• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.69-73
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• 2014

The effects of erlotinib combined with celecoxib in a lung cancer xenograft model were here explored with a focus on possible mechanisms. A xenotransplanted lung cancer model was established in nude mice using the human lung cancer cell A549 cell line and animals demonstrating tumour growth were randomly divided into four groups: control, erlotinib, celecoxib and combined (erotinib and celecoxib). The tumor major axis and short diameter were measured twice a week and after 40 days tissues were collected for immunohistochemical analyses of Bcl-2 and Bax positive cells and Western-blotting analyses for the epidermal growth factor recepto (EGFR), P-EGFR, and cyclooxygenase-2 (COX-2). Tumor size in the combined group was smaller than in the others (p<0.01) and the percentage of Bcl-2 positive cells was fewer in most cases (p<0.01), while that of Bax positive cells was greater than in the erlotinib and celecoxib groups (P>0.05). Western blotting showed decreased expression of P-EGFR and COX-2 with both erlotinib and celecoxib treatments, but most pronouncedly in the combined group (P<0.05). Simultaneous blockage of the EGFR and COX-2 signal pathways exerted stronger growth effects in our human xenotransplanted lung cancer model than inhibition of either pathway alone. The anti-tumor effects were accompanied by synergetic inhibition of tumor cell apoptosis, activation of p-EGFR and expression of COX-2.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.205-213
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• 2014

The outcomes of first-generation EGFR-TKIs (Gefitnib and Erlotinib) have shown great advantages over traditional treatment strategies in patients with non-small cell lung cancer (NSCLC), but unfortunately we have to face the situation that most patients still fail to respond in the long term despite initially good control. Up to now, the mechanism of acquired resistance to EGFR-TKIs has not been fully clarified. Herein, we sought to compile the available clinical reports in the hope to better understanding the subsequent treatment choices, particularly on whether restoring after a drug holiday or switching to another EGFR-TKI is the better option after failure of one kind of EGFR-TKI.

• Asian Pacific Journal of Cancer Prevention
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• 제16권18호
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• pp.8191-8196
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• 2016

Inhibition of EGFR-EGF interactions forms an important therapeutic rationale in treatment of non-small cell lung carcinoma. Established inhibitors have been successful in reducing proliferative processes observed in NSCLC, however patients suffer serious side effects. Considering the narrow therapeutic window of present EGFR inhibitors, the present study centred on identifying high efficacy EGFR inhibitors through structure based virtual screening strategies. Established inhibitors - Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib formed parent compounds to retrieve similar compounds by linear fingerprint based tanimoto search with a threshold of 90%. The compounds (parents and respective similars) were docked at the EGF binding cleft of EGFR. Patch dock supervised protein-protein interactions were established between EGF and ligand (query and similar) bound and free states of EGFR. Compounds ADS103317, AKOS024836912, AGN-PC-0MXVWT, GNF-Pf-3539, SCHEMBL15205939 were retrieved respectively similar to Afatinib, Dacomitinib, Erlotinib, Lapatinib, Rociletinib. Compound-AGN-PC-0MXVWT akin to Erlotinib showed highest affinity against EGFR amongst all the compounds (parent and similar) assessed in the study. Further, AGN-PC-0MXVWT brought about significant blocking of EGFR-EGF interactions in addition showed appreciable ADMET properties and pharmacophoric features. In the study, we report AGN-PC-0MXVWT to be an efficient and high efficacy inhibitor of EGFR-EGF interactions identified through computational approaches.

• Tuberculosis and Respiratory Diseases
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• 제74권1호
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• pp.37-40
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• 2013

Epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been widely used for non-small-cell lung cancer patients. Its untoward cutaneous effects are largely well known and developed in many patients treated with EGFR TKIs. However trichomegaly of eyelash is rarely reported. Although trichomegaly is not a drug-limiting side effect, it could be troublesome of continuing the treatment because of cosmetic issue or eyeball irritation by long eyelashes. Therefore clinicians are needed to pay attention to this uncommon effect. We herein describe erlotinib induced trichomegaly of eyelashes in a woman with adenocarcinoma of the lung.

