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, 13–15
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 . 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.  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  or the situation seen occasionally in acute lymphoblastic
Copyright 2010 Neoplasia Press, Inc. All rights reserved 1944-7124/10/$25.00
leukemia  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.  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  and higher CNS human immunodeficiency virus titer
with for decades [5,7–9]. In this short note, the rationale is discussed
 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 , 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 .
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 .
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 
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
http://www.lundbeckinc.com/USA/products/CNS/desoxyn). 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 , 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 , and this transactivation is an important element-enhancing
growth in more than half of the glioblastomas .
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.
 de Groot J and Milano V (2009). Improving the prognosis for patients with
glioblastoma: the rationale for targeting Src. J Neurooncol 95 (2), 151–163.
 Du J, Bernasconi P, Clauser KR, Mani DR, Finn SP, Beroukhim R, Burns M,
Given glioblastoma’s reliably fatal outcome within several years of diag-
Julian B, Peng XP, Hieronymus H, et al. (2009). Bead-based profiling of tyrosine
nosis, and that 1 year after diagnosis, half of all patients are dead, BBB
kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy.
opening to allow higher imatinib brain tissue levels in addition to cur-
 Milano V, Piao Y, LaFortune T, and de Groot J (2009). Dasatinib-induced autophagy is
rent treatments might be rewarding. After CNS relapse, CML patients
enhanced in combination with temozolomide in glioma. Mol Cancer Ther 8, 394–406.
may likewise benefit from methamphetamine-assisted opening of the
 Giles FJ, O’Dwyer M, and Swords R (2009). Class effects of tyrosine kinase inhibitors
BBB to allow better TK inhibition and more effective treatment.
in the treatment of chronic myeloid leukemia. Leukemia 23 (10), 1698–1707.
 Srinivasan D, Kaetzel DM, and Plattner R (2009). Reciprocal regulation of Abl
and receptor tyrosine kinases. Cell Signal 21 (7), 1143–1150.
 Jabbour E and Soverini S (2009). Understanding the role of mutations in therapeutic
The authors have no conflict of interest or industry affiliations.
decision making for chronic myeloid leukemia. Semin Hematol 46 (2 Suppl 3),S22–S26.
 Porkka K, Koskenvesa P, Lundán T, Rimpiläinen J, Mustjoki S, Smykla R, Wild R,
 Isobe Y, Sugimoto K, Masuda A, Hamano Y, and Oshimi K (2009). Central
Lou R, Arnan M, Brethon B, et al. (2008). Dasatinib crosses the blood-brain barrier
nervous system is a sanctuary site for chronic myelogenous leukaemia treated
and is an efficient therapy for central nervous system Philadelphia chromosome–
with imatinib mesylate. Intern Med J 39, 408–411.
positive leukemia. Blood 112, 1005–1012.
 Altintas A, Cil T, Kilinc I, Kaplan MA, and Ayyildiz O (2007). Central nervous
 Apperley JF, Cortes JE, Kim DW, Roy L, Roboz GJ, Rosti G, Bullorsky EO,
system blastic crisis in chronic myeloid leukemia on imatinib mesylate therapy: a
Abruzzese E, Hochhaus A, Heim D, et al. (2009). Dasatinib in the treatment of
case report. J Neurooncol 84, 103–105.
chronic myeloid leukemia in accelerated phase after imatinib failure: the START
 Takayama N, Sato N, O’Brien SG, Ikeda Y, and Okamoto S (2002). Imatinib
a trial. J Clin Oncol 27 (21), 3472–3479.
mesylate has limited activity against the central nervous system involvement of
 Hochhaus A, Müller MC, Radich J, Branford S, Kantarjian HM, Hanfstein B,
Philadelphia chromosome–positive acute lymphoblastic leukaemia due to poor
Rousselot P, Kim DW, Lipton JH, Bleickardt E, et al. (2009). Dasatinib-associated
penetration into cerebrospinal fluid. Br J Haematol 119, 106–108.
major molecular responses in patients with chronic myeloid leukemia in chronic
 le Coutre P, Kreuzer KA, Pursche S, Bonin M, Leopold T, Baskaynak G, Dörken B,
phase following imatinib failure: response dynamics and predictive value. Leukemia
Ehninger G, Ottmann O, Jenke A, et al. (2004). Pharmacokinetics and cellular up-
take of imatinib and its main metabolite CGP74588. Cancer Chemother Pharmacol
 Guerrouahen BS, Wieder E, Blanchard EG, Lee FY, Aplenc R, and Corey SJ
(2009). Flow cytometric determination of Src phosphorylation in pediatric patients
 Senior K (2003). Gleevec does not cross blood-brain barrier. Lancet Oncol 4, 198.
treated with dasatinib. Pediatr Blood Cancer 53 (6), 1132–1135.
 Bihorel S, Camenisch G, Lemaire M, and Scherrmann JM (2007). Modulation
 Dumont RA, Hildebrandt I, Su H, Haubner R, Reischl G, Czernin JG, Mischel PS,
of the brain distribution of imatinib and its metabolites in mice by valspodar,
and Weber WA (2009). Noninvasive imaging of αVβ3 function as a predictor of the
zosuquidar and elacridar. Pharm Res 24, 1720–1728.
antimigratory and antiproliferative effects of dasatinib. Cancer Res 69, 3173–3179.
 Salgaller ML and Liau LM (2006). Current status of clinical trials for glioblastoma.
 Kast RE (2007). Using blood brain barrier disruption by methamphetamine for
Rev Recent Clin Trials 1, 265–281.
drug delivery. J Neurooncol 85, 109–110.
