Wolff Nicholas C, Richardson James A, Egorin Merrill, Ilaria Robert L
Division of Hematology/Oncology, Department of Medicine, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas 75390, USA.
Blood. 2003 Jun 15;101(12):5010-3. doi: 10.1182/blood-2002-10-3059. Epub 2003 Feb 20.
The chronic myelogenous leukemia (CML)-like myeloproliferative disorder observed in the BCR/ABL murine bone marrow transduction and transplantation model shares several features with the human disease, including a high response rate to the tyrosine kinase inhibitor imatinib mesylate (STI571). To study the impact of chronic imatinib mesylate treatment on the CML-like illness, mice were maintained on therapeutic doses of this drug and serially monitored. Unexpectedly, despite excellent systemic control of the CML-like illness, many of the mice developed progressive neurologic deficits after 2 to 4 months of imatinib mesylate therapy because of central nervous system (CNS) leukemia. Analysis of imatinib mesylate cerebral spinal fluid concentrations revealed levels 155- fold lower than in plasma. Thus, in the mouse, the limited ability of imatinib mesylate to cross the blood-brain barrier allowed the CNS to become a sanctuary for Bcr/Abl-induced leukemia. This model will be a useful tool for the future study of novel anti-CML drugs and in better defining the mechanisms for limited imatinib mesylate penetration into the CNS.
在BCR/ABL小鼠骨髓转导和移植模型中观察到的慢性粒细胞白血病（CML）样骨髓增殖性疾病与人类疾病有几个共同特征，包括对酪氨酸激酶抑制剂甲磺酸伊马替尼（STI571）的高反应率。为了研究甲磺酸伊马替尼长期治疗对CML样疾病的影响，给小鼠维持该药物的治疗剂量并进行连续监测。出乎意料的是，尽管甲磺酸伊马替尼对CML样疾病有出色的全身控制效果，但许多小鼠在接受甲磺酸伊马替尼治疗2至4个月后，由于中枢神经系统（CNS）白血病而出现进行性神经功能缺损。对甲磺酸伊马替尼脑脊液浓度的分析显示，其水平比血浆中低155倍。因此，在小鼠中，甲磺酸伊马替尼穿过血脑屏障的能力有限，使得中枢神经系统成为Bcr/Abl诱导的白血病的庇护所。该模型将成为未来研究新型抗CML药物以及更好地确定甲磺酸伊马替尼进入中枢神经系统能力有限的机制的有用工具。
