• Tuberculosis and Respiratory Diseases
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• 제75권3호
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• pp.95-103
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• 2013

Background: Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms. Methods: We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment. Results: Resistant cell lines to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL-387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines were established. Among them, two resistant cell lines, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expressions of CD56 while increased synaptophysin, Rb, p16 and poly(ADP-ribose) polymerase were found only in A549/GR in western blotting, suggesting that NE differentiation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, chemotherapeutic drugs for SCLC, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A549 cells, which also made them more sensitive to etoposide and cisplatin than parental cells. Furthermore, we found a tissue sample from a patient which showed increased expressions of CD56 and synaptophysin after development of resistance to erlotinib. Conclusion: NE differentiation can occur during acquisition of resistance to EGFR-TKI, leading to increased chemosensitivity.

• Tuberculosis and Respiratory Diseases
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• 제69권4호
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• pp.271-278
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• 2010

Background: Recent studies have demonstrated that the epidermal growth factor receptor (EGFR) genotype is the most important predictive marker to EGFR-tyrosine kinase inhibitors (TKIs) and first-line gefitinib treatment will be approved in the near future for use in non-small cell lung cancer (NSCLC) patients with the EGFR mutation. Direct sequencing is known to be the standard for detecting EGFR mutations; however, it has limited sensitivity. Peptide nucleic acids (PNA)-mediated PCR clamping method is a newly introduced method for analyzing EGFR mutations with increased sensitivity and stability. Methods: A total of 71 NSCLC patients were analyzed for EGFR mutations using the PNA-mediated PCR clamping technique. Sixty-nine patients were analyzed for clinicopathologic correlation with EGFR genotype; 2 patients with indeterminate results were excluded. In order to determine EGFR-TKI drug response, 57 patients (42 gefitinib, 15 erlotinib) were included in the analysis. Results: The EGFR mutation rate was 47.8%. Being female, a non-smoker, and having adenocarcinoma were favorable clinicopathologic factors, as expected. However, more than a few smokers (33.3%), male (28.1%), and patients with non-adenocarcinoma (28.6%) had the EGFR mutation. Having a combination of favorable clinicopathologic factors did not increase the EGFR mutation rate significantly. Drug response to EGFR-TKIs showed significant differences depending on the EGFR genotype; ORR was 14.3% for wild type vs 69.0% for mutant type; DCR is 28.6% for wild type vs 96.6% for mutant type. The median EGFR-TKI treatment duration is 7.6 months for mutant type group and 1.4 months for wild type group. Conclusion: EGFR genotype determined using the PNA-mediated PCR clamping method is significantly correlated with the clinical EGFR-TKI responses and PNA-mediated PCR.

• Asian Pacific Journal of Cancer Prevention
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• 제15권1호
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• pp.321-326
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• 2014

Background: Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) are predictive of response to EGFR-targeted therapy in advanced stages of disease. This study aimed to determine the frequency of EGFR mutations in NSCLCs and to correlate their presence with clinical characteristics in multiethnic Malaysian patients. Materials and Methods: In this prospective study, EGFR mutations in exons 18, 19, 20 and 21 in formalin-fixed paraffin-embedded biopsy specimens of consecutive NSCLC patients were asessed by real-time polymerase chain reaction. Results: EGFR mutations were detected in NSCLCs from 55 (36.4%) of a total of 151 patients, being significantly more common in females (62.5%) than in males (17.2%) [odds ratio (OR), 8.00; 95% confidence interval (CI), 3.77-16.98; p<0.001] and in never smokers (62.5%) than in ever smokers (12.7%) (OR, 11.50; 95%CI, 5.08-26.03; p<0.001). Mutations were more common in adenocarcinoma (39.4%) compared to non-adenocarcinoma NSCLCs (15.8%) (p=0.072). The mutation rates in patients of different ethnicities were not significantly different (p=0.08). Never smoking status was the only clinical feature that independently predicted the presence of EGFR mutations (adjusted OR, 5.94; 95%CI, 1.94-18.17; p=0.002). Conclusions: In Malaysian patients with NSCLC, the EGFR mutation rate was similar to that in other Asian populations. EGFR mutations were significantly more common in female patients and in never smokers. Never smoking status was the only independent predictor for the presence of EGFR mutations.

