scholarly journals Three Paths to Better Tyrosine Kinase Inhibition Behind the Blood-Brain Barrier in Treating Chronic Myelogenous Leukemia and Glioblastoma with Imatinib

2010 ◽  
Vol 3 (1) ◽  
pp. 13-15 ◽  
Author(s):  
Richard E. Kast ◽  
Daniele Focosi
Keyword(s):  
Tyrosine Kinase ◽  
Blood Brain Barrier ◽  
Chronic Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Brain Barrier ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition ◽  
Blood Brain

A Population (Registry) Based Analysis of the Impact of Bcr-Abl Specific Tyrosine Kinase Inhibition on Survival after Diagnosis of Philadelphia Chromosome Positive Chronic Myelogenous Leukemia..

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3237-3237
Author(s):  
A. Robert Turner ◽  
Joanne D Hewitt ◽  
Anmmd Kamruzzaman ◽  
Loree M. Larratt ◽  
Deborah A. Rusnak ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Alpha Interferon ◽  
Cell Transplant ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition ◽  
The Impact ◽  
Philadelphia Chromosome Positive

Abstract Specific tyrosine kinase inhibition (TKI) of the bcr-abl fusion protein in Philadelphia chromosome positive chronic myelogenous leukemia (CML) was introduced into general use in 2000 after a plenary abstract presentation to ASH in December 1999. Here we report the impact of the use of TKI on survival of all patients with CML in a total population based registry in the province of Alberta in Canada where BMT has been in use since 1980, α interferon +/− cytarabine since 1990 and TKI since 2000. All therapies have been fully funded by the public health care system in Alberta. Alberta’s population in 2000 was 2.97 million. Prior to 2000, allogeneic stem cell transplant (BMT) was the only curative therapy available but its application was limited to a minority of patients with CML. Alpha interferon induced a cytogenetic remission in some CML and alpha interferon plus cytarabine prolonged survival in CML. CML AML n 5 yr survival % BMT n 5 yr survival % BMT *59% of deaths occurred in the first year after diagnosis in the 2000–06 cohort 1980–89 303 40% NA 540 13% NA 1990–99 276 48% 25 692 15% 13 2000–06 216 83%* 8 680 25% 16 p<0.0001 p<0.0001 A 5 year survival for CML (1980–89) of 40% is consistent with published data. The 48% 5 year survival for CML (1990–99) reflects the benefit of interferon. The 5 year survival of acute myelogenous leukemia (AML) in Alberta is provided for comparison to reflect general improvement in care. The proportion of AML patients who had a BMT did not significantly change while there was a significant reduction in numbers of CML transplanted in 2000–06. Transplant status did not significantly affect outcome in CML patients with 75% of non-BMT and 84% of BMT patients still alive at 5 years (p=0.08). In contrast, transplant status was statistically significant in AML, with 5 year survival of 49% in those treated with BMT, compared to 17% of those not transplanted (p<0.0001). The results of this study show that TKI therapy (primarily imatinib) has had a major impact on the outcome of CML treatment in the province of Alberta. Long term survival, >80%, has been achieved and it appears that almost all of these patients can look forward to a normal life expectancy without the need for BMT.

BMS-354825, a Dual SRC/ABL Kinase Inhibitor, Displays Potent Anti-Tumor Activity in a Model of Intracranial CML Growth.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1988-1988 ◽  
Author(s):  
Robert Wild ◽  
Stephen Castaneda ◽  
Christine Flefleh ◽  
Krista Fager ◽  
Ivan Inigo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Blood Brain Barrier ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
High Rate ◽  
Brain Barrier ◽  
Preclinical Model ◽  
Dual Function ◽  
Imatinib Resistance ◽  
Blood Brain

