ARG tyrosine kinase activity is inhibited by STI571

Okuda, Keiko; Weisberg, Ellen; Gilliland, D. Gary; Griffin, James D.

doi:10.1182/blood.v97.8.2440

Cited by 234 publications

(142 citation statements)

References 31 publications

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“…Imatinib mesylate (STI571, Glivec s , Gleevec s -Novartis, Basel, Switzerland) is a potent competitive inhibitor of the tyrosine kinases associated with ABL Druker et al, 1996), KIT (Buchdunger et al, 2000;Heinrich et al, 2000), PDGFr (Buchdunger et al, , 2000 and ARG (Okuda et al, 2001), which impedes the interaction of ATP with the SH1 domain of these proteins (Schindler et al, 2000), thereby inhibiting the phosphorylation of downstream target proteins. Imatinib is a phenylaminopyrimidine derivative and represents the first of a new class of drugs known as signal transduction inhibitors.…”

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confidence: 99%

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

et al. 2003

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The inhibition by imatinib of the cytochrome P450 3A4 isoenzyme may reduce the CYP3A4-mediated metabolic clearance of clinically important coadministered drugs. The main purpose of this study was to evaluate the effect of the coadministration of imatinib on the pharmacokinetics of simvastatin, a probe CYP3A4 substrate. In total, 20 patients with chronic myeloid leukaemia received an oral dose of 40 mg of simvastatin on study day 1. On study days 2 -7, each patient received 400 mg of imatinib once daily orally and on study day 8, 400 mg imatinib together with 40 mg of simvastatin was given. Blood levels of simvastatin were measured predose and for 24 h postdose on study days 1 and 8. Two additional blood samples were taken for imatinib pharmacokinetic (PK) assessment on day 8 before, and 24 h after, imatinib administration. Imatinib increased the mean maximum concentration (C max ) value of simvastatin two-fold and the area under concentration -time curve (AUC (0 -inf) ) value 3.5-fold (Po0.001) compared with simvastatin alone. There was a statistically significant decrease in total-body clearance of drug from the plasma (CL/F) with a mean reduction of 70% for simvastatin (Po0.001): the mean half-life of simvastatin was prolonged from 1.4 -2.7 h when given together with imatinib. No changes in imatinib PK parameters were found when given concomitantly with simvastatin. In conclusion, the coadministration of imatinib at steady state with 40 mg simvastatin increases the exposure (C max and AUCs) of simvastatin significantly (Po0.001) by two-three-fold. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window. The coadministration of simvastatin with imatinib (400 mg) was well tolerated and no major safety findings were reported in this study.

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confidence: 99%

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

et al. 2003

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“…The first of these to be developed was imatinib, a 2-phenylaminopyrimidine that inhibits the activity of BCR-ABL and, to varying degrees, several other tyrosine kinases. [5][6][7][8] Imatinib induces durable responses, prolongs event-free and progression-free survival in patients with CML, and is the current standard of care for this disease. 9,10 Imatinib has activity in all phases of CML, but the most extensive and durable responses are seen in chronic-phase patients, particularly those newly diagnosed with the disease.…”

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confidence: 99%

Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

et al. 2009

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“…Crystal structure studies have revealed that imatinib binds to the kinase domain of ABL in its inactive conformation and therefore locks it in an inactive state [43,44]. Imatinib inhibits not only ABL but also the receptor for platelet-derived growth factor A and B (PDGFR-α, β), stem cell factor receptor (KIT) and ARG (abl-related gene) tyrosine kinases, making it useful in attenuating oncogenic events triggered upon activation of these kinases [45][46][47]. Imatinib appears to selectively induce apoptosis in numerous BCR-ABL-positive leukemic cell lines and BCR-ABL-transduced hematopoietic cells (BaF3 and 32D), but not in BCR-ABL-negative hematopoietic cancer cell lines (HL60, Jurkat and U937), or non-transformed growth factordependent hematopoietic cells.…”

Section: The Tyrosine Kinase Activity Of Bcr-abl and Avenues For Therapymentioning

confidence: 99%

FoxO tumor suppressors and BCR–ABL-induced leukemia: A matter of evasion of apoptosis

Jagani

Singh

Khosravi‐Far

2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Numerous studies have revealed that the BCR-ABL oncoprotein abnormally engages a multitude of signaling pathways, some of which may be important for its leukemogenic properties. Central to this has been the determination that the tyrosine kinase function of BCR-ABL is mainly responsible for its transforming potential, and can be targeted with small molecule inhibitors, such as imatinib mesylate (Gleevec, STI-571). Despite this apparent success, the development of clinical resistance to imatinib therapy, and the inability of imatinib to eradicate BCR-ABL-positive malignant hematopoietic progenitors demand detailed investigations of additional effector pathways that can be targeted for CML treatment. The promotion of cellular survival via the suppression of apoptotic pathways is a fundamental characteristic of tumor cells that enables resistance to anti-cancer therapies. As substrates of survival kinases such as Akt, the FoxO family of transcription factors, particularly FoxO3a, has emerged as playing an important role in the cell cycle arrest and apoptosis of hematopoietic cells. This review will discuss our current understanding of BCR-ABL signaling with a focus on apoptotic suppressive mechanisms and alternative approaches to CML therapy, as well as the potential for FoxO transcription factors as novel therapeutic targets.

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ARG tyrosine kinase activity is inhibited by STI571

Cited by 234 publications

References 31 publications

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia

FoxO tumor suppressors and BCR–ABL-induced leukemia: A matter of evasion of apoptosis

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