Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA.
Transl Oncol. 2010 Feb;3(1):13-5. doi: 10.1593/tlo.09280.
Chronic myelogenous leukemia (CML) can be controlled for years with the tyrosine kinase inhibitor imatinib but because imatinib poorly penetrates the blood-brain barrier (BBB), on occasion, the CML clone will thrive and evolve to an accelerated phase in the resulting imatinib sanctuary within the central nervous system. In this, CML resembles glioblastoma in that imatinib, which otherwise may be effective, cannot get to the tumor. Although a common street drug of abuse, methamphetamine is Food and Drug Administration-approved and marketed as a pharmaceutical drug to treat attention-deficit disorders. It has shown the ability to open the BBB in rodents. We have some clinical hints that it may do so in humans as well. This short note presents three new points potentially leading to better tyrosine kinase inhibition behind the BBB: 1) Pharmaceutical methamphetamine may have a useful role in treating both CML and glioblastoma by allowing higher imatinib concentrations behind the BBB. 2) The old antidepressant and monoamine oxidase inhibitor selegiline, used to treat Parkinson disease, is catabolized to methamphetamine. Selegiline, as a nonscheduled drug,may therefore be an easier way to open the BBB, allowing more effective chemotherapy with tyrosine kinases. 3) Dasatinib is a tyrosine kinase inhibitor with a spectrum of inhibition only partially overlapping that of imatinib and a mechanism of tyrosine kinase inhibition that is different from that of imatinib. The two should be additive. In addition, dasatinib crosses the BBB poorly, and it can therefore be expected to benefit from methamphetamine-assisted entry.
慢性髓性白血病（CML）可以通过酪氨酸激酶抑制剂伊马替尼控制多年，但由于伊马替尼很难穿透血脑屏障（BBB），有时 CML 克隆会在中枢神经系统内的伊马替尼庇护所中茁壮成长并演变为加速期。在这方面，CML 与胶质母细胞瘤相似，即伊马替尼可能有效，但无法到达肿瘤。虽然冰毒是一种常见的街头滥用药物，但它已获得美国食品和药物管理局的批准，并作为一种治疗注意力缺陷障碍的药物上市。它已显示出在啮齿动物中打开 BBB 的能力。我们有一些临床线索表明它也可能在人类中这样做。这篇简短的笔记提出了三个新观点，可能会在 BBB 后面更好地抑制酪氨酸激酶：1）药用冰毒可能通过允许更高的伊马替尼浓度在 BBB 后面，在治疗 CML 和胶质母细胞瘤方面具有有用的作用。2）用于治疗帕金森病的旧抗抑郁药和单胺氧化酶抑制剂司来吉兰会代谢为冰毒。因此，司来吉兰作为一种非规定药物，可能是打开 BBB 的一种更容易的方法，允许用酪氨酸激酶进行更有效的化疗。3）达沙替尼是一种酪氨酸激酶抑制剂，其抑制谱与伊马替尼部分重叠，抑制酪氨酸激酶的机制与伊马替尼不同。两者应该是相加的。此外，达沙替尼很难穿透 BBB，因此可以预期它将受益于冰毒辅助进入。
