Genistein is a high specific and noncompetitive inhibitor of epidermal growth factor receptor tyramine kinase domain (EGFR-TK). In the paper, a molecular docking between genistein and EGFR-TK was studied to explore the mechanism of their interaction and antitumor mechanism of genistein by AUTODOCK 3.05 program. The results indicated that genistein located in the active cavity of EGFR-TK by high affinity (deltaG = -31.2 kJ/mol), and genistein inhibited EGFR-TK by interfering with forming of Lys721/Glu738 ion pair. The inhibition belonged to noncompetitive interaction, in which hydrophobic force and hydrogen bond played key roles.
Catalytic Domain ; Genistein ; metabolism ; pharmacology ; Models, Molecular ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; metabolism

OBJECTIVETo build 3D-pharmacophore model of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors using distance comparisons method and design novel EGFR inhibitors.

METHODSThirteen typical EGFR inhibitors were selected, and their biologically active conformations were obtained by using DOCK5.0 program, then 3D-pharmacophore model of EGFR inhibitors was built using distance comparisons method.

RESULTSValidation of the 3D-pharmacophore model was carried out and novel structures with potential inhibitory activity were selected by means of 3D-searching and docking method.

CONCLUSIONThis method can improve hit rate of lead compounds discovery and can be used to design novel EGFR inhibitors.

Drug Design ; Enzyme Inhibitors ; Epidermal Growth Factor ; metabolism ; Models, Chemical ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; chemistry ; pharmacology ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; chemistry ; Structure-Activity Relationship

Carcinoma, Non-Small-Cell Lung ; pathology ; therapy ; Humans ; Immunotherapy ; Lung Neoplasms ; pathology ; therapy ; Neoplasm Staging ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Vascular Endothelial Growth Factor A ; antagonists & inhibitors

The overall survival of patients with gastric cancer has increased markedly in Korea, even higher than those of developed nations in Western world. It is due to the virtue of Korean National Cancer Screening Program and nowadays more than half of patients are diagnosed at the early stage of gastric cancer. However, for patients with unresectable gastric cancer, the outcomes of traditional cytotoxic chemotherapy regimens stay at a median survival of 9-11 months. The knowledge of cancer biology and the data from gene expression profiling has explosively expanded. Alternations in the expression of receptor tyrosine kinases pathways including Human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), phosphatydyl inositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) were proved to be critical in cancer cell survival and biological agents targeting those altered receptor tyrosine kinases, their ligands and downstream effector molecules are developed for anti-cancer purpose. Until now, only trastuzumab succeeded to significantly increase overall survival of patients with HER2 overexpressing gastric cancer. Other agents including bevacizumab, gefitinib, erlotinib, and lapatinib failed to achieve the efficacy in survival gain over standard chemotherapy. Insights about the variations between regions, races, and individuals call for the effort to find reliable predictive biomarkers for drug efficacy and to design finely stratified clinical trials. Compared to current treatment paradigms, it is hoped that molecularly targeted treatment along with conventional cytotoxic chemotherapy will lead to significant gains in survival.
Antineoplastic Agents/*therapeutic use ; Biological Markers/*metabolism ; Humans ; Molecular Targeted Therapy ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Receptor, erbB-2/antagonists & inhibitors/metabolism ; Stomach Neoplasms/*drug therapy/metabolism/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism

The overall survival of patients with gastric cancer has increased markedly in Korea, even higher than those of developed nations in Western world. It is due to the virtue of Korean National Cancer Screening Program and nowadays more than half of patients are diagnosed at the early stage of gastric cancer. However, for patients with unresectable gastric cancer, the outcomes of traditional cytotoxic chemotherapy regimens stay at a median survival of 9-11 months. The knowledge of cancer biology and the data from gene expression profiling has explosively expanded. Alternations in the expression of receptor tyrosine kinases pathways including Human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), phosphatydyl inositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR), hepatocyte growth factor receptor (HGFR/MET), and fibroblast growth factor receptor (FGFR) were proved to be critical in cancer cell survival and biological agents targeting those altered receptor tyrosine kinases, their ligands and downstream effector molecules are developed for anti-cancer purpose. Until now, only trastuzumab succeeded to significantly increase overall survival of patients with HER2 overexpressing gastric cancer. Other agents including bevacizumab, gefitinib, erlotinib, and lapatinib failed to achieve the efficacy in survival gain over standard chemotherapy. Insights about the variations between regions, races, and individuals call for the effort to find reliable predictive biomarkers for drug efficacy and to design finely stratified clinical trials. Compared to current treatment paradigms, it is hoped that molecularly targeted treatment along with conventional cytotoxic chemotherapy will lead to significant gains in survival.
Antineoplastic Agents/*therapeutic use ; Biological Markers/*metabolism ; Humans ; Molecular Targeted Therapy ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Receptor, erbB-2/antagonists & inhibitors/metabolism ; Stomach Neoplasms/*drug therapy/metabolism/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism

BACKGROUND: Cutaneous adverse reactions are often observed during chemotherapy with epidermal growth factor receptor (EGFR) inhibitors including papulopustular eruptions, xerosis and paronychia. OBJECTIVE: To investigate and compare the cutaneous adverse reactions induced by EGFR inhibitors including erlotinib, gefitinib and cetuximab which have commonly been used as chemotherapeutic agents in Korea. METHODS: We reviewed cutaneous adverse effects through the medical records and clinical photographs of 43 Korean patients who had been treated with erlotinib, gefitinib or cetuximab at Pusan Paik Hospital between June 2003 and January 2010. RESULTS: Papulopustular eruptions occurred in 28 patients (65.1%); they were easily controlled by topical benzoyl peroxide, clindamycin and a retinoid, or by oral minocycline and tetracycline. There were no significant differences in incidence, duration and severity grades of papulopustular eruptions among EGFR inhibitors. In contrast to previous studies, the frequency and severity of papulopustular eruptions were not significantly correlated with treatment responses to EGFR inhibitors. Xerosis appeared in 14 patients (41%), and was easily controlled by topical emollients and steroids, and by systemic steroids and antihistamines. Paronychia occurred in 8 patients (18.6%) and were controlled by conservative treatments. CONCLUSION: Papulopustular eruptions, xerosis and paronychia are common cutaneous adverse reactions associated with EGFR inhibitors and there are no significant differences in adverse cutaneous reactions among EGFR inhibitors. As these cutaneous adverse reactions are relatively easily controlled with treatment, it will be helpful to detect and treat these adverse reactions early, including reassuring the patients, which should increase compliance of patients during treatment with EGFR inhibitors.
Antibodies, Monoclonal, Humanized ; Benzoyl Peroxide ; Clindamycin ; Compliance ; Emollients ; Epidermal Growth Factor ; Histamine Antagonists ; Humans ; Incidence ; Medical Records ; Minocycline ; Paronychia ; Quinazolines ; Receptor, Epidermal Growth Factor ; Steroids ; Tetracycline ; Cetuximab ; Erlotinib Hydrochloride

