Gleevec scientific update |
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Genes Chromosomes Cancer. 2010 Jul 6.
Schnittger S, Bacher U, Dicker F, Kern W, Alpermann T, Haferlach T, Haferlach C.
MLL Munich Leukemia Laboratory GmbH, Munich, Germany.
Relation with regard to avoidance of imatinib projecting mutations. [Associations between imatinib resistance conferring mutations and Philadelphia positive clonal cytogenetic evolution in CML]
In patients with chronic myeloid leukemia (CML), resistance against imatinib is associated with mutations in the kinase domain (KD) of the BCR-ABL1 fusion gene and/or with additional chromosomal abnormalities (ACAs) secondary to the Philadelphia chromosome. To evaluate associations between these molecular and cytogenetic events, we correlated cytogenetic data with results of KD mutation analysis in 205 CML patients with acquired resistance to imatinib (100 females, 105 males, 17.9-90.3 years). In 79/205 patients (38.5%), at least one KD mutation was detected; in 13/79 (16.5%) even two different mutations were observed. A second KD mutation was frequent in cases with G250E (4/9), E255V (1/3), T315I (5/18), F317L (2/7), F359C/V (4/7), or H396R (2/3), but was never detected in cases with V299L (n = 3) or Y253H (n = 4). With respect to cytogenetics, ACAs were identified in 76/205 patients (37.1%), in 29 (36.7%) together with KD mutations. ACAs were frequent in cases with E255V (2/3), T315I (8/18), F317L (4/7), F359C/V (4/7), or H396R (2/3), but rare in those with M351T (1/9). Therefore, some KD mutations (e.g., T315I) might be associated with higher genetic instability paving the way to additional cytogenetic and molecular genetics events.
Prostate. 2010 Jul 6. [Epub ahead of print]
Pinto AC, Moreira JN, Simões S.
Faculty of Pharmacy, Laboratory of Pharmaceutical Technology, University of Coimbra, Coimbra, Portugal.
Imatinib and mitoxantrone combination in formulation and evaluation for prostate cancer. [Liposomal imatinib-mitoxantrone combination: Formulation development and therapeutic evaluation in an animal model of prostate cancer]
BACKGROUND: Mitoxantrone plus prednisone is a palliative treatment for hormone-refractory prostate cancer (HRPC) but without survival benefit. Imatinib has shown activity against HRPC but only in the preclinical setting. Our previous in vitro cytotoxicity screening study established that their free combination act additively to inhibit proliferation of PC-3 cells. We aim to develop a liposomal imatinib-mitoxantrone (LIM) formulation with improved in vivo therapeutic activity. METHODS: Imatinib and mitoxantrone were simultaneously co-loaded into DSPC/Chol liposomes by means of a (NH(4))(2)SO(4)-generated proton gradient method. The optimized formulation was characterized in terms of mean size diameter, loading parameters and drug retention in human serum. In vivo antitumor activity of developed LIM formulation was evaluated in a nude mice bearing subcutaneous PC-3 xenograft model. RESULTS: LIM formulation exhibited maximal encapsulation efficiency (>95%) and enhanced drug retention for both drugs. Additionally, this LIM formulation, administered at a low mitoxantrone dose (0.5 mg/kg), showed a tumor inhibition activity (TGI = 66.7% and 4.0-fold tumor volume increase) slightly superior to that of liposomal mitoxantrone (LM) at 2 mg/kg (TGI = 53.0% and 4.2-fold volume increase). Therefore, therapeutic activity of mitoxantrone was significantly improved by co-loading with imatinib since a four times lower dose was needed to achieve an equivalent growth inhibition effect. CONCLUSIONS: The loading parameters and drug retention properties of our LIM formulation, combined with its in vivo antitumor activity, make this formulation an excellent strategy to improve the therapeutic index of mitoxantrone and a promising candidate for clinical development in prostate cancer therapy.
Indian J Pharmacol. 2010 Feb;42(1):50-2.
Varma MR, Mathew S, Krishnadas D, Vinayakumar KR.
Department of Medical Gastroenterology, Medical College, Thiruvananthapuram, India.
Pancreatitis indeced by imatinib. [Imatinib-induced pancreatitis]
Drug-induced pancreatitis is a rare but serious complication of many drugs, some of which have been well documented. Here we present a case of a middle-aged man with chronic myeloid leukemia who developed acute pancreatitis after being initiated on imatinib mesylate. The case history, the pharmacodynamics, uses, and adverse effects of imatinib mesylate are discussed in detail.
Intern Med. 2010;49(13):1297-301. Epub 2010 Jul 1.
Sumimoto H, Tsujimura H, Ise M, Mimura N, Sakai C, Takagi T, Kumagai K.
Division of Hematology-Oncology, Chiba Cancer Center Hospital.