• Tuberculosis and Respiratory Diseases
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• 제75권1호
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• pp.9-17
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• 2013

Background: In cancer cells, autophagy is generally induced as a pro-survival mechanism in response to treatment-associated genotoxic and metabolic stress. Thus, concurrent autophagy inhibition can be expected to have a synergistic effect with chemotherapy on cancer cell death. Monensin, a polyether antibiotic, is known as an autophagy inhibitor, which interferes with the fusion of autophagosome and lysosome. There have been a few reports of its effect in combination with anticancer drugs. We performed this study to investigate whether erlotinib, an epidermal growth factor receptor inhibitor, or rapamycin, an mammalian target of rapamycin (mTOR) inhibitor, is effective in combination therapy with monensin in non-small cell lung cancer cells. Methods: NCI-H1299 cells were treated with rapamycin or erlotinib, with or without monensin pretreatment, and then subjected to growth inhibition assay, apoptosis analysis by flow cytometry, and cell cycle analysis on the basis of the DNA contents histogram. Finally, a Western blot analysis was done to examine the changes of proteins related to apoptosis and cell cycle control. Results: Monensin synergistically increases growth inhibition and apoptosis induced by rapamycin or erlotinib. The number of cells in the sub-$G_1$ phase increases noticeably after the combination treatment. Increase of proapoptotic proteins, including bax, cleaved caspase 3, and cleaved poly(ADP-ribose) polymerase, and decrease of anti-apoptotic proteins, bcl-2 and bcl-xL, are augmented by the combination treatment with monensin. The promoters of cell cycle progression, notch3 and skp2, decrease and p21, a cyclin-dependent kinase inhibitor, accumulates within the cell during this process. Conclusion: Our findings suggest that concurrent autophagy inhibition could have a role in lung cancer treatment.

• 한국임상약학회지
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• 제18권2호
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• pp.75-83
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• 2008

Purpose: Currently lung cancer ranks second in cancer for incidence rate and is a disease that ranks first for a death rate by cancerous growth because it is already advanced at the time of diagnosis. The purpose of this paper was to analyze the factors that affect the effectiveness of and rash occurrence by Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) in patients with non-small cell lung cancer. Methods: A retrospective chart review of 100 patients, who took EGFR TKI (erlotinib, gefitinib) among patients who were diagnosed with non-small cell lung cancer in a Hospital in Korea between May 2005 and February 2008, was conducted. The drug effectiveness was evaluated by Response Evaluation Criteria In Solid Tumor. Results: EGFR mutation was the only factor associated with drug response (complete response and partial response). When stable disease was added to drug response as the evaluation parameter, ECOG and rash as well as EGFR mutation were found to be important factors. Survival, however, was not affected by EGFR mutation. The factors influenced on survival were older age (${\geq}65$), low ECOG ($1{\sim}2$), adenocarcinoma and rash. In the case of rash, group with EGFR mutation or low ECOG showed significantly higher chance of occurrence. There was no significant difference in rash occurrence between gefitinib and erlotinib groups. Conclusions: Based on the results, EGFR mutation positive and low ECOG ($1{\sim}2$) were significantly important factors for both effectiveness of EGFR TKI and rash occurrence. Also, rash itself was found to be an independently significant factor for the disease control and survival. Therefore, while administering EGFR TKI, patients who have the factors associated with rash occurrence should be closely monitored for effective and safe drug therapy.

• Journal of Yeungnam Medical Science
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• 제33권1호
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• pp.64-67
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• 2016

We report on a 64-year-old man with leptomeningeal metastasis (LM) from an epidermal growth factor receptor (EGFR)-mutated adenocarcinoma of the lung. He was treated with paclitaxel, cisplatin. After completion of chemotherapy, he complained of headache, nausea, and vomiting. EGFR-mutated tumor cells were identified from the cerebrospinal fluid (CSF). Second-line therapy with gefitinib, methotrexate was started. After receiving gefitinib for 4 weeks, he had no more headaches or vomiting. Eleven months after initiation of gefitinib, he developed headache and nausea. Chest computed tomography showed aggravation of bone metastasis. Third-line therapy was started with gemcitabine and carboplatin. Two weeks later, he experienced disorientation. After a fourth relapse within the central nervous system, the therapy was switched to erlotinib and significant improvement of LM was achieved. This case shows that LM can be diagnosed by detecting EGFR mutation in CSF and EGFR tyrosine kinase inhibitors are effective for LM from EGFR mutant non-small cell lung cancer.