• Asian Pacific Journal of Cancer Prevention
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• 제16권2호
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• pp.689-692
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• 2015

Background: Incorporation of molecular analysis of the epidermal growth factor receptor (EGFR) gene into routine clinical practice has shown great promise to provide personalized therapy of the non-small cell lung cancer (NSCLC) in the developed world. However, the genetic testing of EGFR mutations has not yet become routine clinical practice in territories remote from the central regions of Russia. Therefore, we aimed to study the frequency of major types of activating mutations of the EGFR gene in NSCLC patients residing in West Siberia. Materials and Methods: We examined EGFR mutations in exons 19 and 21 in 147 NSCLC patients (excluding squamous cell lung carcinomas) by real time polymerase chain reaction. Results: EGFR mutations were detected in 28 of the 147 (19%) patients. There were 19 (13%) cases with mutations in exon 19 and 9 cases (6%) in exon 21. Mutations were more frequently observed in women (42%, p=0.000) than in men (1%). A significantly higher incidence of EGFR mutations was observed in bronchioloalveolar carcinomas (28%, p=0.019) and in adenocarcinomas (21%, p=0.024) than in large cell carcinomas, mixed adenocarcinomas, and NOS (4%). The EGFR mutation rate was much higher in never-smokers than in smokers: 38% vs. 3% (p=0.000). The frequency of EGFR mutations in the Kemerovo and Tomsk regions was 19%. Conclusions: The incorporation of molecular analysis of the EGFR gene into routine clinical practice will allow clinicians to provide personalised therapy, resulting in a significant increase in survival rates and improvement in life quality of advanced NSCLC patients.

• Tuberculosis and Respiratory Diseases
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• 제73권6호
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• pp.303-311
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• 2012

Background: This study was designed to analyze the efficacy of gefitinib as a second-line therapy, according to the clinical characteristics in Korean patients with non-small-cell lung cancer (NSCLC). Methods: In this Phase IV observational study, we recruited patients, previously failed first-line chemotherapy, who had locally advanced or metastatic NSCLC, and who were found to be either epidermal growth factor receptor (EGFR) mutation-positive or satisfied 2 or more of the 3 characteristics: adenocarcinoma, female, and non-smoker. These patients were administered with gefitinib 250 mg/day, orally. The primary endpoints were to evaluate the objective response rate (ORR) and to determine the relationship of ORRs, depending on each patient's characteristics of modified intent-to-treat population. Results: A total of 138 patients participated in this study. One subject achieved complete response, and 42 subjects achieved partial response (ORR, 31.2%). The subgroup analysis demonstrated that the ORR was significantly higher in patients with EGFR mutation-positive, compared to that of EGFR mutation-negative (45.8% vs. 14.0%, p=0.0004). In a secondary efficacy variable, the median progression-free survival (PFS) was 5.7 months (95% confidence interval, 3.9~8.4 months) and the 6-month PFS and overall survival were 49.6% and 87.9%, respectively. The most common reported adverse events were rash (34.4%), diarrhea (26.6%), pruritus (17.5%), and cough (15.6%). Conclusion: Gefitinib was observed in anti-tumor activity with favorable tolerability profile as a second-line therapy in these selected patients. When looking at EGFR mutation status, EGFR mutation-positive showed strong association with gefitinib by greater response and prolonged PFS, compared with that of EGFR mutation-negative.

