• Tuberculosis and Respiratory Diseases
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• v.59 no.4
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• pp.423-426
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• 2005

Imatinib-mesylate (Gleevec, Glivec) is a protein-tyrosine kinase inhibitor that inhibits the Bcr-Abl tyrosine kinase created by the Philadelphia chromosome abnormality in CML. Imatinib is also used to treat patients with c-kit (CD 117)-positive unresectable tumors, or metastatic malignant gastrointestinal stromal tumors, or both. Imatinib is a welltolerated drug with few side effects. However, it has been associated with gastrointestinal irritation, fluid retention and edema, skin rashes, depigmentation, hepatotoxicity, hemorrhage, and hematological toxicity (anemia, neutropenia, and thrombocytopenia). In addition, imatinib has been associated with dyspnea and cough, which are mainly secondary to the pleural effusion and pulmonary edema, which represent local or general fluid retention. These events appear to be dose related and are more common encountered in the elderly. However, there has been no report of hypersensitivity pneumonitis associated with imatinib-mesylate in Korea. We report a case of 51-year old woman who developed hypersensitivity pneumonitis that might have been induced by imatinib-mesylate during the treatment of a gastrointestinal stromal tumor.

• Biomolecules & Therapeutics
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• v.25 no.5
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• pp.490-496
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• 2017

Imatinib resistance has become a major clinical problem for chronic myeloid leukemia. The aim of the present study was to investigate the involvement of MEG3, a lncRNA, in imatinib resistance and demonstrate its underlying mechanisms. RNAs were extracted from CML patients' peripheral blood cells and human leukemic K562 cells, and the expression of MEG3 was measured by RT-qPCR. Cell proliferation and cell apoptosis were evaluated. Western blotting was used to measure the protein expression of several multidrug resistant transporters. Luciferase reporter assay was performed to determine the binding between MEG3 and miR-21. Our results showed that MEG3 was significantly decreased in imatinib-resistant CML patients and imatinib-resistant K562 cells. Overexpression of MEG3 in imatinib-resistant K562 cells markedly decreased cell proliferation, increased cell apoptosis, reversed imatinib resistance, and reduced the expression of MRP1, MDR1, and ABCG2. Interestingly, MEG3 binds to miR-21. MEG3 and miR-21 were negatively correlated in CML patients. In addition, miR-21 mimics reversed the phenotype of MEG3-overexpression in imatinib-resistant K562 cells. Taken together, MEG3 is involved in imatinib resistance in CML and possibly contributes to imatinib resistance through regulating miR-21, and subsequent cell proliferation, apoptosis and expression of multidrug resistant transporters.

• Journal of Yeungnam Medical Science
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• v.36 no.2
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• pp.155-158
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• 2019

Imatinib mesylate is currently used as the first-line treatment for metastatic gastrointestinal stromal tumors (GISTs). Imatinib-induced hepatotoxicity in patients with GIST is very rare. Its features vary from subclinical elevation of serum aminotransferase to clinically apparent acute hepatitis, which is associated with immunologic reactions. Imatinib-induced hepatotoxicity with autoimmune-like features can be treated by the discontinuation of imatinib mesylate and the administration of oral steroids. Here, we report a case of late-onset imatinib-induced hepatitis with autoimmune-like features in a patient with metastatic GIST, which was improved by oral corticosteroids.

• Journal of Life Science
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• v.30 no.8
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• pp.661-671
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• 2020

The resistance of cancer cells to anti-cancer drugs is the leading cause of chemotherapy failure. The clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been gradually extended to cancer treatment through combination with anti-cancer drugs. In the current study, we investigated whether NSAIDs including celecoxib (CCB), 2,5-dimethyl celecoxib (DMC), and ibuprofen (IBU) could enhance the cytotoxic effects of imatinib and TNF-related apoptosis inducing ligand (TRAIL) on human cancer cells. We found that the NSAIDs potentiated TRAIL and imatinib cytotoxicity against human hepatocellular carcinoma (HCC) cell lines SNU-354, SNU-423, SNU-449, and SNU-475/TR and against leukemic K562 cells with high level of CD44 (CD44^highK562), respectively. More specifically, CCB induced endoplasmic reticulum stress via up-regulation of ATF4/CHOP which is associated with the induction of autophagy against HCC and CD44^high K562 cells. NSAID-induced autophagic activity accelerated TRAIL cytotoxicity of HCC cells through up- and down-regulation of DR5 and c-FLIP, respectively. The NSAIDs also potentiated imatinib-induced cytotoxicity and apoptosis through down-regulation of markers in CD44^highK562 cells that express a stemness phenotype. Our results suggest that the ability of NSAIDs to induce autophagy could enhance the cytotoxicity of TRAIL and imatinib, leading to a reverse resistance to these drugs in the cancer cells. In conclusion, NSAIDs in combination with low-dose TRAIL or imatinib may constitute a novel clinical strategy that maximizes therapeutic efficacy of each drug and effectively reduces the toxic side effects.

• BMB Reports
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• v.38 no.6
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• pp.725-738
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• 2005

Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a $1\;{\mu}M$ imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.43 no.2
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• pp.120-124
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• 2017

Osteonecrosis of the jaw (ONJ) is commonly described as an adverse effect of the use of bisphosphonates. A few cases of ONJ associated with tyrosine kinase inhibitors (sunitinib, imatinib) have been reported in the literature and usually they occurred in patients simultaneously treated with bisphosphonates. We report an atypical case of ONJ related only to imatinib. A 72-year-old male patient was treated with imatinib for metastases from gastrointestinal stromal tumors (GISTs). The patient developed ONJ after 22 months of imatinib only therapy. During his whole life, the patient had never been treated with bisphosphonates or radiotherapy. Microscope examination of the tissues confirmed the clinical diagnosis of diffuse osteonecrosis and showed absence of neoplastic cells. Thus, secondary localisations from GISTs were ruled out. Osteonecrosis of the lower jaw appeared 22 months after initial and exclusive therapy with imatinib. Therefore, imatinib monotherapy can induce ONJ in patients that have never been treated with bisphosphonates or radiotherapy.

