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Richard E. Kast*,1 and Daniele Focosi,1 *Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA; †Division of Hematology,University of Pisa, 56126 Pisa, Italy Treating Chronic MyelogenousLeukemia and Glioblastomawith Imatinib Chronic myelogenous leukemia (CML) can be controlled for years with the tyrosine kinase inhibitor imatinib but be- cause 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 glio- blastoma 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 totreat 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 non- scheduled 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 addi- tive. In addition, dasatinib crosses the BBB poorly, and it can therefore be expected to benefit from methamphetamine- Translational Oncology (2010) 3, 1315 foundly suppressed by imatinib yet the neoplasm reappears in the “The battle is fought and decided by the quartermasters before the CNS. This is understandable because the cerebrospinal fluid (CSF) con-shooting begins,” said Erwin Rommel, Nazi general who won many centration of imatinib is less than 3% that of plasma in patients [1,3– smaller battles against much superior forces but ultimately lost all his 5] and mice [6]. The retention of a malignant CML clone protected bigger battles by his opponents’ superior quartermasters. The quarter- from exposure to imatinib behind the BBB, growing and evolving most master corps supplies the tools and equipment of war to the combat dangerously even in the systemic presence of a safe and potent drug troops—ammunition, food, fuel, transport, and weapons.
that would otherwise suppress it, parallels our predicament in glioblas-toma where the cells start and finish their life course behind the BBB.
IntroductionIsobe et al. [1] showed the consequences of chronic myelogenous leu-kemia (CML) of imatinib’s poor penetration of the blood-brain barrier Address all correspondence to: Richard E. Kast, MD, Assistant Professor, Department of (BBB). They reported a patient with CML with blast crisis limited to Psychiatry, University of Vermont, 22 Church St, Burlington, VT 05401.
E-mail: [email protected] the central nervous system (CNS) compartment reminiscent of simi- 1Both authors contributed equally to this work.
lar reports of CNS blast crisis occurring in otherwise well-treated patients Received 21 September 2009; Revised 28 September 2009; Accepted 2 October 2009 on imatinib [2] or the situation seen occasionally in acute lymphoblastic Copyright 2010 Neoplasia Press, Inc. All rights reserved 1944-7124/10/$25.00 leukemia [3] where the systemic malignant clone seems absent or pro- Translational Oncology Vol. 3, No. 1, 2010 Therefore, prognosis remains unusually poor. We require a better We also have indirect evidence that abuse of street methamphetamine quartermaster corps than we now have to win that big battle, too.
leads to BBB opening. Street methamphetamine users have a higher The recent article by Isobe et al. [1] points out the problem in the incidence of hepatitis C encephalitis than hepatitis C virus–infected context of CML that glioblastoma researchers have been wrestling nonusers [34] and higher CNS human immunodeficiency virus titer with for decades [5,7–9]. In this short note, the rationale is discussed [35] indicating loss of BBB integrity.
for using two currently marketed drugs with significant potential toopen the BBB allowing better entry of tyrosine kinases (TKs) and therefore more effective treatment of both CML with CNS involve- The monoamine oxidase inhibitor selegiline is approved, marketed, and used in many countries for treatment of depression (at higher doses) andParkinson disease (at low doses). Relevant here is that selegiline’s primary metabolite is methamphetamine [36–38]. Clinically significant amounts Imatinib has shown good potential for antiglioblastoma activity [10–15], of methamphetamine are circulating in patients currently treated with but the problem, as for the patient of Isobe et al., has always been how to selegiline [37,38]. Is that level enough to decrease BBB integrity? This get adequate imatinib levels across the BBB to the malignant tissue [5,7,8].
matter requires urgent study. If selegiline-derived methamphetamine is Flow cytometry and immunohistochemistry show ample glioblas- disrupting BBB to any significant degree, then selegiline use must stop toma expression of TK targets [16–18], particularly so in the stem cell for all indications except potentially that of opening the BBB to allow subpopulation [16–18], which should be susceptible to inhibition by more effective chemotherapy for CNS-resident malignancies. Because imatinib if we could get the drug in adequate amounts across the BBB it is probable that selegiline catabolism to methamphetamine is primar- to the far-flung paucicellular extensions that remain after primary surgi- ily mediated by P450 2B6 [33], inducers of 2B6 such as pentobarbital, cal resection. In vitro imatinib activity is good with growth arrest at 1 to phenobarbital, or rifampin may enhance this process.