Explosive arena of chronic myeloid in association with lymphoid phenotype for a concise period of time. [Blast phase of chronic myeloid leukemia presenting lymphoid phenotype with a chronic phase of extremely short duration]
Chronic myeloid leukemia (CML) is generally diagnosed in the chronic phase. We have recently encountered two CML-blastic phase (BP) cases, a 71-year-old woman and a 74-year-old man, who resembled de novo acute leukemia. The complete blood count was normal at least 11 and 13 months before the presentation, respectively. The leukemic cells showed predominant lymphoid phenotype. The blasts and granulocytes were positive for BCR-ABL, indicative of CML-BP. Both patients were successfully treated with prednisone and vincristine, followed by Imatinib. Our cases indicate rare presentations of CML-BP with an extremely short chronic phase. Ph-positive de novo acute leukemia should be carefully distinguished from CML-BP.
Indian J Pharmacol. 2009 Aug;41(4):167-72.
Nassar I, Pasupati T, Judson JP, Segarra I.
Departments of Pathology, International Medical University; No. 126, Jalan 19/155B, Bukit Jalil-57000 Kuala Lumpur, Malaysia.
Statistical evidence revealed a decline of imatinib when given acetaminophen to mice. [Reduced exposure of imatinib after coadministration with acetaminophen in mice]
PURPOSE: Imatinib is an efficacious drug against chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST) due to selective inhibition of c-KIT and BCR-ABL kinases. It presents almost complete bioavailability, is eliminated via P450-mediated metabolism and is well tolerated. However, a few severe drug-drug interactions have been reported in cancer patients taking acetaminophen. MATERIALS AND METHODS: Male ICR mice were given 100 mg/kg single dose of imatinib orally or imatinib 100 mg/kg (orally) coadministered with acetaminophen intraperitoneally (700 mg/kg). Mice were euthanized at predetermined time points, blood samples collected, and imatinib plasma concentration measured by HPLC. RESULTS: Imatinib AUC(0-12) was 27.04 +/- 0.38 mg.h/ml, C(max) was 7.21 +/- 0.99 mg/ml and elimination half-life was 2.3 hours. Acetaminophen affected the imatinib disposition profile: AUC(0-12) and C(max) decreased 56% and 59%, respectively and a longer half-life was observed (5.6 hours). CONCLUSIONS: The study shows a pharmacokinetic interaction between acetaminophen and imatinib which may render further human studies necessary if both drugs are administered concurrently to cancer patients.
Curr Hematol Malig Rep. 2009 Jul;4(3):139-47.
Terwey TH, Kim TD, Arnold R.
Department of Hematology and Oncology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany. theis.terwey@charite.de
Cancerous cells of leukaemia requires allogeneic hematopoietic stem cell substitute for adults. [Allogeneic hematopoietic stem cell transplantation for adult acute lymphocytic leukemia]
Allogeneic hematopoietic stem cell transplantation (alloHCT) is the single most potent treatment modality to prevent relapse in adults with acute lymphocytic leukemia, but its optimal use and timing remains a matter of intense debate and research. There is general agreement that patients with clinical features of high risk for relapse should undergo alloHCT in first complete remission. However, newer studies suggest that even patients without these risk factors may benefit. Monitoring of minimal residual disease may improve risk stratification and may complement or replace conventional risk features. Prognosis in relapsed and refractory patients is dismal, and alloHCT should be performed as soon as possible. AlloHCT also offers the only reasonable chance for cure in Philadelphia chromosome-positive acute lymphocytic leukemia; the role of imatinib is not yet clearly defined. Recent developments in unrelated-donor transplantation and reduced-intensity conditioning allow the beneficial effects of alloHCT to reach a considerably wider patient population.
Curr Hematol Malig Rep. 2009 Apr;4(2):59-65.
White DL, Hughes TP.
Division of Haematology, SA Pathology IMVS/RAH Campus, Frome Road, Adelaide, South Australia, Australia.
Tyrosine kinase inhibitor therapy performance among CML patients. [Predicting the response of CML patients to tyrosine kinase inhibitor therapy]
Tyrosine kinase inhibitor (TKI) therapy has significantly changed the treatment paradigm for patients with chronic myeloid leukemia (CML). The firs-tgeneration inhibitor, imatinib, has demonstrated remarkable efficacy in most chronic-phase patients. Disease progression remains a significant risk for the first 2 to 3 years of TKI therapy, but the risk falls significantly thereafter. Early recognition of each individual's risk of progression may facilitate a customized approach to TKI therapy. Using such an approach, drug selection and treatment intensity would be adjusted on the basis of each patient's disease profile. Currently available prognostic indicators have limited value in the setting of the potent kinase inhibition afforded by TKIs. Furthermore, these indicators provide little guidance regarding optimal drug choice and dose intensity. In the future, assays that directly assess the efficacy of the protein-drug interaction, taking into account factors intrinsic to the patient and the amount of drug freely available in the plasma, are likely to be of greater value.
J Thorac Oncol. 2009 Oct;4(10):1270-3.
Giaccone G, Rajan A, Ruijter R, Smit E, van Groeningen C, Hogendoorn PC.
Department of Medical Oncology, VU Medical Center, Amsterdam, The Netherlands.