• Journal of Digestive Cancer Research
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• v.1 no.2
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• pp.100-103
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• 2013

A 79-year-old man was diagnosed with gastrointestinal stromal tumor (GIST) of the gastric cardia. We performed proximal subtotal gastrectomy and started imatinib therapy as adjuvant treatment after surgery. Whole body skin rash with urticaria was onset on 10 days after imatinib treatment, and the patient decided to stop imatinib because of side effect. After 3 months, PET CT revealed GIST was recurred at spleen and abdominal lymph nodes, abdominal wall. The patient was then restarted on imatinib therapy. On follow-up imaging studies, the tumor almost disappeared, but both pleural effusion and pericardial effusion were found. In this paper, we describe a case of clinical course and side effects in recurred GIST after adjuvant imatinib mesylate treatment.

• YAKHAK HOEJI
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• v.60 no.3
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• pp.118-127
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• 2016

A growing number of studies have demonstrated that ABCB1 gene polymorphisms are associated with the variability of responses to imatinib. However, the effects of ABCB1 polymorphisms on imatinib response in chronic myeloid leukemia (CML) are inconsistent. The aim of the present study was to clarify the associations between ABCB1 polymorphisms and imatinib response in CML. A systematic literature review was performed. The databases of PubMed, Embase, and Cochrane Library were searched for all published studies from inception to December 2015. The following terms were used with functions of 'AND' and 'OR': 'chronic myeloid leukemia', 'CML', 'ABCB1', 'MDR1', 'polymorphism', 'SNP', and 'imatinib'. Using the Review Manager 5, odds ratios (ORs) were pooled to estimate the effect of ABCB1 polymorphisms on imatinib response in CML. The pooled analysis showed that ABCB1 2677 G allele was significantly associated with poor response to imatinib in African and Asian patients (GG vs TT, OR: 0.32, p<0.0001; GG+GT vs TT, OR: 0.44, p=0.0005). In subgroup analyses, African patients carrying ABCB1 1236 C allele exhibited higher risk for worse response, whereas Asian patients with 1236 C allele showed better response (CC+CT vs TT, OR: 0.41, p=0.008 for African; OR: 1.65, p=0.03 for Asian). There was no association between C3435T polymorphisms and imatinib response in African, Asian, and Caucasian CML patients.

• Tuberculosis and Respiratory Diseases
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• v.75 no.6
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• pp.256-259
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• 2013

Imatinib mesylate is a targeted therapy that acts by inhibiting tyrosine kinase of the bcr-abl fusion oncoprotein, which is specific to chronic myeloid leukemia (CML), and the c-transmembrane receptor, which is specific to gastrointestinal stromal tumors. Interstitial pneumonitis is a rare adverse event of imatinib therapy. It is clinically difficult to distinguish from infectious pneumonia, which can frequently occur due to the underlying disease. The standard treatment for imatinib-induced pneumonitis is to discontinue the medication and optionally administer corticosteroids. However, there are a few cases of successful retrial with imatinib. We describe a case of successful rechallenge of imatinib in a patient with imatinib-induced interstitial pneumonitis and CML without a recurrence of the underlying disease after 3 months of follow-up.

• Korean Journal of Clinical Pharmacy
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• v.26 no.1
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• pp.53-58
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• 2016

Objective: To estimate the association between ABCG2 C421A polymorphism and response to imatinib in chronic myeloid leukemia. Methods: A systematic review was conducted to evaluate the effect of ABCG2 C421A polymorphism on imatinib response. The databases of PubMed, Embase, Web of science, CINAHL with FullText, and Cochrane Library were searched for all published studies from inception to December 2015. The following terms were used with functions of 'AND' and 'OR': 'chronic myeloid leukemia', 'CML', 'drug transporter', 'ABCG2', 'BCRP', 'polymorphisms', 'SNPs', and 'imatinib'. The studies reporting the association between ABCG2 polymorphism and imatinib response were evaluated. Results: A total of 7 studies were included in the present meta-analysis. The pooled analysis showed that ABCG2 c.421CC genotype was significantly associated with poor response to imatinib under the dominant model (CC vs CA+AA; OR: 0.56; 95% CI: 0.41, 0.77; p = 0.0004). The subgroup analysis of Asian studies demonstrated a significantly lower response in c.421CC genotype than in c.421CA or c.421AA genotype (OR: 0.52; 95% CI: 0.37, 0.73; p = 0.0002). In subgroup analyses of 5 studies, the patients with the c.421CC genotype exhibited higher risk for worse response than the patients with c.421CA or c.421AA genotype (heterozygote codominant model: CC vs. AC; OR: 0.49, 95% CI: 0.33, 0.73; p = 0.0006; homozygote codominant model: CC vs AA; OR: 0.43; 95% CI: 0.25, 0.75, p = 0.003). Conclusion: The ABCG2 c.421CC genotype was significantly associated with poor response to imatinib compared to the c.421CA and c.421AA genotypes in chronic myeloid leukemia, especially in Asian patients.