• 대한암한의학회지
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• 제16권1호
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• pp.55-61
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• 2011

Objectives : Epidermal growth factor receptor-inhibitors have demonstrated improved overall survival in patients with non-small cell lung cancer, but their use is associated with dermatologic adverse reactions that often require symptomatic treatment. Methods : A 44-year-old woman, who started the chemotherapy of Iressa$^{(R)}$ on August 2010, developed cutaneous symptoms such as papulopustular rash, dry skin, and pruritus on her face and scalp after taking Iressa$^{(R)}$ for four weeks. The patient visited our clinic with such symptoms on March 2011 and underwent herebal remedy targeted to alleviate the skin reactions. The severity of dermatologic symptoms was evaluated with the numeric rating scale and the Common Terminology Criteria for Adverse Events version 4.0. Results : Noticeable changes on the skin lesion were observed after the two months of treatment, without any dose modification of the Iressa$^{(R)}$. The cutaneous symptoms as papulopustular rash, dry skin and pruritus were improved and there was no adverse event induced by the treatment with herbal medicine. Conclusions : This case report suggests that the treatment with a herbal medicine, Samultang-gagambang be considered as a useful treatment to relieve EGFR-inhibitor induced dermatologic adverse reactions.

• Archives of Pharmacal Research
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• 제26권4호
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• pp.330-337
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• 2003

The effect of sixteen excipients on the transport of recombinant human epidermal growth factor (rhEGF) across Caco-2 cell monolayers was examined at $37^{\circ}C$. The apparent apical to basolateral (A-B) permeability ($P_{app}$) of 30 $\mu$ M rhEGF was $8.15\times 10^{-7}$ cm/sec, indicative of a poor level of absorption in the GI tract. The Papp was 1.7- and 6.3-fold greater than the $P_{app}$ in the basolateral to apical (B-A) direction and the A-B permeability of mannitol, respectively, and decreased dramatically to a negligible level at $4^{\circ}C$, consistent with a receptor mediated transcytosis of rhEGF. The stability of rhEGF was very poor, undergoing more than 85% degradation in 2 h in the transport medium at $37^{\circ}C$. A significant increase in the $P_{app}$ could be achieved by the addition of certain excipients, as exemplified by 23, 21, 20 and 16-fold increases, in the presence of sodium taurochenodeoxycholate (NaTCDC), sodium taurodeoxycholate (NaTDC), sodium glycodeoxycholate (NaGDC) and sodium laurylsulfate (SLS) (all at a concentration of 1 % w/v), respectively. A significant increase in stability could also be achieved by the addition of some of the excipients, as represented by 1 % SLS, which nearly completely stabilized the rhEGF. Unfortunately, however, an increase in the $P_{app}$ of rhEGF could not be achieved without a simultaneous and extensive decrease in the integrity of the cell membranes. Thus, more efficient excipients, that specifically enhance the permeation of rhEGF and do not alter the membrane integrity, should be pursued in order to safely enhance the permeation of rhEGF.

• Applied Microscopy
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• 제34권4호
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• pp.241-254
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• 2004

신장은 독성물질, 빈혈, 재관류-유도 상해, 급성신부전에 회복 기능을 가지고 있다. 뇨 표피성장인자(EGF)는 신장 사구체연접장치에서 생산된다. 신장은 EGF를 축적하거나 배설한다. 신장 질환의 경우에는 EGF 배설이 감소한다. 본 연구에서는 glycerol-유도 급성신부전에서 스쿠알렌의 효과를 연구하였다. In vitro에서 RT-PCR를 통해 EGF 발현을 관찰하였다. 근위세뇨관 세포를 분리한 후, glycerol (1, 2, 4 mM) 혹은 스쿠알렌(0.1, 0.05 or 0.1%)을 첨가하였다. In vivo에서 BUN, creatine, 조직학적 변화를 관찰하였다. 실험군은 다음과 같다. 실험군 1은 정상군, 실험군 2는 glycerol (50%, 8 ml/kg) 처치 후, 스쿠알렌을 처치하지 않은 군, 실험군 3은 glycerol (50%, 8 ml/kg) 처치 후, 스쿠알렌(180 mg/kg)을 함께 처치한 군으로 각 실험군 당 생쥐 7마리를 사용하였다. 실험 결과, glycerol이 신장에 손상을 주어 EGF mRNA 발현이 감소됨을 확인할 수 있었다. 그러나, 스쿠알렌을 처치한 군에서는 EGF mRNA 발현이 증가함을 관찰할 수 있었다. 또한, BUN과 creatine 수치의 빠른 회복이 관찰되었다(P<0.01). 조직학적 관찰에서도 실험군 2는 사립체의 심한 손상이 관찰되었는데, 실험군 3의 경우 사립체의 빠른 회복이 관찰되었다. 결론적으로, 스쿠알렌이 glycerol-유도 급성신부전에 회복 효과가 있을 것으로 사료된다.

