共查询到20条相似文献,搜索用时 15 毫秒
1.
Jabbour E El Ahdab S Cortes J Kantarjian H 《Expert opinion on investigational drugs》2008,17(7):1127-1136
The successful introduction of the tyrosine kinase inhibitors has initiated a new era in the management of chronic myeloid leukemia (CML). Imatinib mesilate therapy has significantly improved the prognosis of CML. A minority of patients in chronic-phase CML--and more patients in advanced phases--are resistant to imatinib, or develop resistance during treatment. This is attributed, in 40-50% of cases, to the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Nilotinib (Tasigna) is a novel potent selective oral kinase inhibitor. Preclinical and clinical investigations demonstrate that nilotinib effectively overcomes imatinib resistance, and has induced high rates of hematologic and cytogenetic responses in CML post imatinib failure. 相似文献
2.
OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, and drug-drug and drug-food interactions of imatinib and the economic considerations of imatinib in the treatment of chronic myeloid leukemia (CML). DATA SOURCES: Literature accessed through MEDLINE (January 1970-January 2002), abstracts from the 2001 annual meetings of the American Society of Clinical Oncology and the American Society of Hematology, imatinib product labeling, and additional studies or abstracts identified from the bibliographies of the reviewed literature were used to compile data. Key search terms were allogeneic bone marrow transplant and stem cell transplant, chronic myeloid leukemia, imatinib, interferon, Gleevec, leukemia, gastrointestinal stromal tumors, STI-571, and tyrosine kinase inhibitors. FINDINGS: Imatinib is a distinctively characteristic drug targeted toward inhibition of tyrosine kinase activity. Imatinib is indicated for the treatment of patients with CML who failed interferon (IFN)-alpha therapy and for the treatment of patients with gastrointestinal stromal tumors (GISTs) expressing the tyrosine kinase receptor c-kit. Imatinib produces positive short-term hematologic and cytogenetic responses in patients with CML; short-term positive objective responses have been shown for patients with GISTs. To our knowledge, there are no controlled trials demonstrating long-term safety, improvement in disease-related symptoms, or increased survival with imatinib. Serious adverse effects requiring dosage decreases and/or therapy termination are edema, hepatotoxicity, and hematologic toxicity. Imatinib also has been found to inhibit tyrosine kinases involved in the growth of other malignancies. The role of imatinib in tumors that express a tyrosine kinase is constantly evolving with new research results. CONCLUSIONS: Imatinib therapy should be limited to patients whose tumor growth is related to a genetically defective tyrosine kinase. In cases of CML, imatinib should be further limited to patients who have tried and failed IFN-alpha therapy or who are not candidates for an allogeneic stem cell transplant. 相似文献
3.
BCR-ABL, a constitutively active tyrosine kinase, causes chronic myeloid leukaemia (CML). Rational development of drugs targeting BCR-ABL has significantly improved the treatment of CML. Imatinib (a BCR-ABL tyrosine kinase inhibitor) produces haematological and cytogenetic remissions across all phases of CML and is the present standard of care. Imatinib resistance occurs in a significant proportion of patients and mechanisms of resistance include BCR-ABL mutations and activation of alternate oncogenic pathways. Dasatinib is a novel, potent, multi-targeted oral kinase inhibitor. Preclinical and clinical investigations demonstrate that dasatinib effectively overcomes imatinib resistance and has further improved the treatment of CML. Dasatinib was recently approved by the FDA for use in Philadelphia-positive leukaemias in patients who are resistant or intolerant to imatinib. 相似文献
4.
《Expert opinion on investigational drugs》2013,22(5):679-687
BCR-ABL, a constitutively active tyrosine kinase, causes chronic myeloid leukaemia (CML). Rational development of drugs targeting BCR-ABL has significantly improved the treatment of CML. Imatinib (a BCR-ABL tyrosine kinase inhibitor) produces haematological and cytogenetic remissions across all phases of CML and is the present standard of care. Imatinib resistance occurs in a significant proportion of patients and mechanisms of resistance include BCR-ABL mutations and activation of alternate oncogenic pathways. Dasatinib is a novel, potent, multi-targeted oral kinase inhibitor. Preclinical and clinical investigations demonstrate that dasatinib effectively overcomes imatinib resistance and has further improved the treatment of CML. Dasatinib was recently approved by the FDA for use in Philadelphia-positive leukaemias in patients who are resistant or intolerant to imatinib. 相似文献
5.