Abstract Chronic myeloid leukemia (CML) is a stem cell disorder caused by a constitutively activated tyrosine kinase, the BCR-ABL oncoprotein. Imatinib (STI571, Gleevec) is a small-molecule inhibitor of this kinase that produces clinical remissions in CML patients and is now frontline therapy for this disease. While this agent has a high rate of clinical success in early phases of CML, development of resistance to this drug is increasingly becoming problematic, particularly in later stages of the disease. Moreover, growing evidence suggests that imatinib has very poor penetration of the blood brain barrier, likely due at least partly to its being a substrate of P-glycoprotin (Pgp), resulting in subtherapeutic levels in the CNS. As a result, several clinical cases have been reported where CNS relapses occurred in imatinib treated CML patients despite peripheral blood and bone marrow complete responses (Leis et al., Leuk Lymphoma. 2004 Apr;45(4):695–8). This phenomenon has also been recapitulated in at least one preclinical model, where the limited ability of imatinib to cross the blood-brain barrier allowed the CNS to become a sanctuary for BCR-ABL-induced leukemia (Wolff et al., Blood. 2003 Jun 15;101(12):5010–3). BMS-354825, a small-molecule dual-function SRC/ABL tyrosine kinase inhibitor, was designed to overcome many of the limitations associated with imatinib therapy. BMS-354825 has more than 500-fold increased potency relative to imatinib versus BCR-ABL and more importantly retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants (Shah et al., Science, 2004 Jul 16;305(5682):399–401). In addition, BMS-354825 proved to be equally effective against several preclinically- and clinically-derived tumor models of imatinib resistance (Lee et al., Proceedings of the AACR, Volume 45, March 2004). In the current study, we assessed the efficacy of BMS-354825, which is not a Pgp substrate, in a model of established intracranial CML tumors. SCID-beige mice bearing K562 CML tumors implanted intracranially (2x106 cells per animal) were treated with BMS-354825 orally b.i.d. for a period of up to 40 days. BMS-354825 proved to be exceptionally efficacious resulting in increased lifespan of animals by 450% and 268% for the 15 mg/kg and 5 mg/kg dose levels, respectively. In order to more directly assess the anti-tumor activities of BMS-354825 in this intracranial CML model, we implanted K562 cells stably transfected with the firefly luciferase gene intracranially into SCID-beige animals. Bioluminescent imaging (BLI) then allowed the non-invasive monitoring of in vivo growth of these tumors. BMS-354825 at 15 mg/kg (2qdx14;6 po) achieved tumor regressions and subsequent complete stasis of intracranial K562 growth while animals were on therapy. In summary, these results suggest that BMS-354825 may have therapeutic advantages over imatinib in the management of intracranial CML disease and warrants further clinical investigation.

The non-receptor tyrosine kinase Lyn is localised in the developing murine blood-brain barrier

1995 ◽  
Vol 59 (1) ◽  
pp. 15-24 ◽  
Author(s):  
Marc G. Achen ◽  
Matthias Clauss ◽  
Harald Schnürch ◽  
Werner Risau
Keyword(s):  
Tyrosine Kinase ◽  
Blood Brain Barrier ◽  
Receptor Tyrosine Kinase ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Brain Metastasis Treatment: The Place of Tyrosine Kinase Inhibitors and How to Facilitate Their Diffusion across the Blood–Brain Barrier

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1446
Author(s):  
Eurydice Angeli ◽  
Guilhem Bousquet
Keyword(s):  
Brain Metastases ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Blood Brain Barrier ◽  
Kinase Inhibitors ◽  
Brain Barrier ◽  
Molecular Alterations ◽  
Blood Brain ◽  
Recent Advances ◽  
Breast Cancer Brain Metastases

The incidence of brain metastases has been increasing constantly for the last 20 years, because of better control of metastases outside the brain, and the failure of most drugs to cross the blood–brain barrier at relevant pharmacological concentrations. Recent advances in the molecular biology of cancer have led to the identification of numerous molecular alterations, some of them targetable with the development of specific targeted therapies, including tyrosine kinase inhibitors. In this narrative review, we set out to describe the state-of-the-art in the use of tyrosine kinase inhibitors for the treatment of melanoma, lung cancer, and breast cancer brain metastases. We also report preclinical and clinical pharmacological data on brain exposure to tyrosine kinase inhibitors after oral administration and describe the most recent advances liable to facilitate their penetration of the blood–brain barrier at relevant concentrations and limit their physiological efflux.

scholarly journals Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

2014 ◽  
Vol 21 (3) ◽  
pp. R247-R259 ◽  
Author(s):  
José O Alemán ◽  
Azeez Farooki ◽  
Monica Girotra
Keyword(s):  
Tyrosine Kinase ◽  
Targeted Therapies ◽  
Mineral Metabolism ◽  
Myelogenous Leukemia ◽  
Cytotoxic Agents ◽  
Imatinib Treatment ◽  
Vegf Inhibitors ◽  
Kinase Inhibition ◽  
Tyrosine Kinase Inhibition ◽  
Oncologic Treatment

Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.

scholarly journals The blood-brain barrier internalisesCryptococcus neoformansvia the EphA2-tyrosine kinase receptor

2018 ◽  
Vol 20 (3) ◽  
pp. e12811 ◽  
Author(s):  
Phylicia A. Aaron ◽  
Mantana Jamklang ◽  
John P. Uhrig ◽  
Angie Gelli
Keyword(s):  
Tyrosine Kinase ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tyrosine Kinase Receptor ◽  
Blood Brain
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