的：17-去甲氧基17-[[（2-二甲基氨基）乙基]氨基]格尔德霉素（17 DMAG，NSC 707545）是17-（烯丙基氨基）-17-去甲氧基格尔德霉素（17 AAG）的水溶性类似物，目前该化合物处于临床试验中。这些临床前研究：（1）表征静脉内递送至小鼠后血浆、正常组织和肿瘤中的17 DMAG浓度;和（2）将肿瘤和正常组织17 DMAG浓度与热休克蛋白90（HSP 90）和选定的HSP 90-伴侣蛋白的改变相关联。方法：17 DMAG 75 mg/kg静脉注射后，在特定时间，用SCID小鼠皮下注射17 DMAG，观察17 DMAG对SCID小鼠免疫功能的影响。杀死MDA-MB-231人乳腺异种移植物，保留血浆和组织。17 DMAG浓度通过HPLC测定。Western blotting法检测组织中Raf-1、热休克蛋白70（HSP 70）和HSP 90的表达。结果：血浆17 DMAG浓度峰值为15.4 ± 1.4 μ g/ ml。血浆17 DMAG浓度对时间曲线下面积为1072 μ g/ml/min，对应于70 ml/kg/min的总体清除率。（118.8 +/- 5.7 mug/g），肾脏（122.9 +/- 10.6 mug/g），心脏（81.3 +/- 8.1 mug/g）和肺（110.6 +/- 25.4 μ g/g）出现在5 - 10分钟，而脾脏中的峰浓度在30 - 45分钟时，17 DMAG（70.6 +/- 9.6 μ g/g）和肿瘤（9.0 +/- 1.0 μ g/g）出现。在48小时时，17 DMAG在肿瘤中可检测到，但在任何正常组织中均不可检测到。在4、7、24和48 h处死的17只经DMF处理的小鼠的肿瘤中，Raf-1比经溶剂处理的小鼠的肿瘤中的Raf-1低约20%。17只动物肿瘤中的HSP 90和HSP 70在4、7和24 h均显著低于对照动物肿瘤中的HSP 90和HSP 70。在17 DMAG处理后，肝脏Raf-1在所有时间均降低超过60%;然而，肝脏HSP 90不受影响。HSP 70在溶剂处理的小鼠或17 DMAG处理后2或4 h处死的小鼠的肝脏中检测不到，但在7、24和48 h的肝脏中检测到。17 DMAG对肾脏Raf-1无影响。相反，肾HSP 70和HSP 90在17 DMAG处理后2和4 h下降超过50%。肾脏HSP 70增加约两倍以上，在肾脏溶剂处理的对照组小鼠在7和24小时，而HSP 90相对蛋白浓度与对照组没有什么不同。结论：17 DMAG在荷瘤小鼠中的血浆药代动力学与先前报道的在非荷瘤小鼠中的相似。17 DMAG在肿瘤组织中分布广泛，但在肿瘤组织中的滞留时间较正常组织长。在17只动物的肿瘤、肝脏和肾脏中，Raf-1、HSP 90和HSP 70均发生了不同程度的改变。这些数据说明了对17 DMAG的生物反应的复杂性。
Purpose: 17-demethoxy 17-[[(2-dimethylamino) ethyl] amino] geldanamycin (17DMAG, NSC 707545) is a water-soluble analogue of 17-( allylamino)-17-demethoxygeldanamycin (17AAG), a compound currently in clinical trials. These preclinical studies: ( 1) characterized 17DMAG concentrations in plasma, normal tissues, and tumor after i.v. delivery to mice; and ( 2) correlated tumor and normal tissue 17DMAG concentrations with alterations in heat shock protein 90 (HSP90) and selected HSP90-chaperoned proteins. Methods: At specified times after i.v. administration of 75 mg/kg 17DMAG, SCID mice bearing s.c. MDA-MB-231 human breast xenografts were killed and plasma and tissues were retained. 17DMAG concentrations were determined by HPLC. Raf-1, heat shock protein 70 (HSP70), and HSP90 in tissues were determined by Western blotting. Results: Peak plasma 17DMAG concentration was 15.4 +/- 1.4 mug/ ml. The area under the plasma 17DMAG concentration versus time curve was 1072 mug/ml min, corresponding to a total body clearance of 70 ml/kg/min. Peak 17DMAG concentrations in liver (118.8 +/- 5.7 mug/g), kidney (122.9 +/- 10.6 mug/g), heart (81.3 +/- 8.1 mug/g), and lung (110.6 +/- 25.4 mug/g) occurred at 5 - 10 min, while peak concentrations in spleen (70.6 +/- 9.6 mug/g) and tumor (9.0 +/- 1.0 mug/g) occurred at 30 - 45 min. At 48 h, 17DMAG was detectable in tumor but not in any normal tissue. Raf-1 in tumors of 17DMAG-treated mice killed at 4, 7, 24 and 48 h was about 20% lower than in tumors from vehicle-treated mice. HSP90 and HSP70 in tumors of 17DMAG-treated animals were significantly lower than in tumors of control animals at 4, 7, and 24 h. Hepatic Raf-1 was decreased by more than 60% at all times after 17DMAG treatment; however, hepatic HSP90 was not affected. HSP70 was undetectable in livers of vehicle-treated mice or mice killed at 2 or 4 h after 17DMAG treatment, but was detected in livers at 7, 24 and 48 h. 17DMAG did not affect renal Raf-1. In contrast, renal HSP70 and HSP90 were decreased by more than 50% at 2 and 4 h after 17DMAG treatment. Renal HSP70 increased approximately twofold above that in kidneys from vehicle-treated control mice at 7 and 24 h, while HSP90 relative protein concentration was no different from that in controls. Conclusions: Plasma pharmacokinetics of 17DMAG in tumor-bearing mice were similar to those previously reported in nontumor-bearing mice. 17DMAG was distributed widely to tissues but was retained for longer in tumors than normal tissues. Raf-1, HSP90, and HSP70 were altered to different degrees in tumors, livers, and kidneys of 17DMAG-treated animals. These data illustrate the complex nature of the biological responses to 17DMAG.