Imatinib mesylate (STI571, Gleevec, Glivec, a selective inhibitor of the BCR-ABL tyrosine kinase causative of chronic myeloid leukemia (CML), represents the paradigm of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a targeted molecular therapy. Phase II clinical trials have shown marked therapeutic activity of imatinib in all evolutive phases of CML, but notably in the chronic phase, where it induces complete hematological responses in almost 100% of patients resistant or intolerant to interferon, with a major cytogenetic response rate of 60%, including 41% complete cytogenetic responses. The preliminary results of an ongoing phase III multicenter randomized study comparing imatinib with interferon plus cytarabine as first-line treatment for CML favor imatinib in terms of efficacy and safety. If confirmed with longer follow-up,these results would establish imatinib as the choice therapy for the majority of CML patients, with allogeneic transplantation being restricted as initial therapy only to younger patients with a family donor. Longer follow-up will answer some questions, such as those on long-term safety, durability of the responses, whether these will translate into a survival prolongation and the possibility of molecular responses. In addition, further information on the mechanisms involved in the primary and acquired resistance to imatinib is needed. Besides the Bcr-Abl protein, the drug is also active against other tyrosine kinases, such as Abl, the stem-cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this sense, it must be pointed out that imatinib has shown a remarkable activity in gastrointestinal stromal tumors. 相似文献
6.
《Expert opinion on drug safety》2013,12(1):97-107
Importance of the field: Several therapeutic options, including tyrosine kinase inhibitors, exist for the treatment of patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Despite impressive results, there is room for improvement for those patients who are either resistant or intolerant to imatinib.Areas covered in this review: An overview is given on the clinical results with nilotinib, a rationally designed second-generation tyrosine kinase inhibitor, as first- and second-line therapy in patients with Ph-positive CML. Important factors in predicting resistance to nilotinib and guiding therapeutic decisions are addressed.What the reader will gain: Knowledge on the clinical efficacy and safety of nilotinib after imatinib failure and as first-line treatment. Point mutations in the kinase domain (KD) of BCR-ABL1 are important determinants of clinical sensitivity to currently available tyrosine kinase inhibitors, including nilotinib. Information on specific BCR-ABL1 KD mutations and safety profiles assist in therapeutic decision making.Take home message: Nilotinib is a highly effective and well-tolerated therapeutic option in patients with Ph-positive CML after imatinib failure. Early evidence demonstrating increased efficacy has allowed expanding nilotinib to previously untreated patients in chronic phase. Insights into mechanisms of resistance to tyrosine kinase inhibitors and predictive factors for response will allow for a more individualized use of these agents. 相似文献
7.
Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) is a highly effective inhibitor of the deregulated kinase activity of BCR-ABL in chronic myelogenous leukemia (CML) and represents the current standard of care for patients with this disease. Mutations within the ABL kinase domain that interfere with drug binding have been identified as the main mechanism of resistance to imatinib. Currently, more than 50 different BCR-ABL mutants conferring varying degrees of resistance to tyrosine kinase inhibitors have been identified. Nilotinib (Tasigna; Novartis) is a second-generation tyrosine kinase inhibitor with 30-fold higher potency against BCR-ABL kinase than imatinib. Notably, nilotinib is active against a wide range of imatinib-resistant or-intolerant patients, except for T315I. Results from the pivotal phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy indicate that nilotinib has a favorable toxicity profile and is highly efficacious in this setting. Studies exploring the efficacy of nilotinib as front-line therapy for patients with newly diagnosed CML are ongoing. Here, we review the preclinical and clinical development of nilotinib for the treatment of CML. 相似文献
8.
Omacetaxine mepesuccinate was originally identified more than 35 years ago and initial studies in chronic myeloid leukemia (CML) showed promising activity. It has also been studied in other hematologic and solid tumors as both a single agent and in combination with other treatments. However, the introduction of imatinib and related tyrosine kinase inhibitors (TKIs) abated the clinical development of omacetaxine as a treatment for CML. The advent of resistance to imatinib and other TKIs in CML patients (often due to the presence of an ABL mutation at position 315) has led to a revived clinical interest in omacetaxine in CML patients who failed TKIs. Here we review omacetaxine's mechanism of action (MOA) as a protein translation inhibitor, how its MOA may translate into activity in treatment of cancers, its potential to eradicate leukemia initiating cells and other cancer stem cells and the potential significance of this activity in clinical practice. 相似文献
9.
