• 한국임상약학회지
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• 제30권1호
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• pp.1-10
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• 2020

Objective: The aim of the study was to perform a meta-analysis of randomized clinical trials to compare the clinical efficacy and safety between combination of cyclin-dependent kinase (CDK) 4/6 inhibitors with aromatase inhibitors (AIs) and AIs alone in patients with hormone receptor+/human epidermal growth factor receptor type2-(HR+/HER2-) advanced breast cancer. Methods: Published clinical studies were identified through electronic database searches until February 2019. Literature qualities were assessed by the Scottish Intercollegiate Guidelines Network Checklist. Key endpoints of efficacy were progression-free survival (PFS), objective response rate (ORR), and clinical benefit (CB). Endpoints of safety were adverse events (AEs) (neutropenia, leukopenia, any grade 3/4 AEs, and serious AEs) and on-treatment death. Meta-analysis was performed using the RevMan 5.3 software. Results: The selected five studies were evaluated as "good" in quality assessment. Compared to AIs alone, the combination therapy significantly improved PFS (pooled hazard ratio=0.55; 95% confidence interval (CI) 0.49-0.62), ORR (odds ratio=1.78; 95% CI=1.49-2.13), and CB (odds ratio=1.86; 95% CI=1.51-2.28). The prevalence of AEs was significantly higher in the combination group than in the AIs alone group. On-treatment death was greater in the combination group than in the AIs alone group, although insignificant. Conclusion: The combination therapy of CDK4/6 inhibitors with AIs was more effective for the treatment of HR+/HER2- advanced breast cancer, but less safe than AIs alone. The combination therapy should be effectively managed through patient monitoring, and further studies are needed to reduce AEs in the combination therapy of CDK4/6 inhibitors with AIs.

• Asian Pacific Journal of Cancer Prevention
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• 제13권10호
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• pp.5081-5086
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• 2012

Background: The liver is one of the most common metastatic sites of breast cancer, hepatic metastases developing in 6%-25% of patients with breast cancer and being associated with a poor prognosis. The aim of this study was to analyze the survival and clinical characteristics of patients with hepatic metastases from breast cancer of different molecular subtypes and to investigate the prognostic and predictive factors that effect clinical outcome. Methods: We retrospectively studied the charts of 104 patients with breast cancer hepatic metastases diagnosed at Sun Yat-sen University Cancer Center from December 1990 to June 2009. Subtypes were defined as luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) enriched, triple-negative (TN). Prognostic factor correlations with clinical features and treatment approaches were assessed at the diagnosis of hepatic metastases. Results: The median survival time was 16.0 months, and the one-, two- three-, four-, five-year survival rates were 63.5%, 31.7%, 15.6%, 10.8%, and 5.4%, respectively. Median survival periods after hepatic metastases were 19.3 months (luminal A), 13.3 months (luminal B), 18.9 months (HER2-enriched), and 16.1 months (TN, P=0.11). In multivariate analysis, a 2 year-interval from initial diagnosis to hepatic metastasis, treatment with endocrine therapy, and surgery were independent prognostic factors. Endocrine therapy could improve the survival of luminal subtypes (P=0.004) and was a favorable prognostic factor (median survival 23.4 months vs. 13.8 months, respectively, P=0.011). Luminal A group of patients treated with endocrine therapy did significantly better than the Luminal A group of patients treated without endocrine therapy (median survival of 48.9 vs. 13.8 months, P=0.003). Conclusions: Breast cancer subtypes were not associated with survival after hepatic metastases. Endocrine therapy was a significantly favorable treatment for patients with luminal subtype.

• Clinical and Experimental Reproductive Medicine
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• 제24권1호
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• pp.13-20
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• 1997