10 μM and cytotoxicity at 20 μM against glioblastoma cell lines [18].
It may be parenthetically noted here that pentobarbital, a drug available Although glioblastoma are commonly said to have leaky BBBs, this worldwide since the 1950s, showed in vitro evidence of antiglioblastoma is true only for the main tumor mass and then only parts of it. The far- effects seemingly independent of any selegiline exposure [39].
flung microscopic extensions have intact BBBs [7,8].
Selegiline and methamphetamine are both chiral molecules and, The TK’s activities in malignancy promotion in glioblastoma [19– as such, have a complicated pharmacology. Dextro and levo enan- 21] are less clear, less well identified than the TK’s overactivity in CML tiomers have different pharmacological attributes. If both or only one [22–24], but Src overactivity is one of them. Dasatinib is a good in- methamphetamine enantiomer opens, the BBB is unknown.
hibitor of the specific TK BCR-ABL of CML, is clinically effectivein CML [25–27], and is a much more potent inhibitor of Src than is In principle, dasatinib should be additive to some degree with imatinibon three accounts: Opening the BBBHaving free access to CSF and glioblastoma tissue and the normal Although they are both called TKs, dasatinib and imatinib work brain tissue surrounding the fine, microscopic extensions will greatly by different and independent mechanisms. Imatinib binds to the advance our ability to treat both CML and glioblastoma.
ATP binding site of susceptible TKs, preventing required dona- Although only documented in rodents, methamphetamine has the tion of the high-energy phosphate. Dasatinib binds to tyrosine- unusual attribute of massively disrupting the BBB for several hours containing peptide’s recognition site on TK, preventing target (reviewed in Kast [30,31]). First synthesized in Japan in 1893, and al- peptide binding and any consequent tyrosine phosphorylation.
though a common current drug of abuse [32,33], methamphetamine Dasatinib also penetrates the BBB poorly, achieving about a tenth is a registered and marketed pharmaceutical drug in the USA and of the CSF concentration compared with that of plasma [25] elsewhere (Desoxyn, Ovation Pharmaceuticals, recently purchased by and may well benefit from methamphetamine-assisted CNS entry Lundbeck Pharmaceuticals) and approved to treat attention-deficit pro- blems in people older than 12 years (full prescribing information at If methamphetamine indeed can provide us with free daily access It is also to the brain tissue, then Src dephosphorylation (deactivation) be- approved for weight loss in women in the United States. Clinical ex- comes possible, too [31], to augment Src inhibition by dasatinib.
perience suggests that it does not work for weight loss but does work The arrays of different TKs that are inhibited by each are different.
well for relieving attention or concentration problems. For obvious rea- Although this may not be as important for CML where there is one sons, it should not be used for either indication.
prominent TK, the BCR-ABL TK, it seems that there are several Patients report feeling no different on pharmaceutically prescribed overactive TKs in glioblastoma and multiple paths to activating methamphetamine than they do on the more commonly used methyl- each, so a net casted more broadly would be potentially useful.
phenidate (Ritalin, Concerta, and other brand names) or dexamphetamine We have several preclinical experimental indicators that dasatinib- (dextroamphetamine, Adderal, and other brand names).
inhibited TKs are important in glioblastoma growth, prominent Pharmaceutical methamphetamine has a circulating half-life of 9 to among them is Src [19,20,25]. Src can and does activate epidermal 15 hours, Cmax of 1 hour, and a US Food and Drug Administration– growth factor receptor in the absence of the epidermal growth fac- approved maximum daily dose of 25 mg. Metabolism is hepatic; ex- tor [31], and this transactivation is an important element-enhancing growth in more than half of the glioblastomas [40].
Given that rodent studies show that 64-kDa albumin can leak after Because the two have different mechanisms by which they inhibit methamphetamine treatment, we might expect imatinib, 494 Da, to TK, dasatinib/imatinib cross-resistance would be expected to de- Translational Oncology Vol. 3, No. 1, 2010 It is currently unknown if there would be steric hindrance at any tyrosine kinase inhibitor imatinib on glioblastoma cell proliferation. J Neurooncol; given TK between dasatinib and imatinib.
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