Pulmonary fibrosis is a fatal progressive disease with no effective therapy. Transforming growth factor (TGF)-beta1 has long been regarded as a central mediator of tissue fibrosis that involves multiple organs including skin, liver, kidney, and lung. Thus, TGF-beta1 and its signaling pathways have been attractive therapeutic targets for the development of antifibrotic drugs. However, the essential biological functions of TGF-beta1 in maintaining normal immune and cellular homeostasis significantly limit the effectiveness of TGF-beta1-directed therapeutic approaches. Thus, targeting downstream mediators or signaling molecules of TGF-beta1 could be an alternative approach that selectively inhibits TGF-beta1-stimulated fibrotic tissue response while preserving major physiological function of TGF-beta1. Recent studies from our laboratory revealed that TGF-beta1 crosstalk with epidermal growth factor receptor (EGFR) signaling by induction of amphiregulin, a ligand of EGFR, plays a critical role in the development or progression of pulmonary fibrosis. In addition, chitotriosidase, a true chitinase in humans, has been identified to have modulating capacity of TGF-beta1 signaling as a new biomarker and therapeutic target of scleroderma-associated pulmonary fibrosis. These newly identified modifiers of TGF-beta1 effector function significantly enhance the effectiveness and flexibility in targeting pulmonary fibrosis in which TGF-beta1 plays a significant role.
Animals ; Drug Design ; Hexosaminidases/antagonists & inhibitors/metabolism ; Humans ; Lung/*drug effects/metabolism/pathology ; Molecular Targeted Therapy ; Pulmonary Fibrosis/*drug therapy/metabolism/pathology ; Receptor Cross-Talk ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Receptors, Transforming Growth Factor beta/antagonists & inhibitors/metabolism ; Signal Transduction ; Transforming Growth Factor beta1/*antagonists & inhibitors/metabolism

Colorectal cancer is the third most common malignant disease in incidence according to a report in 2009 from Korea. The 5-fluorouracil (5-FU) remains to be a major chemotherapeutic agents. But, over the last 10-15 years, the treatment pattern for metastatic colorectal cancer changed significantly. Irinotecan and oxaliplatin are cytotoxic drugs, or bevacizumab and cetuximab are monoclonal antibodies against molecular targets. The introduction of novel agents targeting specific molecular features of cancer cells promises more options and marked improvements in efficacy for the treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-FU-based chemotherapy, and the addition of cetuximab to irinotecan and 5-FU-based chemotherapy eliminates irinotecan resistance. Better understanding of the tumor biology and the molecular pathway and mechanisms of tumorigenesis has led to the discovery of novel agents with improved outcomes.
Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/*therapeutic use ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Molecular Targeted Therapy ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism

Colorectal cancer is the third most common malignant disease in incidence according to a report in 2009 from Korea. The 5-fluorouracil (5-FU) remains to be a major chemotherapeutic agents. But, over the last 10-15 years, the treatment pattern for metastatic colorectal cancer changed significantly. Irinotecan and oxaliplatin are cytotoxic drugs, or bevacizumab and cetuximab are monoclonal antibodies against molecular targets. The introduction of novel agents targeting specific molecular features of cancer cells promises more options and marked improvements in efficacy for the treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-FU-based chemotherapy, and the addition of cetuximab to irinotecan and 5-FU-based chemotherapy eliminates irinotecan resistance. Better understanding of the tumor biology and the molecular pathway and mechanisms of tumorigenesis has led to the discovery of novel agents with improved outcomes.
Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Agents/*therapeutic use ; Colonic Neoplasms/*drug therapy/metabolism/pathology ; Humans ; Molecular Targeted Therapy ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/metabolism ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism

Decorin (DCN) is a member of the small leucine-rich proteoglycan gene family. Many studies indicated that DCN inhibited fibrosis and scar-formation by neutralization of TGF-P and interfering the binding of TGF-beta with its receptor, which induced ectopic deposition of extracellular matrix. Additionally, DCN can prevent the proliferation and metastasis of tumor cells by activating EGFR/MAPK/p21 signal pathway and inhibiting the cell proliferation pathway mediated by EGF-EGFR. It is suggested that the recombinant DCN had potential pharmaceutical potency in treatment of chronic fibrosis and neoplasm for its critical biological activities and low immunogenicity.
Animals ; Antineoplastic Agents ; pharmacology ; Decorin ; Extracellular Matrix Proteins ; chemistry ; pharmacology ; Fibrosis ; prevention & control ; Humans ; Proteoglycans ; chemistry ; pharmacology ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Recombinant Proteins ; pharmacology ; Transforming Growth Factor beta1 ; antagonists & inhibitors