본 연구는 EGF가 체외수정된 생쥐배의 착상전 발달 및 inner cell mass (ICM) 과 trophectoderm (TE) 세포수에 미치는 영향을 조사하고, 그와 더불어 간접 면역형광방법을 이용하여 배 발달 단계에 따른 EGF-receptor (EGF-R) 단백의 발현유무를 조사하기 위해 실시하였다. 그 결과를 요약하면 다음과 같다. 2-세포기 배의 group (5/25 ${\mu}l$)배양은 단독 배양보다 양호한 배 발달을 유도 할 수 있었으며, 단독 배양에서의 저조한 배 발달은 EGF를 첨가함으로서 개선시킬 수 있었다. 특히, 10 ng/ml의 EGF가 첨가된 단독배양군 (62.4%)은 단독대조군 (47.9%)에 비하여 유의하게 높은 배 발달을 나타냈다. 또한, ICM과 TE세포수 공히 EGF첨가에 의해 증가되는 것을 differential labelling기법으로 확인 할 수 있었다. 발달단계에 미치는 EGF의 효과를 검토하였던 바 4-세포기 이후의 배 발달에 유의하게 영향을 미치는 것을 알 수 있었고, 특히 배반포기배의 ICM도 동시에 증가되는 것을 알 수 있었다. 한편, 간접면역형광에 의한 EGF-R의 발현유무를 조사한 결과, 4-세포기 이후에 EGF-R가 발현되는 것을 확인할 수 있었다. 따라서, EGF는 착상전 생쥐배의 4-세포기 이후에 발현되는 EGF-R에 반응하여 배 발달을 유기하며, 또한 배반포기배의 ICM과 TE세포수의 증가에 영향을 미치는 것을 알 수 있었다.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제35권3호
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• pp.143-154
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• 2013

Purpose: This study was to find efficacy of integrin alpha2 (${\alpha}_2$) and epidermal growth factor receptor (EGFR) as tumor marker of oral squamous cell carcinoma (SCC) and clarify the selective cell death effect of anti-integrin ${\alpha}_2$ and anti-EGFR on SCC cells, additionally testify conjugated gold nanoparticles (GNP) with air plasma for selective cell death of oral SCC. Methods: Expression of integrin ${\alpha}_2$, EGFR on human SCC cells (SCC25) were examined by western blot. SCC25 cells were treated with anti-integrin ${\alpha}_2$, anti-EGFR and analysed by Hemacolor staining, immunoflorescence staining, FACS flow cytometry. Conjugated GNP with integrin ${\alpha}_2$, EGFR antibody were treated by air plasma on SCC cells. Results: Integrin ${\alpha}_2$ and EGFR were over-expressed on SCC25 cells than normal lung WI-38 cells. The cell viability rate of SCC25 cells treated with anti-integrin ${\alpha}_2$, anti-EGFR was lower than WI-38 cells. The concentration changes of nucleus, releasing cytochrome c and apoptosis inducing factor (AIF) from mitochondria to cytosol were observed. The changes of proteins related with apoptosis were observed. Increase of bax, bcl-xL, activation of caspase-3, -7, -9, and fragmentation of PARP, DFF45 and decrease of lamin A/C in SCC25 cells were observed. In FACS, increase of sub-$G_1$ and S phase was observed. Cell cycle related proteins, Such as cyclin D1, cyclin dependent kinase (CDK) 4, cyclin A, cyclin E, CDK 2, p27 were decreased. After SCC25 cells treated with conjugatged GNP-Integrin ${\alpha}_2$, GNP-EGFR, additionally air plasma, the cell death rate was significantly increased. Conclusion: Integrin ${\alpha}_2$, EGFR were over-expressed in oral SCC cells. Anti-integrin ${\alpha}_2$, anti-EGFR in SCC25 cells induced apoptosis selectively. When GNP-anti integrin ${\alpha}_2$, GNP-anti EGFR were treated with air plasma on SCC25 cells, cancer cells were died more selectively. GNP-anti integrin ${\alpha}_2$, GNP-anti EGFR with air plasma could be treatment choice of oral SCC.

• Radiation Oncology Journal
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• 제14권2호
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• pp.87-93
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• 1996

목적 : 악성 성상세포종에서 표피 성장 인자 수용체의 과발현의 빈도와 예후 인자로서 가능성을 조사하기 위하여 본 연구를 시행하였다. 대상 및 방법 : 조직학적으로 악성 성상세포종으로 확진되고 방사선 치료를 받은 23명(역형성성상세포종 7예, 다형성 교아세포종 16예)의 파라핀 블록에 antihuman EGFR polyclonal antibody를 이용하여 면역염색을 시행하였다. 결과 : 표피 성장 인자 수용체는 역형성 성상세포종에서는 7예중 2예에서 양성이었고 다형성 교아세포종은 16예중 9예에서 양성으로 양군간의 발현 빈도의 차이는 통계적으로 유의하지 않았다 (p=0.44). 55세 미만의 환자는 11예중 3예에서 양성이었고 55세 이상은 12예중 8예에서 양성이었다(p=0.141). 표피 성장 인자 수용체 음성인 역형성 성상세포종 환자의 평균 생존기간(중앙값)은 37개월이었다. 다형성 교아세포종 환자의 평균 생존 기간은 표피 성장 인자 수용체 음성 군은 중앙값 11개월, 양성 군은 중앙값 7개월이었으나 두 군간의 통계적인 차이는 없었다(p=0.17). 결론 : 55세 이상 연령군에서 표피성장인자 수용체의 과발현의 빈도가 높았다. 다형성 교아세포종 환자의 생존율은 표피성장인자 수용체 과발현에 의하여 감소하였으나 유의한 영향을 받지 않았다.

