Abrogation of the Cell Death Response to Oxidative Stress by the c-Abl Tyrosine Kinase Inhibitor STI571

2003 ◽  
Vol 63 (2) ◽  
pp. 276-282 ◽  
Author(s):  
Shailendra Kumar ◽  
Neerad Mishra ◽  
Deepak Raina ◽  
Satya Saxena ◽  
Donald Kufe
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Abl Tyrosine Kinase ◽  
Cell Death Response ◽  
Abl Tyrosine Kinase Inhibitor

Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl–positive cells

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3195-3199 ◽  
Author(s):  
J. Tyler Thiesing ◽  
Sayuri Ohno-Jones ◽  
Kathryn S. Kolibaba ◽  
Brian J. Druker
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor

Abstract Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

scholarly journals Phase I Study of Bosutinib, a Src/Abl Tyrosine Kinase Inhibitor, Administered to Patients with Advanced Solid Tumors

2011 ◽  
Vol 18 (4) ◽  
pp. 1092-1100 ◽  
Author(s):  
Adil I. Daud ◽  
Smitha S. Krishnamurthi ◽  
Mansoor N. Saleh ◽  
Barbara J. Gitlitz ◽  
Mitesh J. Borad ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitor ◽  
Solid Tumors ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Advanced Solid Tumors ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor

scholarly journals Renovascular hypertension from the BCR‐ABL tyrosine kinase inhibitor ponatinib

2020 ◽  
Vol 22 (4) ◽  
pp. 678-682 ◽  
Author(s):  
Syed O. Amin ◽  
Marcel Ruzicka ◽  
Kevin D. Burns ◽  
Isabelle A. Bence‐Bruckler ◽  
Stephen E. Ryan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Renovascular Hypertension ◽  
Kinase Inhibitor ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor

Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance

Blood ◽  
2007 ◽  
Vol 110 (10) ◽  
pp. 3540-3546 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Francis Giles ◽  
Norbert Gattermann ◽  
Kapil Bhalla ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Philadelphia Chromosome Positive

Abstract Nilotinib, an orally bioavailable, selective Bcr-Abl tyrosine kinase inhibitor, is 30-fold more potent than imatinib in pre-clinical models, and overcomes most imatinib resistant BCR-ABL mutations. In this phase 2 open-label study, 400 mg nilotinib was administered orally twice daily to 280 patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP) after imatinib failure or intolerance. Patients had at least 6 months of follow-up and were evaluated for hematologic and cytogenetic responses, as well as for safety and overall survival. At 6 months, the rate of major cytogenetic response (Ph ≤ 35%) was 48%: complete (Ph = 0%) in 31%, and partial (Ph = 1%-35%) in 16%. The estimated survival at 12 months was 95%. Nilotinib was effective in patients harboring BCR-ABL mutations associated with imatinib resistance (except T315I), and also in patients with a resistance mechanism independent of BCR-ABL mutations. Adverse events were mostly mild to moderate, and there was minimal cross-intolerance with imatinib. Grades 3 to 4 neutropenia and thrombocytopenia were observed in 29% of patients; pleural or pericardial effusions were observed in 1% (none were severe). In summary, nilotinib is highly active and safe in patients with CML-CP after imatinib failure or intolerance. This clinical trial is registered at http://clinicaltrials.gov as ID no. NCT00109707.

scholarly journals Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 1834-1839 ◽  
Author(s):  
Philipp le Coutre ◽  
Oliver G. Ottmann ◽  
Francis Giles ◽  
Dong-Wook Kim ◽  
Jorge Cortes ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Abl Tyrosine Kinase ◽  
Imatinib Resistant ◽  
Abl Tyrosine Kinase Inhibitor ◽  
Grade 3

Patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia (CML-AP) have very limited therapeutic options. Nilotinib is a highly selective BCR-ABL tyrosine kinase inhibitor. This phase 2 trial was designed to characterize the efficacy and safety of nilotinib (400 mg twice daily) in this patient population with hematologic response (HR) as primary efficacy endpoint. A total of 119 patients were enrolled and had a median duration of treatment of 202 days (range, 2–611 days). An HR was observed in 56 patients (47%; 95% confidence interval [CI], 38%-56%). Major cytogenetic response (MCyR) was observed in 35 patients (29%; 95% CI, 21%-39%). The median duration of HR has not been reached. Overall survival rate among the 119 patients after 12 months of follow-up was 79% (95% CI, 70%-87%). Nonhematologic adverse events were mostly mild to moderate. Severe peripheral edema and pleural effusions were not observed. The most common grade 3 or higher hematologic adverse events were thrombocytopenia (35%) and neutropenia (21%). Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients, respectively, resulting in treatment discontinuation in one patient. In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP. This trial is registered at www.clinicaltrials.gov as NCT00384228.

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