• Bulletin of the Korean Chemical Society
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• 제31권12호
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• pp.3525-3529
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• 2010

Tyrosine kinase inhibitors (TKIs) are currently used in the treatment of patients with advanced lung cancer. Recent studies on non-small cell lung cancer have shown that some patients carry somatic mutations in the epidermal growth factor receptor (EGFR) gene. Such mutations correlate with the effectiveness of certain TKIs. To detect a small amount of mutant EGFR among an abundance of wild-type EGFR, we have developed a highly sensitive and simple method using PNA-mediated real-time PCR clamping. The PNA-mediated real-time PCR clamping enables detection of EGFR mutants down to approximately 1% mutant -to- wild type. The total assay time was short as it required only 2.0 hr. Thus, PNA-mediated real-time PCR clamping can easily be applied to clinical samples for identification of DNA carrying EGFR mutations and also appear to be the best assay to detect somatic mutations.

• Asian Pacific Journal of Cancer Prevention
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• 제13권1호
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• pp.255-260
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• 2012

Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors ((EGFR-TKIs)-namely gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. Despite the fact that this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as T790M or amplification of the MET proto-oncogene, there are other mechanisms which need to be explored. MicroRNAs (miRs) are a class of small non-coding RNAs that play pivotal roles in tumorigenesis, tumor progression and chemo-resistance. In this study, we firstly successfully established a gefitinib resistant cell line-HCC827/GR, by exposing normal HCC827 cells (an NSCLC cell line with a 746E-750A in-frame deletion of EGFR gene) to increasing concentrations of gefitinib. Then, we found that miR-214 was significantly up-regulated in HCC827/GR. We also showed that miR-214 and PTEN were inversely expressed in HCC827/GR. Knockdown of miR-214 altered the expression of PTEN and p-AKT and re-sensitized HCC827/GR to gefitinib. Taken together, miR-214 may regulate the acquired resistance to gefitinib in HCC827 via PTEN/AKT signaling pathway. Suppression of miR-214 may thus reverse the acquired resistance to EGFR-TKIs therapy.

• 한국임상수의학회지
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• 제36권6호
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• pp.319-324
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• 2019

Receptor tyrosine kinases (RTK) are major promising targets in anticancer therapy in human and veterinary medicine. Using immunohistochemistry method, we evaluated the expressionof five types RTK (PDGFR-α, PDGFR-β, VEGFR 2, c-Kit and Abl) in the six canine brain tumor samples (2 meningioma, 2 astrocytoma, 1 ependymoma and 1 choroid plexus papilloma). A total of five samples expressed PDGFR-β (5/6), one sample, the choroid plexus papilloma, expressed c-Kit (1/6), and a total of two samples expressed Abl (2/6). None of the samples showed expression of PDGFR-α and VEGFR 2. We demonstrate that a significant portion of canine brain tumors express tyrosine receptors for growth factors and show that these receptors generally localize to tumor cell membranes and the cytoplasm. Evaluation of immunohistochemical expression for the RTKs PDGFR-β, c-Kit, and Alb in canine brain samples reveals an interesting potential for molecular targeting by TKIs in therapeutic studies of canine brain tumors, and more studies will be needed to assess the interactions and efficacy of these RTKs and TKIs. Based on these results, we have some evidence for novel chemotherapeutic trials using TKIs for canine nervous tumors.

• Tuberculosis and Respiratory Diseases
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• 제82권1호
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• pp.62-70
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• 2019

Background: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR. Methods: We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. Results: The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were independent predictors of PFS. ECOG PS 0-1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. Conclusion: Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

• 항공우주의학회지
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• 제31권3호
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• pp.82-83
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• 2021

Chronic myeloid leukemia (CML) is myeloproliferative neoplasm associated with a characteristic chromosomal translocation (bcr-abl) called Philadelphia chromosome which plays a key role in the pathogenesis. Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis. During this phase, patients are well tolerated and have few symptoms. But untreated, over the course of several years progresses to an accelerated phase and ultimately to a blast crisis, the terminal phase. CML is largely treated with targeted drug therapy called tyrosine-kinase inhibitors (TKIs) which have led to dramatically improved long-term survival rates since 2001. These drugs became standard treatment of this disease and allow most patients to have much better quality of life when compared to the former chemotherapy drugs and the bone marrow transplantation. Imatinib (Gleevec or Glivec, Norvatis) was the first of these TKIs and found to inhibit the progression of CML in the majority of patients (65%-75%) sufficiently to achieve remission. Since the advent of imatinib, CML has become the first neoplasm in which a medical treatment can give to the patient a normal life expectancy.