Analysis among the B3 thymomas and thymic carcinoma patients of imatinib mesylate. [Imatinib mesylate in patients with WHO B3 thymomas and thymic carcinomas]
Thymic malignancies are rare tumors of the mediastinum. c-KIT is highly expressed in thymic carcinomas (TC) but infrequently in thymomas. Anecdotal experience suggests activity of imatinib mesylate in TC. Patients with unresectable World Health Organization B3 thymomas or TC, performance status 0 to 2, good organ function, and measurable disease were enrolled in this study. Imatinib was administered at 600 mg PO daily. Seven patients were recruited at one institution: two World Health Organization B3 thymomas and five TC. Imatinib treatment was generally well tolerated. Two patients had stable disease and five progressed. Median survival was 4 months, and median time to progression was 2 months. c-KIT expression was found in one of four samples by immunohistochemistry. No mutations were detected in the c-KIT or PDGFRA genes in three samples analyzed. Imatinib has no major activity in this rare tumor. Given the small number of patients treated in this study, selection based on presence of c-KIT mutations might be warranted.
Hepatol Int. 2008 Dec;2(4):498-9. Epub 2008 Oct 2.
Lakhani S, Davidson L, Priebat DA, Sherker AH.
Section of Gastroenterology and Hepatology, Washington Hospital Center, Georgetown University School of Medicine, 110 Irving Street NW, Washington, DC, 20010, USA.
Imatinib mesylate therapy reactivates chronic hepatitis B. Reactivation of chronic hepatitis B infection related to imatinib mesylate [therapy]
Imatinib (Gleevec, Novartis), an inhibitor of BCR-ABL, platelet-derived growth factor, and KIT receptor tyrosine kinases, is widely used in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors. We describe a case of activation of chronic hepatitis B infection associated with imatinib therapy.
Biomol NMR Assign. 2008 Jun;2(1):41-2. Epub 2008 Mar 5.
Vajpai N, Strauss A, Fendrich G, Cowan-Jacob SW, Manley PW, Jahnke W, Grzesiek S.
Biozentrum, University of Basel, Klingelbergstrasse 70, Basel, Switzerland.
Project of the Abelson kinase domain in confined imatinib. [Backbone NMR resonance assignment of the Abelson kinase domain in complex with imatinib]
Imatinib (Glivec or Gleevec) potently inhibits the tyrosine kinase activity of BCR-ABL, a constitutively activated kinase, which causes chronic myelogenous leukemia (CML). Here we report the first almost complete backbone assignment of c-ABL kinase domain in complex with imatinib.
Indian J Urol. 2008 Jul;24(3):343-7.
Rekha PR, Rajendiran S, Rao S, Shroff S, Joseph LD, Prathiba D.
Classification and characterization in renal cell carcinoma. [Histological reclassification, histochemical characterization and c-kit immunoexpression in renal cell carcinoma]
OBJECTIVES: Renal cell carcinoma is the most lethal of all urologic malignancies. Several parameters such as histological subtype, nuclear grade and TNM staging help in determining the prognosis and treatment options. A newer therapeutic modality has been suggested based on expression of c-kit antigen by the tumor cells. This study was designed to evaluate various histological parameters and correlate them with c-kit expression. MATERIALS AND METHODS: The study was done on 40 consecutive cases of renal epithelial tumors. Histological sections were reviewed and reclassified according to WHO (2004) classification and nuclear grade assessed. Hale's colloidal iron stain was done to identify the chromophobe variant. Immunostaining with c-kit was done and its expression was studied. The results were correlated and statistical significance was assessed. RESULTS: The age range was 31-81 years, with a male to female ratio of 2:1. Seventy per cent of the cases were clear cell RCC (ClRCC), 17.5% were chromophobe type, 7.5% were papillary RCCs and 5% cases were oncocytomas. Fuhrman nuclear grading revealed 60.5% cases to be of low grade and 39.5% high grade. Hale's colloidal iron staining was positive in chromophobe RCC and oncocytomas, while it was negative in ClRCC. Immunostaining with c-kit was positive only in oncocytomas. CONCLUSIONS: Clear cell RCC was the most common histological subtype of RCC. Clear cell RCC known to have a poor prognosis, showed a statistically significant higher nuclear grade than chromophobe and papillary RCCs which have a better prognosis. Hale's colloidal iron staining was extremely useful in distinguishing chromophobe RCC and oncocytoma from the granular cell variant of clear RCC. Our study revealed c-kit negativity in all RCC. As Imatinib could be ineffective in such tumors, its clinical activity has to be carefully assessed in such tumors through further studies.
Prescrire Int. 2008 Dec;17(98):226-8.