Imatinib mesylate is a tyrosine kinase inhibitor used as first-line treatment in Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and metastatic or unresectable gastrointestinal stromal tumors (GIST). Therapeutic drug monitoring (TDM) for imatinib has been suggested to improve efficacy, assess compliance, and evaluate drug-drug interactions. Imatinib has proven efficacy in improving treatment response and survival in patients with Ph+ CML and GIST. Several analytical methods are available to quantify total plasma imatinib concentrations. A good relationship exists between total imatinib plasma concentrations and pharmacologic response. Clinical evaluation of pharmacologic response to imatinib alone may be insufficient given the long duration of therapy before clinical response in patients with Ph+ CML and GIST. Thus, the authors have used a previously published 9-step decision-making algorithm to evaluate the utility of TDM for imatinib. The suggested trough concentrations for improved complete cytogenetic or major molecular response in patients with Ph+ CML and improved time to progression for patients with GIST are >1000 and >1100 ng/mL, respectively. Imatinib exhibits interindividual pharmacokinetic variability. Increased apparent clearance of imatinib has been observed in chronic phase chronic myeloid leukemia and increased body weight. Decreased apparent clearance has been observed in renal impairment and patients on concomitant medications with potent inhibition of cytochrome P450 3A4. Duration of therapy in patients with Ph+ CML and GIST is lifelong. Based on the available evidence, TDM for imatinib may provide additional information on efficacy, compliance, and safety than clinical evaluation alone. Patients with suboptimal response to treatment, treatment failure, rare adverse events, drug interactions, or suspected nonadherence will attain the greatest benefit from TDM. 相似文献
10.
Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond 总被引:1,自引:0,他引:1
Jabbour E Cortes J Giles F O'Brien S Kantarijan H 《IDrugs : the investigational drugs journal》2007,10(7):468-479
Chronic myelocytic leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl. Inhibitors ofBcr-Abl have significantly improved the treatment of CML. Most notable is the inhibitor imatinib, which produces remissions in all phases of CML and is the current standard of care. However, imatinib resistance occurs in a significant proportion of patients, mainly through the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Attempts to circumvent resistance to imatinib led to the discovery of nilotinib (Tasigna; Novartis AG), a novel, potent and selective oral Bcr-Abl kinase inhibitor. Preclinical and clinical investigations have demonstrated that nilotinib effectively overcomes imatinib resistance. Efficacy has been observed in models of CML and other myeloproliferative disorders that are driven by Bcr-Abl and related kinases. In a phase II clinical trial in CML, major cytogenetic response rates were 52 and 33% for chronic- and accelerated-phase disease, respectively. Nilotinib has been filed for approval in the US and EU for use in Philadelphia-positive leukemias in patients who are resistant or intolerant to imatinib. Nilotinib is undergoing clinical trials in patients with newly diagnosed CML, acute lymphoblastic leukemia and gastrointestinal stromal tumors, among other indications. 相似文献
11.
Imatinib mesilate (Glivec) is a protein-tyrosine kinase inhibitor that potently inhibits the Bcr-Abl tyrosine kinase as well as the receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, at in vitro and cellular kinase assay levels. Since Bcr-Abl tyrosine kinase plays a key role in chronic myelogenous leukemia (CML) patients, treatment with imatinib mesilate that potently inhibits Bcr-Abl tyrosine kinase could be a promising therapeutic approach to CML. Imatinib mesilate was shown to inhibit proliferation of bcr-abl-positive cell lines and suppress the formation of bcr-abl-positive colonies in cells derived from bone marrow of CML patients. This compound induced apoptosis in a variety of bcr-abl-positive cells. Moreover, in vivo data indicated that imatinib mesilate suppress growth and formation of bcr-abl-positive tumors in mice. As the profile expected from the preclinical studies, imatinib mesilate showed impressive hematological and cytogenic responses in the clinical trials, including interferon-alpha-resistant or intolerant patients. 相似文献
12.
Santos FP Kantarjian H Cortes J Quintas-Cardama A 《Current opinion in investigational drugs (London, England : 2000)》2010,11(12):1450-1465
Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. In preclinical studies, bafetinib was 25- to 55-fold more potent than imatinib in vitro and ≥ 10-fold more potent in vivo. Bafetinib inhibits 12 of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with imatinib-resistant or -intolerant CML have confirmed that bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors. 相似文献
13.