• 약학회지
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• 제41권6호
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• pp.737-748
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• 1997

Distribution of rhEGF in the skin, plasma and several organ tissues following topical application of $^{125}I-rhEGF$ (0.4${\mu}$Ci) solution in 25% Pluronic F-127 on 154$mm^2$ normal and damaged (burned and stripped) skins of hairless mice was examined. The radioactivity in the stripped skin tissues increased as a function of time, and was 10-20 times higher than that in the normal and burned skins. The fractions of intact drug in the skin tissues were 40-60% for the normal and burned skins, and 60-80% for the stripped skin. It indicates that the stratum corneum layer behaves as a barrier for the dermal penetration of the drug. The radioactivity in the plasma was much higher for the stripped skin than for the normal and burned skins. However, the concentration of intact drug in the stripped skin was comparable to those in the normal and burned skins indicating most severe degradation (or metabolism) of the drug in the stripped skin. As a result, the fraction of intact drug in the plasma was lowest for the stripped skin (<10%). Body organ distribution of the drug was much higher for the stripped skin. The concentration in the stomach. Both in total radioactivity and intact drug, showed more than 10-times higher value than in the other organs (liver, kidney and spleen). The fraction of intact drug in each organ tissue was below 10-20%. And generally lowest for the stripped skin. The lowest fraction of the drug for the stripped skin could not be explained by the activity of the aminopeptidases in the skin since it was lower for the stripped skin than for the normal skin. Thereover, the fraction of intact drug appears to be determined by the balance between dermal uptake and systemic elimination of the drug, for example. The mechanism of dermal uptake of rhEGF was examined by topical applying 200${\mu}$l of 25% Pluronic F-127 solution containing 0.4 ${\mu}$Ci of $^{125}I-rhEGF$ and 0.14${\mu}$Ci of $^{14}C$-inulin (a marker of passive diffusion). The radioactivity of $^{125}I-rhEGF$ at each sampling time point (0.5, 1, 2, 4 and 8hr) was correlated (p<0.05) with the corresponding radioactivity of $^{14}C$-inulin. It appears to indicate the rhEGF may be uptaken into the skins mainly by the passive diffusion. This hypothesis was supported by the constant specific binding of EGF to the skin homogenates regardless of the skin models. Receptor mediated endocytosis (RME) appears to contribute negligibly, if any, to the overall uptake process.

• Asian Pacific Journal of Cancer Prevention
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• 제14권12호
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• pp.7621-7628
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• 2013

Human epidermal growth factor receptor (HER) status is an important prognostic factor in breast cancer. There is no globally accepted method for determining its status, and which method is most precise is still a matter of debate. We here analyzed HER2 mRNA expression by quantitative reverse transcription-PCR (qRT-PCR) and HER2 DNA amplification using multiplex ligation-dependent probe amplification (MLPA). In parallel, we performed a routine evaluation of HER2 protein by immunohistochemistry (IHC). To assess the accuracy of the RT-PCR and MLPA techniques, a combination of IHC and fluorescence in situ hybridization (FISH) was used, substituting FISH when the results of IHC were ambiguous (2+) and for those IHC results that disagreed with MLPA and qRT-PCR, this approach being termed IHC-FISH. The IHC results for four samples were not compatible with the MLPA and qRT-PCR results; the MLPA and qRT-PCR results for these samples were confirmed by FISH. The correlations between IHC-FISH and qRT-PCR or MLPA were 0.945 and 0.973, respectively. The ASCO/CAP guideline IHC/FISH correlation with MLPA was (0.827) and with RT-PCR was (0.854). The correlations between the IHC results (0, 1+ as negative, and 3+ as positive) and qRT-PCR and MLPA techniques were 0.743 and 0.831, respectively. Given the shortcomings of IHC analysis and greater correlations between MLPA, qRT-PCR, and FISH methods than IHC analysis alone with each of these three methods, we propose that MLPA and real-time PCR are good alternatives to IHC. However a suitable cut-off point for qRTPCR is a prerequisite for determining the exact status of HER2.