Advantages of imatinib in chronic myeloid leukaemia. [Imatinib: a second look. Longer follow-up in chronic myeloid leukaemia: clear advantages]
(1) In 2002/2003, the clinical evaluation of imatinib, a tyrosine kinase inhibitor, in the treatment of chronic myeloid leukaemia left many questions unanswered. This article examines data published since then; (2) The only new data on first-line efficacy are the 5-year results of an unblinded trial comparing imatinib versus the interferon plus cytarabine combination. The survival rate was 89% with imatinib, versus about 70% in previous clinical trials of interferon plus cytarabine. Fewer than 2% of patients relapsed after responding to imatinib; (3) As second-line treatment for patients in the chronic phase, we now have non-comparative follow-up data on 532 patients in whom interferon had failed. At 5 years the overall survival rate was 79%, versus about 50% with standard treatments; (4) As second-line treatment for patients in the accelerated phase, we now have non-comparative follow-up data on 235 patients. After 3 years 55% of the patients were still alive, while the usual survival time is 3 to 18 months; (5) As second-line treatment of the blast crisis, we now have non-comparative follow-up data on 260 patients. After 3 years 14% of the patients were still alive, while the usual survival time for patients at this stage is 2 to 4 months; (6) The only new study is a non-comparative follow-up study of 50 children and adolescents aged 2 to 19 years treated with imatinib. The estimated 2-year survival rate was 84%. The haematological and cytogenetic response rates were similar to those reported in adults; (7) The initial clinical evaluation of imatinib showed that its main adverse effects were nausea and vomiting, oedema, fluid retention, muscle cramps, and cutaneous disorders. It was estimated that heart failure occurred in 1 to 10 per 1000 patients. A study of 54 patients confirmed the high incidence of cutaneous disorders. Cases of prostate and bladder cancer have been reported in patients treated with imatinib in France. A study of 16 patients suggests that imatinib might alter bone metabolism; (8) In France, treatment with imatinib costs about 25% more than the interferon plus cytarabine combination; (9) In practice, imatinib seems to increase survival time when used as a first-line or second-line treatment for patients in different phases of chronic myeloid leukaemia. Adverse effects must continue to be closely monitored.
Postepy Hig Med Dosw (Online). 2007 Jun 9;62:272-81.
Mac K, Wójcik M.
Zakład Biologii Strukturalnej, Katedra Endokrynologii Ogólnej, Uniwersytet Medyczny w Łodzi. katarzynamac@o2.pl
Clinical characterization of stromal tumours. [Clinical and molecular characterization of gastrointestinal stromal tumors (GIST)] [Article in Polish]
Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors of the gastrointestinal tract, the diagnosis of which is difficult. The presence of membrane receptor c-KIT on GIST cells implies their origin from a precursor of interstitial cells of Cajal. Mutations in the c-kit gene result in the constitutive ligand-independent activation of the c-KIT receptor and, consequently, aberrant cell division and tumor growth. Imatinib (STI571), used in the treatment of unresectable GIST, selectively inhibits the enzymatic activity of the tyrosine kinase c-KIT. However, it is known that some mutations in the c-kit gene lead to resistance to imatinib. Therefore, the search for new effective agents is being continued. In this paper the clinical and molecular characterization of the GIST is presented as well as data related to imatinib in the treatment of GIST. Moreover, novel agents for the treatment of patients with advanced GIST are described.
Oncology. 2007;73(5-6):324-7. Epub 2008 May 23.
Zhu J, Wang Y, Hou M, Li HY, Zhang J.
3rd Department of Cancer Center, West China Hospital, Cheng Du, China. zhujiang1@medmail.com.cn
Study to analyze imatinib mesylate treatment for stromal tumour Imatinib mesylate treatment for advanced gastrointestinal stromal tumor: a pilot study focusing on patients experiencing sole liver metastasis after a prior radical resection.
BACKGROUND: About 80% of patients with gastrointestinal stromal tumor (GIST) experience tumor recurrence or metastasis after a prior radical resection, and the most common metastatic site is the liver. Imatinib mesylate has been proven to be effective in advanced GIST. The current pilot study was designed to observe imatinib mesylate treatment for GIST patients who experienced sole liver metastasis after primary tumor resection. METHODS: From June 2004 to July 2005, 21 patients who met the eligibility criteria were enrolled in this study. They were administered Glivec at an initial dose of 400 mg/day. The primary end points were grade 3-4 hematological or non-hematological toxicity and progression-free survival; the secondary end points were response rate and overall survival. RESULTS: Edema was the most common toxicity, whereas grade 3 and 4 side effects were rare. The overall response rate was 52.4%. Only 1 patient died in the course of the study; the 2-year progression-free and overall survival rates were 85.7 and 95.2%, respectively. CONCLUSIONS: Imatinib mesylate treatment proved safe and effective for GIST patients who had liver metastasis alone. A prolonged survival was observed, and long-term follow-up is still continued.
Zhonghua Nei Ke Za Zhi. 2007 Dec;46(12):1003-6.
Chen ZC, You Y, Zhu XM, Li QB, Li WM, Zou P.
Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Treatment of leukaemia by imatinib mesylate. [A clinical study of treating 120 cases of adult chronic myelocytic leukemia with imatinib mesylate] [Article in Chinese]
OBJECTIVE: To analyze and evaluate the clinical efficacy and safety of imatinib mesylate (IM) as a tyrosine kinase inhibitor on Ph-positive or BCR/ABL positive chronic myelogenous leukemia (CML). METHODS: 120 patients diagnosed as CML with positive Ph chromosome were treated with IM 400 mg/d for CML in chronic phase (CP) (n = 90) or 600 mg/d for CML in accelerated or blastic phase (AP or BP) (n = 30) once daily. Hematological, cytogenetic and molecular effects of IM on the disease process of these patients were evaluated with blood and marrow cells morphology examination, G-band conventional cytogenetics analysis for Ph chromosome and PCR assay for BCR/ABL gene. The treatment efficacy and safety were retrospectively studied. RESULTS: (1) In CML-CP patients, after a follow-up of 9 ( range 3-42) months, cumulative complete hematological response (CHR), complete cytogenetic response (CCyR) and complete molecular response (CMR) rates were 73.3%, 66.7% and 54.4%, which was not influenced by prior treatment of interferon. CMR was better when time from diagnosis to treatment with IM was < or = 6 months (P < 0.05). The effect was not related with sex or age (P < 0.05). It is significant that the time to first CHR and time to first CCyR were related with the time to first CCyR and the time to first negative BCR/ ABL, respectively (both P < 0.05), while there was no relation between the time to first CHR and the time to first negative BCR/ABL (P > 0.05). (2) CHR, CCyR and CMR rates of the patients with progressive course (AP and BP) were 43.3%, 25.9% and 25.0%, respectively. The total mortality rate was 30.0%. (3) The mortality rate of the patients with age < or = 25 was higher than those >25 (P < 0.05). (4) Grade 3 leukocytopenia occurred in 16.0% of the patients and grade 3 thrombocytopenia in 18.0% of the patients and they 12 (5-20) weeks and 9 (3-16) weeks after the treatment, respectively. Nonhematological toxicities were common and tolerable. CONCLUSION: IM can lead to considerable hematological, cytogenetic and molecular response rates in CML, especially CML-CP patients, with minor tolerable side effects.
Zhonghua Yi Xue Za Zhi. 2007 Dec 25;87(48):3399-405.
Wang XD, Qiu L, Lu RZ, Chen LJ, Zhan ZM, Han BH, Zhang BL, Ma J.
Institute of Hematology & Oncology, Harbin 150010, China.
Varied features of imatinib instigated by cell distinction in vitro. [Growth inhibition and differentiation of imatinib-resistant chronic myeloid leukemia cell induced by cell differentiation agent in vitro]
OBJECTIVE: To investigate the effects of uroacitide (CDA-2), a cell differentiation agent, on the growth inhibition and differentiation of imatinib-(IM) resistant chronic myeloid leukemia (CML) cells. METHODS: IM resistant CML cell line K562R was established from the line K562. K562 and K562R CML cells were cultured with CDA-2 of different concentrations. MTI method was used to detect the survival rates. Bone marrow cells of IM-resistant and non-IM-resistant CML patients were collected and co-incubated with K562 and K562R cells. MTT and colony-forming assays were used to evaluate the efficacy of CDA-2 treatment for cell growth in K562 and K562R cell lines, and IM-resistant or non-IM-resistant bone marrow cells of the CML patients; Annexin-V staining was employed to detect the apoptosis. Cell differentiation was assessed by flow cytometry analysis with CD11b/CD14 markers, reverse transcriptase PCR (RT-PCR) for mRNA levels of NCF-1 and ORM-1 genes and Giemsa staining for the observation in morphology. Cell cycle distribution was detected by stained with propidium iodide and then analyzed by flow cytometer. RT-PCR also was employed for the expression of DNA methyltransferase. RESULTS: Significant cell growth inhibition was found at a dose-dependent manner in the IM-resistant K562R cell line and IM-resistant bone marrow cells of the CML patients compared with the non-resistant K562 cell line and bone marrow cells of the CML patients following 7 days exposure to CDA-2. Although CDA-2 could significantly induce the apoptosis of K562R (15.38%) compared with K562 (5.28%) (P < 0.05), the major reason for the cell growth inhibition of K562R is CDA-2-induced cell differentiation, including the increase of expression of differentiation-related antigens CD11b/CD14, mRNA expression of NCF-1 and ORM-1, and cell cycle arrest in G1-phase at a dose-dependent manner. Because CDA-2 could significantly activate the p21 and p27 gene expression, downregulate the expression of cyclin D1, and down-regulate the expressions of DNMT1 and DNMT(3B) at mRNA level, CDA-2 might be a DNMT inhibitor for restoring some gene function that involved in cell cycle control by demethylation. CONCLUSION: Inhibiting the growth and inducing the differentiation of K562R cells, CDA-2 is very likely to be a potential agent for the treatment of IM resistance CML patients.
Haematologica. 2008 Aug 25.
Kancha RK, von Bubnoff N, Miething C, Peschel C, Götze KS, Duyster J.
Klinikum rechts der Isar, Technical University of Munich, Germany.
Imatinib and leptomycin B are effective in overcoming imatinib-resistance due to Bcr-Abl amplification and clonal evolution but not due to Bcr-Abl kinase domain mutation.
Treatment with imatinib is very effective in Bcr-Abl positive leukemia, but development of resistance to this drug is a common phenomenon in late stage disease. For conquering this problem a partial inhibition of Bcr-Abl by imatinib is required for this approach in agreement with the proposed mode of action.
