Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome‐positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid

Takayama, Nobuki; Sato, Norihide; O’Brien, Stephen G.; Ikeda, Yasuo; Okamoto, Shin

doi:10.1046/j.1365-2141.2002.03881.x

Cited by 136 publications

(106 citation statements)

References 8 publications

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“…Contrary to these findings, we found subchronic administration of imatinib in rats had no effect on the level of A␤40 in plasma despite achieving a plasma exposure in excess of the cellular IC 50 . Consistent with published findings (29), administration of imatinib resulted in a low exposure in the brain that was far below the cellular IC 50 to have a pharmacodynamic effect on brain A␤. Our findings clearly demonstrate that imatinib has no effect on A␤ levels in vivo and these findings coupled with its poor brain penetration demonstrate that imatinib is of limited therapeutic value for the treatment of AD.…”

Section: Discussionsupporting

confidence: 88%

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Hussain

Fabrègue

Anderes

et al. 2013

Journal of Biological Chemistry

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Background: ␥-Secretase activating protein, GSAP, was identified as a novel regulator of ␥-secretase and amyloid-␤ production. Results: Reducing GSAP expression in cells decreased amyloid-␤ generation. However, overexpression of GSAP in cells and recombinant GSAP in vitro did not modulate amyloid-␤ generation. Conclusion:The relationship between GSAP and ␥-secretase is unclear. Significance: GSAP is not a validated therapeutic target for Alzheimer disease.

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Section: Discussionsupporting

confidence: 88%

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Hussain

Fabrègue

Anderes

et al. 2013

Journal of Biological Chemistry

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“…The increased rates of CNS metastases in this series may be explained by the limited penetration of small molecule kinase inhibitors into the brain, as documented in other imatinibsensitive malignancies such as chronic myeloid leukaemia, Philadelphia chromosome-positive acute lymphocytic leukaemia and GIST in which relapse within the CNS has been reported (Takayama et al, 2002;Hughes et al, 2004;Altintas et al, 2007). This is likely to represent a significant clinical problem as the brain is a frequent site of relapse in melanoma.…”

Section: Discussionmentioning

confidence: 71%

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

et al. 2010

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BACKGROUND: Mutations in KIT are more frequent in specific melanoma subtypes, and response to KIT inhibition is likely to depend on the identified mutation. METHODS: A total of 32 patients with metastatic acral or mucosal melanoma were screened for mutations in KIT exons 11, 13 and 17. RESULTS: KIT mutations were found in 38% of mucosal and in 6% of acral melanomas. Three patients were treated with imatinib and one with sorafenib. All four patients responded to treatment, but three have since progressed within the brain. CONCLUSIONS: The observed clinical responses support further investigation of KIT inhibitors in metastatic melanoma, selected according to KIT mutation status.

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“…Gleevec does not accumulate in brain at therapeutic concentrations, owing to its rapid efflux from the brain by the p-glycoprotein and other efflux pumps that form the blood-brain barrier (20)(21)(22). We tested i.p.…”

Section: Resultsmentioning

confidence: 99%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.Alzheimer's disease | Gleevec | nonamyloidogenic | β-cleavage

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Imatinib mesylate has limited activity against the central nervous system involvement of Philadelphia chromosome‐positive acute lymphoblastic leukaemia due to poor penetration into cerebrospinal fluid

Cited by 136 publications

References 8 publications

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

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