Mechanisms of resistance imatinib (STI571) in preclinical models and in leukemia patients. 总被引:5,自引:0,他引:5
The tyrosine kinase inhibitor imatinib (STI571, Glivec) blocks the activity of the BCR/ABL oncogene and induces hematologic remissions in the majority of patients with chronic myeloid leukemia (CML). Glivec is an aminopyrimidine derivative that interacts with the ATP-binding site within the kinase domain of ABL and several other tyrosine kinases, including c-KIT, PDGF beta receptor, and ARG. The compound is currently in phase III clinical trials. Although patients with chronic phase CML have been found to develop drug resistance only rarely so far, patients in more advanced phases of the leukemia develop resistance frequently. The available information on Glivec resistance will be reviewed. 相似文献
14.
伊马替尼是一种小分子酪氨酸激酶抑制剂(TKIs),主要用于治疗费城染色体阳性的慢性粒细胞白血病(CML)和不可切除或发生转移的胃肠道间质瘤(GIST)。伊马替尼自上市以来显示出了较好的疗效,但研究发现,服用相同剂量药物时,达稳态时伊马替尼血浆谷浓度的差异大,而血浆谷浓度与药物反应及患者的临床获益密切相关。因此,研究伊马替尼血药浓度影响因素,对判断药物疗效、评价治疗效果、调整治疗方案和规避毒副反应等方面有重要意义。笔者将从病理生理状态、代谢酶和转运体的基因多态性、联合用药等方面探讨影响伊马替尼血药浓度的因素,旨在为临床合理用药、制定个体化给药方案提供参考。 相似文献
15.
Imatinib mesylate, Abl tyrosine kinase inhibitor, has improved the treatment of Bcr-Abl-positive leukemia such as chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph(+)ALL). However, resistance is often reported in patients with advanced-stage disease. Several novel tyrosine kinase inhibitors, which have been developed to override imatinib resistance mechanisms such as overexpression of Bcr-Abl and point mutations within the Abl kinase domain, are currently competing. Inhibitors of Abl tyrosine kinase are divided into two main groups, namely, ATP-competitive and ATP non-competitive inhibitors. Moreover, ATP-competitive inhibitors are fall into two subclasses, i.e. the Src/Abl inhibitors, and 2-phenylaminopyrimidin-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606 and PD166326 are classified as Src/Abl inhibitors while AMN107 and NS-187 (INNO-406) belong to the latter subclass of inhibitors. Among these agents, clinical studies on dasatinib and AMN107 had started earlier than the others and favorable results are accumulating. Clinical studies of other compounds including NS-187 (INNO-406) will be performed in rapid succession. Because of its strong affinity, most ATP competitive inhibitors may be effective against imatinib-resistant patients. However, to date, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl has not yet been developed. To address this problem, ATP non-competitive inhibitors such as ON012380, Aurora kinase inhibitor VX-680 and p38 MAP kinase inhibitor BIRB-796 have been developed. It may be necessary for the improvement of CML and Ph(+)ALL treatment to be taken into consideration of the combination therapy with novel ATP-competitive inhibitors and these agents. 相似文献
16.
Gora-Tybor J 《Current cancer drug targets》2012,12(5):458-470
Chronic myeloid leukemia (CML) therapy has dramatically changed in the last decade due to the introduction of tyrosine kinase inhibitors (TKIs) - imatinib, nilotinib and dasatinib. Despite the significant prolongation of overall survival of CML patients there is still room for improvement. Approximately 20-25% of patients initially treated with imatinib will need alternative therapy, due to drug resistance which is often caused by the appearance of clones expressing mutant forms of BCR-ABL. Second generation TKIs dasatinib and nilotinib have shown promising results in imatinibresistant or intolerant CML patients, but are not active against CML clones with highly resistant T315I mutation. In recent years special attention is placed on small pool of leukemic stem cells which may contribute to the persistence of the leukemia. This article provides a review of preclinical and clinical data concerning the most promising new directions in CML treatment, with special emphasis on new drugs active in T315I mutation and compounds affecting leukemic stem cells. 相似文献
17.
Recent results of phase II trials which used dasatinib or nilotinib as single agent, or phase III trials comparing second-generation tyrosine kinase inhibitors to imatinib, showed greater potency of these two inhibitors in newly diagnosed chronic myeloid leukemia (CML) patients in chronic phase (CP). In the present review we detail and summarize clinical results of both agents as first-line therapeutic strategy, and also discuss on critical points emerged from the last follow-up of trials comparing new generation tyrosine kinase inhibitors with imatinib. In terms of safety, dasatinib and nilotinib have shown favorable toxicity profile, with peculiar and distinct pattern of adverse events. Based on these results, USA FDA approved both drugs as first-line treatment in newly diagnosed CML: now several therapeutic strategies are available to treat patients at onset of disease. Longer follow-up is however needed to prove the advantages of faster and deeper responses in terms of disease progression compared to imatinib. 相似文献
18.