Treatment with imatinib is very effective in Bcr-Abl positive leukemia. However, development of resistance to this drug is a common phenomenon in late stage disease. The Bcr-Abl protein localizes to the cytoplasm in transformed cells but can enter the nucleus upon treatment with imatinib. Using leptomycin B (LMB), a nuclear export blocker, it has been shown that reactivated nuclear Bcr-Abl kinase activity can induce cell death, thus presenting an interesting potential treatment option for imatinib resistant disease. Here we show that the combination of imatinib and LMB effectively induces cell death in imatinib-resistant Ba/F3 cells which display Bcr-Abl amplification or signs of clonal evolution. However, no such synergism is observed in imatinib-resistant Ba/F3 cells carrying the T315I mutation of Bcr-Abl or those which have lost Bcr-Abl expression. Thus, a partial inhibition of Bcr-Abl by imatinib is required for this approach in agreement with the proposed mode of action.
Ther Clin Risk Manag. 2008 Feb;4(1):149-62.
Din OS, Woll PJ.
Academic Department of Clinical Oncology, University of Sheffield Weston Park Hospital, Sheffield, UK.
Treatment of gastrointestinal stromal tumor: focus on imatinib mesylate.
Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. The present review summarizes the current knowledge of GIST and imatinib treatment and possible future developments.
Gastrointestinal stromal tumor (GIST) is a rare primary neoplasm of the gastrointestinal tract, mesentery, or omentum. In the past, surgery has been the only effective treatment. The diagnosis and treatment of GIST has been revolutionized over the past decade, since expression of the receptor tyrosine kinase KIT was shown to occur on these tumors. Mutations in this proto-oncogene commonly cause constitutive activation of the KIT tyrosine kinase receptor, an important factor in the pathogenesis of the disease. The development of specific tyrosine kinase inhibitors, such as imatinib mesylate, has led to a breakthrough in the treatment of advanced GIST. Treatment with this drug has led to significant improvements in survival, with overall response rates in excess of 80%. Side effects are common, but usually manageable. The success of this drug has led to further trials investigating its use in the pre- and postoperative situation. This review summarizes the current knowledge of GIST and imatinib treatment and possible future developments.
Anticancer Res. 2008 Jul-Aug;28(4C):2317-20.
Pectasides D, Nikolaou M, Pectasides E, Koumarianou A, Valavanis C, Economopoulos T.
Second Department of Internal Medicine, Propaedeutic, Oncology Section, General Hospital Attikon, University of Athens, Haidari, Athens, Greece.
Complete response after imatinib mesylate administration in a patient with chemoresistant stage IV seminoma.
The present study revealed that following treatment with imatinib plus third-line chemotherapy (paclitaxel, oxaliplatin, gemcitabine), the levels of beta-HCG were reduced to within the normal limits during the first month of treatment. Therefore, the patient underwent surgical resection of the residual disease from the retroperitoneum and liver, which proved to be only necrotic tissue.
The case of a young man with stage IV chemoresistant pure seminoma overexpressing KIT, who achieved complete remission (CR) after the administration of imatinib mesylate (400 mg once daily), along with a third-line chemotherapy regimen, consisting of paclitaxel (150 mg/m2), oxaliplatin (100 mg/m2) and gemcitabine (800 mg/m2) every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support is reported. The patient had received first- and second-line regimens consisting of ifosfamide, bleomycin, etoposide cisplatin (5 cycles, every 3 weeks) and methotrexate, vinblastine, actinomycin D, cyclophosphamide, cisplatin (3 cycles, every 3 weeks) respectively, without having normalized beta-human chorionic gonadotrophin (beta-HCG) levels. Following treatment with imatinib plus third-line chemotherapy (paclitaxel, oxaliplatin, gemcitabine), the levels of beta-HCG were reduced to within the normal limits during the first month of treatment. Therefore, the patient underwent surgical resection of the residual disease from the retroperitoneum and liver, which proved to be only necrotic tissue. The patient is under close follow-up, with no evidence of disease, 36 months after the completion of chemotherapy and 32 months post surgery.
Leukemia. 2008 Aug 28.
Cortes J, Kim DW, Raffoux E, Martinelli G, Ritchie E, Roy L, Coutre S, Corm S, Hamerschlak N, Tang JL, Hochhaus A, Khoury HJ, Brümmendorf TH, Michallet M, Rege-Cambrin G, Gambacorti-Passerini C, Radich JP, Ernst T, Zhu C, Van Tornout JM, Talpaz
Department of Leukemia; MD Anderson Cancer Center, Houston, TX, USA.
Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase.
Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this study dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively.