• 한국임상약학회지
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• 제34권1호
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• pp.71-78
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• 2024

Background: Oral cancer drugs, particularly tyrosine kinase inhibitors (TKIs), are increasingly popular due to their convenience. However, they pose challenges like drug interactions, especially with medications like azole antifungals. While the FDA provides some guidance, more detailed information is needed to manage these interactions effectively. A meta-analysis was conducted to understand the impact of interactions between TKIs and azole antifungals on adverse events during clinical studies. Methods: A meta-analysis followed PRISMA guidelines. Data from PubMed, EMBASE, and references were searched until November 30, 2021. Inclusion criteria encompassed studies on TKI-antifungal interactions in English. Study selection and quality assessment were conducted by two independent investigators. Results: Out of 158 articles, 11 were selected for analysis. Combination therapy showed a slight increase in adverse events but was not statistically significant (OR 1.02, 95% CI 0.49-2.13, p=0.95). AUC and Cmax fold changes did not significantly impact adverse event development. Both itraconazole and ketoconazole showed no significant difference in adverse event development compared to TKI alone. Conclusions: Study finds TKI-DDI not significantly linked to AE increase; azole antifungal types not related to AE. Future DDI research crucial for drug development.

• Asian Pacific Journal of Cancer Prevention
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• 제13권10호
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• pp.5177-5182
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• 2012

Purpose: To compare the efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitormonotherapy (EFGR-TKIs: gefitinib or erlotinib) with standard second-line chemotherapy (single agent docetaxel or pemetrexed) in previously treated advanced non-small-cell lung cancer (NSCLC). Methods: We systematically searched for randomized clinical trials that compared EGFR-TKI monotherapy with standard second-line chemotherapy in previously treated advanced NSCLC. The end points were overall survival (OS), progression-free survival (PFS), overall response rate (ORR), 1-year survival rate (1-year SR) and grade 3 or 4 toxicities. The pooled hazard ratio (HR) or risk ratio (RR), with their corresponding 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. Results: Eight randomized controlled trials (totally 3218 patients) were eligible. Our meta-analysis results showed that EGFR-TKIs were comparable to standard second-line chemotherapy for advanced NSCLC in terms of overall survival (HR 1.00, 95%CI 0.92-1.10; p=0.943), progression-free survival (HR 0.90, 95%CI 0.75-1.08, P=0.258) and 1-year-survival rate (RR 0.97, 95%CI 0.87-1.08, P=0.619), and the overall response rate was higher in patients who receiving EGFR-TKIs(RR 1.50, 95%CI 1.22-1.83, P=0.000). Sub-group analysis demonstrated that EGFR-TKI monotherapy significantly improved PFS (HR 0.73, 95%CI: 0.55-0.97, p=0.03) and ORR (RR 1.96, 95%CI: 1.46-2.63, p=0.000) in East Asian patients, but it did not translate into increase in OS and 1-year SR. Furthermore, there were fewer incidences of grade 3 or 4 neutropenia, febrile neutropenia and neutrotoxicity in EGFR-TKI monotherapy group, excluding grade 3 or 4 rash. Conclusion: Both interventions had comparable efficacy as second-line treatments for patients with advanced NSCLC, and EGFR-TKI monotherapy was associated with less toxicity and better tolerability. Moreover, our data also demonstrated that EGFR-TKImonotherapy tended to be more effective in East Asian patients in terms of PFS and ORR compared with standard second-line chemotherapy. These results should help inform decisions about patient management and design of future trials.