• Asian Pacific Journal of Cancer Prevention
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• 제17권2호
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• pp.785-789
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• 2016

A key drug for treatment of EGFR mutation-positive non-small cell lung cancer is epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). While the dosage of many general anti-tumor drugs is adjusted according to the patient body surface area, one uniform dose of most TKIs is recommended regardless of body size. In many cases, dose reduction or drug cessation is necessary due to adverse effects. Disease control, however, is frequently still effective, even after dose reduction. In this study, we retrospectively reviewed the characteristics of 26 patients at Fukuoka University Hospital between January 2004 and January 2015 in whom the EGFR-TKI dose was reduced with respect to progression free survival and overall survival. There were 10 and 16 patients in the gefitinib group and the erlotinib group, respectively. The median progression-free survival in the gefitinib group and the erlotinib group was 22.4 months and 14.1 months, respectively, and the median overall survival was 30.5 months and 32.4 months, respectively. After stratification of patients by body surface area, the overall median progression-free survival was significantly more prolonged in the low body surface area (<1.45 m2) group (25.6 months) compared to the high body surface area (>1.45 m2) group (9.7 months) (p=0.0131). These results indicate that low-dose EGFR-TKI may sufficiently control disease without side effects in lung cancer patients with a small body size.

• 대한암한의학회지
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• 제14권1호
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• pp.13-20
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• 2009

Lung cancer remains the leading cause of cancer-related death throughout the world. Non-small cell lung cancer(NSCLC) is the most deadly form of lung cancer. Patients with non-small cell lung cancer are often found to be unavailable for operation at primary diagnosis. They are typically given conventional chemotherapy. When the tumor progresses during chemotherapy, a change in regimen is considered. The average period of administration differs with the regimen. In this case report, the authors introduce two cases of non-small cell lung cancer patients treated with allergen removed Rhus verniciflua stokes based herbal medicine along with pemetrexed($Alimta^{(R)}$) and erlotinib($Tarceva^{(R)}$). The authors report this case because these molecular-targeted agents were used for longer periods than expected, while improving the performance and other symptoms. Further studies illuminating the synergistic effects through conjunctive treatment with both conventional and Eastern medicine in lung cancer treatment should be performed in the future.

• Biomolecules & Therapeutics
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• 제20권6호
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• pp.513-519
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• 2012

Although the immense efforts have been made for cancer prevention, early diagnosis, and treatment, cancer morbidity and mortality has not been decreased during last forty years. Especially, lung cancer is top-ranked in cancer-associated human death. Therefore, effective strategy is strongly required for the management of lung cancer. In the present study, we found that novel daphnane diterpenoids, yuanhualine (YL), yuanhuahine (YH) and yuanhuagine (YG) isolated from the flower of Daphne genkwa (Thymelaeaceae), exhibited potent anti-proliferative activities against human lung A549 cells with the $IC_{50}$ values of 7.0, 15.2 and 24.7 nM, respectively. Flow cytometric analysis revealed that the daphnane diterpenoids induced cell-cycle arrest in the G0/G1 as well as G2/M phase in A549 cells. The cell-cycle arrests were well correlated with the expression of checkpoint proteins including the up-regulation of cyclin-dependent kinase inhibitor p21 and p53 and down-regulation of cyclin A, cyclin B1, cyclin E, cyclin dependent kinase 4, cdc2, phosphorylation of Rb and cMyc expression. In the analysis of signal transduction molecules, the daphnane diterpenoids suppressed the activation of Akt, STAT3 and Src in human lung cancer cells. The daphnane diterpenoids also exerted the potent anti-proliferative activity against anticancer-drug resistant cancer cells including gemcitabine-resistant A549, gefitinib-, erlotinib-resistant H292 cells. Synergistic effects in the growth inhibition were also observed when yuanhualine was combined with gemcitabine, gefitinib or erlotinib in A549 cells. Taken together, these findings suggest that the novel daphnane diterpenoids might provide lead candidates for the development of therapeutic agents for human lung cancers.