Dasatinib is an inhibitor of BCR-ABL and SRC-family kinases for patients with imatinib-resistant or -intolerant chronic myelogenous leukemia (CML). In this international phase II trial, dasatinib was administered orally (70 mg twice daily) to patients with myeloid blast phase (MBP, n=109) or lymphoid blast phase (LBP, n=48) CML. After a minimum follow-up of 12 months (range 0.03-20.7 months), major hematologic responses were induced in 34% (MBP-CML) and 35% (LBP-CML) of patients. Major cytogenetic responses were attained in 33% (MBP-CML) and 52% (LBP-CML) of patients and complete cytogenetic responses were attained in 26 and 46%, respectively. Median progression-free survival was 6.7 (MBP-CML) and 3.0 (LBP-CML) months. Median overall survival was 11.8 (MBP-CML) and 5.3 (LBP-CML) months. Overall, dasatinib had acceptable tolerability. Fluid retention events were more frequent in the MBP-CML than the LBP-CML cohort: pleural effusion occurred in 36 and 13% (all grades) and 15 and 6% (grades 3/4), respectively. Other non-hematologic side effects were primarily grade 1/2; grade 3/4 events were recorded in
Bone Marrow Transplant. 2008 Sep 1.
Magro L, Catteau B, Coiteux V, Bruno B, Jouet JP, Yakoub-Agha I.
Service des Maladies du Sang, Lille, France.
Efficacy of imatinib mesylate in the treatment of refractory sclerodermatous chronic GVHD.
Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFbeta) and PDGF pathways. Considering its well-documented clinical profile in other diseases, imatinib is a promising candidate for the treatment of sclerodermatous cGVHD.
Treatment of sclerodermatous chronic GVHD (cGVHD) remains disappointing. Imatinib mesylate enables selective, dual inhibition of the transforming growth factor beta (TGFbeta) and PDGF pathways. Recently, the drug's effects on fibroblasts have been reported in both in vitro and in vivo studies. The inhibition of fibroblast growth and decreased collagen production in dermal fibroblasts is thus a logical therapeutic approach. Two patients who developed refractory sclerodermatous cGVHD following allo-SCT received imatinib mesylate at the dose of 400 mg/day. In both patients, the scleroderma symptoms disappeared within 3 months of initiation of the treatment. At the time of this report, the two patients were both alive and had a very good skin response. This report shows that imatinib is effective in patients with refractory sclerodermatous cGVHD. Considering its well-documented clinical profile in other diseases, imatinib is a promising candidate for the treatment of sclerodermatous cGVHD.
Scott Med J. 2008 Aug;53(3):8-12.
Shepherd P, Dhanapala C, Maguire C, White J, Drummond M, Holyoake T, Johnson PR.
Department of Haematology, Western General Hospital, Edinburgh.
Successful use of National Cancer Registry data to monitor the effective use of imatinib for treating chronic myeloid leukaemia.
Imatinib is a tyrosine kinase inhibitor, which selectively antagonises the BCR-ABL molecular pathway which causes chronic myeloid leukaemia (CML). The present study concluded that ongoing resource for assessing outcomes in a rare form of leukaemia but one which already has major implications for health economics and will continue to do so given the future development of dual tyrosine kinase inhibitors for imatinib resistant case
Imatinib is a tyrosine kinase inhibitor, which selectively antagonises the BCR-ABL molecular pathway which causes chronic myeloid leukaemia (CML). Imatinib was first approved by the Scottish Medicines Consortium (SMC) in January 2002 with the recommendation that its use be audited. The cost of the drug has major financial implications for health resources. METHODS: All imatinib usage since its first prescription in Scotland in September 2000 to July 2003 was audited through pharmacy records and through the Scotland Leukaemia Registry (SLR), an existing national registry of patients with CML. RESULTS: One hundred and four patients in Chronic Phase (CP), 36 in Accelerated Phase (AP) and five in Blast Phase (BP) received imatinib. The median duration of therapy was not reached for CFP 17 months for AFP and two months for BP patients. Major (complete) cytogenetic response rates were 74% (63%) and 38% (24%) respectively for CP and APR Overall survival for all CP patients from the start of imatinib therapy was 94% at one year, 91% at two years and 83% at three years. An audit of the effectiveness of the SLR as an auditing agency, showed complete registration in 95% of cases. CONCLUSIONS: We believe such data collection should be an important ongoing resource for assessing outcomes in a rare form of leukaemia but one which already has major implications for health economics and will continue to do so given the future development of dual tyrosine kinase inhibitors for imatinib resistant cases.
Curr Clin Pharmacol. 2008 Sep;3(3):198-203.
Pursche S, Schleyer E, von Bonin M, Ehninger G, Said SM, Prondzinsky R, Illmer T, Wang Y, Hosius C, Nikolova Z, Bornhäuser M, Dresemann G.
Carl-von-Basedow Klinikum Merseburg, Abteilung Innere Medizin II, Weibetae Mauer 52, 06217 Merseburg, Germany.
Influence of enzyme-inducing antiepileptic drugs on trough level of imatinib in glioblastoma patients.
The present study investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). The resulted data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.