• 한국임상약학회지
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• 제30권1호
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• pp.44-50
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• 2020

Background: Drug-drug interactions (DDIs) in patients using oral anticancer treatment are more common than in those using injectable anticancer agents. In addition, DDIs related to anticancer treatment are known to cause clinically significant outcomes, such as treatment failure and severe toxicity. To prevent these negative outcomes, significant DDIs are monitored and managed using the information provided in drug databases. We aimed to evaluate the consistency of information on clinically significant DDIs for tyrosine kinase inhibitors (TKIs) between representative drug databases. Methods: We selected clinically significant DDIs involving medications that are co-prescribed with TKIs and met the following criteria: the severity level of DDIs was equal or greater than "D" in Lexicomp^® or "major" in Micromedex^®. We then analyzed the consistency of the severity classification and evidence level between the drug databases. Spearman's correlation coefficient was used to identify the relationship between DDI information in the drug databases. Results: In total, 627 DDI pairs were identified as clinically significant; information on these was provided by Lexicomp^® and Micromedex^® for 571 and 438 pairs, respectively, and both drug databases provided information on 382 DDI pairs. There was no correlation between the severity and evidence level of DDIs provided in the two databases; Spearman's correlation coefficient for Lexicomp^® and Micromedex^® was -0.009 (p=0.861) and -0.064 (p=0.209), respectively. Conclusion: To judge the significance of DDIs, healthcare providers should consider that the information on DDIs may be different between drug information databases; hence, clinical factors must be considered concurrently.

• 한국임상수의학회지
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• 제33권4호
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• pp.187-193
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• 2016

A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions. This study aims to show that the actions of growth factors associated with PDGFR-${\alpha}$, PDGFR-${\beta}$, VEGFR-2, c-KIT, and c-ABL, which are used in veterinary medicine, are expressed in canine intractable tumors. This study used archival cases of canine paraganglioma, gastrointestinal adenocarcinoma, hepatocellular carcinoma, and renal cell carcinoma. Tissues had been immunohistochemical analysis. The antibodies used were PDGFR-${\alpha}$, PDGFR-${\beta}$, c-kit, VEGFR-2, and c-Abl. PDGFR-${\alpha}$ was expressed only in HCC, and PDGFR-${\beta}$ was expressed in all tumors. VEGFR was also only expressed in HCC, and c-KIT has been expressed in HCC, paraganglioma, and small intestinal adenocarcinoma. c-Abl was expressed in all cancers, but was weakly expressed in paraganglioma, while more than moderately expressed in other tissues. In conclusion, this study investigated how TKIs used in human medicine can be applied to canine intractable tumors, through immunohistochemistry. The results indicate that there may be an application for TKIs in treating canine intractable tumors.

• Clinical and Experimental Pediatrics
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• 제54권3호
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• pp.111-116
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• 2011

Childhood chronic myelogenous leukemia (CML) is a rare hematologic disease, with limited literature on the methods of treatment. Previously, allogeneic hematopoietic stem cell transplantation (HSCT) was considered the only curative treatment for this disease. Treatment with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase (TKI), has resulted in prolonged molecular response with limited drug toxicity. Imatinib is now implemented in the primary treatment regimen for children, but the paucity of evidence on its ability to result in permanent cure and the potential complications that may arise from long-term treatment with TKIs have prevented imatinib from superseding HSCT as the primary means of curative treatment in children. The results of allogeneic HSCT in children with CML are similar to those observed in adults; HSCT-related complications such as transplant-related mortality and graft-versus-host disease remain significant challenges. An overall consensus has been formed with regards to the need for HSCT in patients with imatinib resistance or those with advanced-phase disease. However, issues such as when to undertake HSCT in chronic-phase CML patients or how best to treat patients who have relapsed after HSCT are still controversial. The imatinib era calls for a reevaluation of the role of HSCT in the treatment of CML. Specific guidelines for the treatment of pediatric CML have not yet been formulated, underscoring the importance of prospective studies on issues such as duration of imatinib treatment, optimal timing of HSCT and the type of conditioning utilized, possible treatment pre-and post-HSCT, and the role of second-generation TKIs.