• Asian Pacific Journal of Cancer Prevention
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• 제15권14호
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• pp.5551-5556
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• 2014

Background: The prognostic value of human epidermal growth factor receptor-2 (HER-2/neu) for survival of patients with colorectal cancer (CRC) is still ambiguous. We therefore performed a meta-analysis to evaluate its prognostic significance. Materials and Methods: We searched the MEDLINE and EMBASE databases for published literature investigating associations between HER-2/neu status and overall survival of patients with CRC. A meta-analysis was performed using a DerSimonian-Laird model and publication bias was investigated by Begg's and Egger's tests. Subgroup analysis was also conducted according to the study design type, study quality score, cut-off value for HER-2/neu overexpression, publication region, patient number and publication year. Results: A total of 17 eligible studies involving 2,347 patients were identified for this meta-analysis. The combined hazard ratio (HR) was 1.31 (95% confidence interval (CI): 0.96-1.79), suggesting that HER-2/neu overexpression was not significantly associated with overall survival of patients with CRC. However, subgroup analysis revealed that HER-2/neu overexpression had an unfavorable impact on survival when the analysis was restricted to subgroups of study quality score ${\leq}5 $(HR=1.56, 95%CI: 1.17-2.10), Asian patients (HR=1.74, 95%CI: 1.22-2.49), patient number ${\leq}106$ (HR=1.57, 95%CI: 1.01-2.44), publication year before 2003 (HR=1.59, 95%CI: 1.02-2.49), and prospectively designed study (HR=3.62, 95%CI: 1.42-9.24). The effect disappeared in subgroups of study quality scores > 5 (HR=0.69, 95%CI: 0.33-1.44), non Asian patients (HR=1.14, 95%CI: 0.77-1.70), patients' number > 106 (HR=1.07, 95%CI: 0.67-1.72), publication year after 2003 (HR=1.13, 95%CI: 0.76-1.69), and retrospectively designed study (HR=1.22, 95%CI: 0.89-1.67). Conclusions: Our meta-analysis suggests that HER-2/neu overexpression might not be a significantly prognostic indicator for patients with CRC. Further studies are required to confirm these results.

• 한국가축번식학회지
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• 제21권1호
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• pp.61-69
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• 1997

본 연구는 EGF와 anti-EGF가 초기 생쥐배아의 발생 및 부화에 미치는 영향을 알아보고자 실행되었다. 초기 2세포기부터 상실배까지의 배아를 EGF와 anti-EGF를 각각 처리한 Ham's F10 배양액에서 배양하여 그 발생률과 부화율을 대조군과 비교하였다. EGF 처리시 배양시간에 따른 발생률은 증진되었으나 통계학적 유의성은 없었다. EGF 처리군에서의 부화율(57.5, 62.5, 65.0, 62.5%)은 대조군(35%)에 비하여 유의하게 (p<0.01) 높았다. Anti-EGF 처리시 각 발생시기별 1:1000 실험군의 발생률은 대조군과 차이가 없었다. 그러나, 1:100 실험군의 경우, 2∼4세포기의 배아는 모두 4∼8세포기에서 정지되었고, 8세포기와 상실배의 포배형성은 48시간 이상 지연되었으며 부화 역시 대조군에 비해 억제되었다(8세포기; 2%, 44%, 상실배; 6.2%, 58.3%). 이 실험에서, EGF는 생쥐 배아의 포배형성과 부화를 증진시키는 반면, anti-EGF는 이를 억제하였다. Anti-EGF 처리시 나타나는 발생정지 현상은 anti-EGF가 배아에서 만들어지는 EGF와 반응하여 EGF의 작용을 억제시키기 때문으로 사료된다. 그러므로 EGF는 paracrine mode로서 뿐만 아니라 antocrine mode로서 생쥐 초기배아의 발생에 중요한 인자로 작용함을 알 수 있었다.