Background: Imatinib mesylate is used in combination with hydroxyurea (HU) in ongoing clinical phase II studies in recurrent glioblastoma multiforme (GBM). CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) like carbamazepine, phenytoin, and oxcarbazepine - as well as non-EIAEDs like valproic acid, levetiracetam, and lamotrigine - are frequently used in patients with GBM. Since CYP3A4 is the major isozyme involved in the metabolism of imatinib, we investigated the influence of EIAEDs on imatinib pharmacokinetics (pk). Methods: GBM patients received 600 mg imatinib p.o./o.d. in combination with 1.0 g HU p.o./o.d..together with either EIAEDs, non-EIAEDs, or no antiepileptic drug (non-AEDs) comedication. Trough plasma levels of imatinib and its active main metabolite N-desmethyl-imatinib (CGP74588) were determined biweekly in these patients, total 543 samples being collected from 224 patients (up to 6 times / patient). All three groups were compared to each other and with historical pharmacokinetic data obtained from patients with chronic myeloid leukemia (CML). Results: Mean imatinib trough levels in patients not receiving AEDs ( 1404 ng/ml, CV 64%) and on non-EIAEDs (1374 ng/ml, CV 46%) were comparable with mean imatinib trough levels of the historical control group of CML patients (1400 ng/ml, CV 50%). Mean trough levels of imatinib were reduced up to 2.9-fold (477 ng/ml, CV 70%) in patients treated with EIAEDs. Only slight, but although significant differences were observed in the mean trough level of the metabolite CGP74588 between EIAED-, non-EIAED and no-AED patients, 240 ng/ml (CV 57%), 351 ng/ml (CV 34%) and 356 ng/ml (CV 52%), respectively. The corresponding mean level for CML patients was 300 ng/ml (CV 50%). Conclusion: Significant decreases of imatinib and CGP74588 trough levels were observed for patients receiving EIAEDs. The EIAED-induced reduction in trough imatinib levels can be avoided by switching to non-EIAEDs comedication or compensated by administering higher imatinib doses. In addition these data demonstrate that there is no significant difference in the pharmacokinetics of imatinib between patients with glioblastoma and CML.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2008 Jun;152(1):121-3.
Skoumalova I, Vondrakova J, Rohon P, Rozmanova S, Jarosova M, Indrak K, Prochazka M, Santava A, Faber E.
Department of Hemato-Oncology, Teaching Hospital Olomouc, Czech Republic.
Successful childbirth in a patient with chronic myelogenous leukemia treated with imatinib mesylate during early pregnancy.
The present study is to report a case of successful pregnancy in a patient with chronic myelogenous leukemia treated with imatinib mesylate for the first 4 months of pregnancy. The present study discusses possible strategies for successful management of pregnancy in CML patients treated with imatinib.
Aims: To report a case of successful pregnancy in a patient with chronic myelogenous leukemia treated with imatinib mesylate for the first 4 months of pregnancy. Results: Imatinib mesylate is potentially teratogenic and its use during pregnancy in humans can lead to abortion or development of fetal abnormalities in nearly 40% of fully reported cases. We report a case of a 28-year-old woman who delivered a healthy child of normal weight after having been treated with imatinib for Ph1-positive CML during the first four months of her pregnancy. She refused advocated interruption and for the rest of the pregnancy was treated with interferon. The treatment was associated with a rapid 2-log increase in the leukemia clone measured by the real-time polymerase chain reaction. Reintroduction of imatinib after delivery resulted in achievement of the complete cytogenetic response again. Conclusions: We discuss possible strategies for successful management of pregnancy in CML patients treated with imatinib.
Cancer Lett. 2008 Sep 20
Weigel MT, Meinhold-Heerlein I, Bauerschlag DO, Schem C, Bauer M, Jonat W, Maass N, Mundhenke C.
Department of Obstetrics and Gynecology, Breast Center, University Hospital Schleswig-Holstein, Campus Kiel, Michaelisstrasse 16, 24105 Kiel, Germany.
Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling.
The present study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR beta and Akt: a downstream modulator of cell growth and survival. This study performed that the growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR beta and Akt.
INTRODUCTION: Imatinib mesylate is a tyrosine kinase receptor inhibitor targeted against PDGFR alpha and beta, c-kit and bcr-abl. These receptors regulate cellular processes such as proliferation, differentiation, and survival. This study was performed to evaluate the effects of imatinib on breast cancer cell lines with respect to the activity of PDGFR beta and Akt: a downstream modulator of cell growth and survival. METHODS: Expression of imatinib targets was analyzed with reverse transciptase PCR and immunoblotting assays in the breast cell lines MDA MB 231, MCF 7, ZR 75-1, and T 47-D. Changes on receptor expression and phosphorylation status under imatinib were evaluated using drug concentrations of 2 to 10muM. The anti-proliferative and pro-apoptotic effects of imatinib alone and in combination with vinorelbine were investigated with an MTT and TUNEL assay. RESULTS: Imatinib inhibited growth and induced apoptosis of all cell lines examined. This effect was increased when combined with vinorelbine. A dose-dependent inhibitory effect on the phosphorylation of PDGFR beta and Akt was detected. CONCLUSIONS: The growth inhibitory effect of imatinib on breast cell lines may be caused by inhibiting the activity of the tyrosine kinases PDGFR beta and Akt. Imatinib is a promising novel drug for targeted therapy of breast cancer patients.
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