• Journal of Life Science
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• v.21 no.3
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• pp.349-357
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• 2011

Inhibitors of EGFR (epidermal growth factor receptor) kinase activity may prove useful to therapeutically intervene in cancer and to treat other proliferative diseases. In this study, we investigated the inhibitive effects of two compounds named 63013 and 63033 possess a [1,4]-dioxino quinazoline structure that links the alkoxy side chains together and their structural characteristics are considered to allow better solubility than the dialkoxyquinazoline derivatives. The EGFR kinase activities of A431 human epidermoid carcinoma cells, stimulated by EGF were inhibited by treatment with 63013 and 63033 in a dose-dependent manner respectively. Consistent with the compound-mediated EGFR kinase suppression, the major EGF-related downstream target molecules, such as MEK1/2, MAPK p44/42, AKT and STAT3, were also suppressed by both compounds. Interestingly, both compounds led to cell growth inhibition at a lower concentration than that of Gefitinib (Iressa$^{(R)}$). Collectively, our study showed that both compounds may have good therapeutic potential as an EGFR kinase specific inhibitor to treat EGFR-related diseases.

• Tuberculosis and Respiratory Diseases
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• v.63 no.1
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• pp.42-51
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• 2007

Background: TRAIL is a cytokine that selectively induces apoptosis in various cancer cell lines. Gefitinib is new targeted drug applied in lung cancer that selectively inhibits EGFR tyrosine kinase. However, lung cancers have shown an initial or acquired resistance to these drugs. This study examined the effect of IGF-1R and its blockade on enhancing the sensitivity of lung cancer cell lines to TRAIL and gefitinib. Methods: Two lung cancer cell lines were used in this study. NCI H460 is very sensitive to TRAIL and gefitinib. On the other hand, A549 shows moderate resistance to TRAIL and gefitinib. The IGF-1R blockade was performed using adenoviruses expressing the dominant negative IGF-1R and shRNA to IGF-1R and AG1024 (IGF-1R tyrosine kinase inhibitor). Results: The adenovirus expressing dominant negative IGF-1R(950st) induced the increased expression of defective IGF-1R on the lung cancer cell surface, and the adenovirus-shIGF-1R effectively decreased the level of IGF-1R expression on cell surface. The genetic blockade of IGF-1R by the adenovirus-dnIGF-1R and AG1024 increased the sensitivity of A549 cells to TRAIL. The reduction of IGF-1R by transduction with ad-shIGF-1R also increased the sensitivity of the A549 cells to gefitinib. Conclusion: The blockade of IGF-1R through various mechanisms increased the sensitivity of the lung cancer cell line that was resistant to TRAIL and gefitinib. However, further studies using other cell lines showing acquired resistance as well as in vivo animal experiments will be needed.

• The Journal of Korean Medicine
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• v.30 no.6
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• pp.112-117
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• 2009

Objective: Rhus verniciflua Stokes (RVS) has anticancer effect confirmed by preclinical studies and historical records. We thus tried to evaluate retrospectively the effect of RVS as a complementary medicine for patients with advanced non-small-cell lung cancer (NSCLC) showing refractory to conventional chemotherapy. Patients and Methods: From June 1, 2006 to June 30, 2007, patients with advanced NSCLC who received both the standardized RVS extract and a standard course of second or more line therapy such as pemetrexed ($Alimta^{(R)}$), erlotinib ($Tarceva^{(R)}$), and gefitinib ($Iressa^{(R)}$) were checked. A total of 13 patients were eligible for the final analysis after fulfilling inclusion/exclusion criteria. Time to progression (TTP) of these patients treated with the standardized RVS extract was checked in the aftercare period. Results: Patients received RVS treatment for a median period of 296 (range 84-698) days. The median TTP was 220.5 (range 36-489) days, and three patients (23.1%) had TTP values of 15 more months. No significant side effects from RVS treatment have been observed. Conclusion: The standardized RVS extract might have synergetic effects by assisting apoptosis in advanced NSCLC with concurrent standard therapy agents, since it prolonged TTP without significant adverse effects. This study suggests that the standardized RVS extract is beneficial to patients with chemotherapy-refractory NSCLC. Further clinical trials and preclinical studies are necessary to determine the efficacy and safety of the standardized RVS extract in NSCLC.