 Hargrave D (2009). Paediatric high and low grade glioma: the impact of tumour
 Kast RE (2009). Use of FDA approved methamphetamine to allow adjunctive
biology on current and future therapy. Br J Neurosurg 23, 351–363.
use of methylnaltrexone to mediate core anti–growth factor signaling effects in
 Bellavance MA, Blanchette M, and Fortin D (2008). Recent advances in blood-
glioblastoma. J Neurooncol 94 (2), 163–167.
brain barrier disruption as a CNS delivery strategy. AAPS J 10, 166–177.
 Sheridan J, Butler R, and Wheeler A (2009). Initiation into methamphetamine
 Reardon DA, Egorin MJ, Desjardins A, Vredenburgh JJ, Beumer JH, Lagattuta TF,
use: qualitative findings from an exploration of first time use among a group of
Gururangan S, Herndon JE II, Salvado AJ, and Friedman HS (2009). Phase I
New Zealand users. J Psychoactive Drugs 41, 11–17.
pharmacokinetic study of the vascular endothelial growth factor receptor tyrosine
 Cruickshank CC and Dyer KR (2009). A review of the clinical pharmacology of
kinase inhibitor vatalanib (PTK787) plus imatinib and hydroxyurea for malignant
methamphetamine. Addiction 104, 1085–1099.
 Letendre S, Paulino AD, Rockenstein E, Adame A, Crews L, Cherner M, Heaton R,
 Benny O, Menon LG, Ariel G, Goren E, Kim SK, Stewman C, Black PM,
Ellis R, Everall IP, Grant I, et al. (2007). Pathogenesis of hepatitis C virus co-
Carroll RS, and Machluf M (2009). Local delivery of poly lactic-co-glycolic acid
infection in the brains of patients infected with HIV. J Infect Dis 196, 361–370.
microspheres containing imatinib mesylate inhibits intracranial xenograft glioma
 Nath A, Maragos WF, Avison MJ, Schmitt FA, and Berger JR (2001). Acceleration
growth. Clin Cancer Res 15 (4), 1222–1231.
of HIV dementia with methamphetamine and cocaine. J Neurovirol 7, 66–71.
 Gal H, Pandi G, Kanner AA, Ram Z, Lithwick-Yanai G, Amariglio N, Rechavi G,
 Magyar K, Szatmáry I, Szebeni G, and Lengyel J (2007). Pharmacokinetic studies
and Givol D (2008). MIR-451 and imatinib mesylate inhibit tumor growth of
of (−)-deprenyl and some of its metabolites in mouse. J Neural Transm Suppl 72,
glioblastoma stem cells. Biochem Biophys Res Commun 376, 86–90.
 Bilir A, Erguven M, Oktem G, Ozdemir A, Uslu A, Aktas E, and Bonavida B
 Nishida K, Itoh S, Inoue N, Kudo K, and Ikeda N (2006). High-performance liq-
(2008). Potentiation of cytotoxicity by combination of imatinib and chlorimipra-
uid chromatographic–mass spectrometric determination of methamphetamine and
mine in glioma. Int J Oncol 32, 829–839.
amphetamine enantiomers, desmethylselegiline and selegiline, in hair samples of
 Shah GD, Silver JS, Rosenfeld SS, Gavrilovic IT, Abrey LE, and Lassman AB
long-term methamphetamine abusers or selegiline users. J Anal Toxicol 30, 232–237.
(2007). Myelosuppression in patients benefiting from imatinib with hydroxyurea
 Kronstrand R, Ahlner J, Dizdar N, and Larson G (2003). Quantitative analysis of
for recurrent malignant gliomas. J Neurooncol 85, 217–222.
desmethylselegiline, methamphetamine, and amphetamine in hair and plasma from
 Gal H, Makovitzki A, Amariglio N, Rechavi G, Ram Z, and Givol D (2007). A
Parkinson patients on long-term selegiline medication. J Anal Toxicol 27, 135–141.
rapid assay for drug sensitivity of glioblastoma stem cells. Biochem Biophys Res
 Xie J, Li Y, Huang Y, Qiu P, Shu M, Zhu W, Ou Y, and Yan G (2009). Anesthetic
pentobarbital inhibits proliferation and migration of malignant glioma cells. Cancer
 Torp SH, Gulati S, Johannessen E, and Dalen A (2007). Coexpression of c-erbB
1-4 receptor proteins in human glioblastomas. An immunohistochemical study.
 Lopez-Gines C, Gil-Benso R, Benito R, Mata M, Pereda J, Sastre J, Roldan P,
J Exp Clin Cancer Res 26, 353–359.
Gonzalez-Darder J, and Cerdá-Nicolás M (2008). The activation of ERK1/2
 Balik V, Mirossay P, Bohus P, Sulla I, Mirossay L, and Sarissky M (2009). Flow cytom-
MAP kinases in glioblastoma pathobiology and its relationship with EGFR ampli-
etry analysis of neural differentiation markers expression in human glioblastomas
fication. Neuropathology 28, 507–515.
may predict their response to chemotherapy. Cell Mol Neurobiol 29 (6–7), 845–858.
 Giles FJ (2009). New directions in the treatment of imatinib failure and/or re-
 Ranza E, Mazzini G, Facoetti A, and Nano R (2009). In-vitro effects of the
sistance. Semin Hematol 46 (2 Suppl 3), S27–S33.
Care after stroke or transient ischaemic attack Information for patients and their carers This booklet is based on the National Clinical Guideline for Stroke , third edition, which includes the National Institute for Health andClinical Excellence recommendations for management of acute stroke Contents Who the booklet is for and what it covers Principles of care for people w
THE KETTLE FRIENDSHIP SOCIETY Casual Employees Great-West Life is a leading Canadian life and health insurer. Great- West Life's financial security advisors work with our clients from coast to coast to help them secure their financial future. We provide a wide range of retirement savings and income plans; as well as life, disability and critical illness insurance for individuals and