Specific targeted therapy of chronic myelogenous leukemia with imatinib 总被引:11,自引:0,他引:11
Chronic myeloid leukemia (CML) is characterized by the Philadelphia translocation that fuses BCR sequences from chromosome 22 upstream of the ABL gene on chromosome 9. The chimerical Bcr-Abl protein expressed by CML cells has constitutive tyrosine kinase activity, which is essential for the pathogenesis of the disease. Imatinib, an ATP-competitive selective inhibitor of Bcr-Abl, has unprecedented efficacy for the treatment of CML. Most patients with early stage disease achieve durable complete hematological and complete cytogenetic remissions, with minimal toxicity. In contrast, responses are less stable in patients with advanced CML. This review highlights the pathogenesis of CML, its clinical features, and the development of imatinib as a specific molecularly targeted therapy. Aspects of disease monitoring and side effects are covered as well as resistance to imatinib and strategies to overcome resistance, such as alternative signal transduction inhibitors and drug combinations. Perspectives for further development are also discussed. 相似文献
19.
Novartis has launched imatinib, an inhibitor of tyrosine kinases, including Bcr-Abl, for the treatment of chronic myeloid leukemia (CML). Imatinib selectively inhibits activation of target proteins involved in cellular proliferation. It also inhibits c-KIT tyrosine kinase activity and is equally effective against both wild-type and constitutively active enzyme. Close correlation between in vitro responses to IFNalpha and imatinib suggested that it may be an alternative to IFNalpha therapy for chronic-phase CML, and the compound has the advantage that it can be administered orally. Futhermore, Bcr-Abl-expressing cells treated with imatinib undergo apoptosis. Imatinib also has potential for the treatment of other cancers that express these kinases, including acute lymphocytic leukemia and certain solid tumors. In February 2002, the FDA approved imatinib for the treatment of inoperable and/or metastatic malignant gastrointestinal stromal tumors (GIST); in September 2001, launch for the indication was expected in 2002. In November 2000, imatinib was granted Orphan Drug status in Japan for the target indication of Philadelphia chromosome-positive leukemia. By May 2001, imatinib had entered phase II trials for small cell lung cancer, prostate cancer and glioma. Imatinib has been launched in more than 35 countries, including the US, Brazil, Switzerland, Australia and the UK. By December 2001, the drug had also been launched in Japan. The drug is marketed as Gleevec (imatinib mesilate) in the US, and Glivec (imatinib) outside the US. In August 2001, Deutsche Bank estimated sales of SFr 233 million in 2001, rising to SFr 850 million in 2005; while Bear Stearns & Co predicted sales of SFr 250 million in 2001, rising to SFr 800 million in 2005. 相似文献
20.
The Philadelphia chromosome found in leukemia cells of chronic myelogenous leukemia (CML) patients is produced by translocation between chromosomes 9 and 22, resulting in expression of a chimera protein of Bcr and Abl kinase in the cytoplasm. Bcr-Abl kinase attracted oncology researchers as a molecular target for CML therapy, and a variety of small Abl kinase inhibitors were synthesized. STI571 (imatinib mesylate) was produced by modification of 2-phenylaminopyrimidine, a core structure of protein kinase C inhibitor, to improve selectivity, stability, solubility, and bioavailability. STI571 competitively binds to the ATP binding site of Bcr-Abl kinase and inhibits Abl tyrosine kinase activity. STI571 showed significant efficacy in the clinical study with CML patients at all stages: chronic phase, accelerated phase, and blast crisis. More than 90% of the patients showed good hematologic response to STI571. STI571 is also a potent inhibitor of a receptor-type c-Kit tyrosine kinase. Therefore, STI571 was examined for therapeutic efficacy against malignant Gastro-Intestinal Stromal Tumors (GIST), which are mainly caused by aberrant expression of a mutated c-Kit that is constitutively active without binding of a ligand, stem cell factor (SCF). More than a half of the metastatic GIST patients enrolled in the clinical study responded to STI571. Thus, STI571 is now used as a therapeutic drug for both CML and GIST in more than 80 countries worldwide. Certain point mutations in the ATP binding site were found to be a cause of resistance to STI571 in both Bcr-Abl and c-Kit kinases. Therefore, it would be better to make a precise therapeutic strategy with STI571 based on the gene analysis data. It is also expected that it will be possible to design an inhibitor to overcome such resistance by using the structural information on the mutants. 相似文献