• 한방안이비인후피부과학회지
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• 제35권4호
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• pp.75-94
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• 2022

Objectives : To identify the active ingredient of Poncirus Trifoliata Immaturus and to explore the mechanism expected to potentially act on dermatitis accompanied by pruritus. Methods : We conducted the network pharmacological analysis. We selected effective ingredients among the active compounds of Poinciri Fructus Immaturus. We found the target protein of the selected active ingredient, disease(dermatitis accompanied by pruritus) and fexofenadine. Then we established the network between the proteins which Poinciri Fructus Immaturus and fexofenadine intersected with disease respectively, and the coregene was also extracted. After that, the active pathways in the human body involving the groups and coregenes were searched. Results : Total of 7 active ingredients were selected, and 202 target proteins were collected. There were 756 proteins related to inflammatory skin disease accompanied by pruritus, and 75 proteins were related to fexofenadine. 42 proteins crossed by Poinciri Fructus Immaturus with a disease, and 31 proteins crossed by fexofenadine with a disease. 12 proteins were found as a coregene from the proteins that cross Poinciri Fructus Immaturus and disease. Coregenes are involved in 'Nitric-oxide synthase regulator activity', 'Epidermal growth factor receptor signaling pathway'. 2 groups that extracted are invloved in 'Fc receptor signaling pathway', 'Central carbon metabolism in cancer', 'Phosphatidylinositol 3-kinase complex, class IB', and 'omega-hydroxylase P450 pathway'. Conclusion : It is expected that Poinciri Fructus Immaturus will be able to show direct or indirect anti-pruritus and anti-inflammatory effects on skin inflammation accompanied by pruritus in the future. And it is also expected to have a synergy effect with fexofenadine on skin disease.

• 생명과학회지
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• 제21권3호
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• pp.349-357
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• 2011

EGFR kinase의 활성을 억제할 수 있는 억제제는 암뿐만이 아니라 성장성 질환에도 효과적인 치료제가 될 수 있다. 본 연구는 새로운 퀴나졸린계 물질인 화합물 63013과 63033의 EGFR kinase 활성억제 효과를 분석하였다. 이들 물질들은 기존의 디알콕시퀴나졸린의 용해성을 증가시키기 위하여 [1,4]-다이옥시노 퀴나졸린 구조를 가지며 알콕시 곁사슬로 연결되어있다. 화합물 63013과 63033은 A431 인간 피부암세포에서 EGF에의해 유도되는 EGFR의 kinase 활성을 저해, 세포 내에서 EGFR 신호체계에 관여하는 MEK1/2, MAPK p44/42, AKT, STAT3과 같은 하위 분자들의 활성저해 효과를 유도하였다. 이러한 활성저해 효과는 현재 상용화되어 있는 Gefitinib (Iressa$^{(R)}$)와의 비교연구에서 화합물 63013과 63033이 보다 더 낮은 처리 농도에서 EGFR kinase의 활성을 저해하며 암세포의 성장을 억제함을 관찰 할 수 있었다. 따라서 본 연구는 이들 신규 물질들의 EGFR-연관 질환에 대한 EGFR kinase 선택적 억제제로서의 이용 가능성을 제시하고 있다.

• BMB Reports
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• 제51권12호
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• pp.660-665
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• 2018

Human epidermal growth factor receptor 2 (HER2) inhibitors, such as trastuzumab and lapatinib are used to treat HER2-positive breast and gastric cancers. However, as with other targeted therapies, intrinsic or acquired resistance to HER2 inhibitors presents unresolved therapeutic problems for HER2-positive gastric cancer. The present study describes investigations with AUY922, a heat shock protein 90 (HSP90) inhibitor, in primary lapatinib-resistant (ESO26 and OE33) and lapatinib-sensitive gastric cancer cells (OE19, N87, and SNU-216) harboring HER2 amplification/over-expression. In order to investigate whether AUY922 could overcome intrinsic and acquired resistance to HER2 inhibitors in HER2-positive gastric cancer, we generated lapatinib-resistant gastric cancer cell lines (OE19/LR and N87/LR) by continuous exposure to lapatinib in vitro. We found that activation of HER2 and protein kinase B (AKT) were key factors in inducing intrinsic and acquired lapatinib-resistant gastric cancer cell lines, and that AUY922 effectively suppressed activation of both HER2 and AKT in acquired lapatinib-resistant gastric cancer cell lines. In conclusion, AUY922 showed a synergistic anti-cancer effect with lapatinib and sensitized gastric cancer cells with intrinsic resistance to lapatinib. Dual inhibition of the HSP90 and HER2 signaling pathways could represent a potent therapeutic strategy to treat HER2-positive gastric cancer with intrinsic and acquired resistance to lapatinib.