Showing papers by "Susumu Kobayashi published in 2005"
TL;DR: In this paper, the authors reported the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission.
Abstract: Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in specimens from patients with non-small-cell lung cancer who have a response to anilinoquinazoline EGFR inhibitors. Despite the dramatic responses to such inhibitors, most patients ultimately have a relapse. The mechanism of the drug resistance is unknown. Here we report the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission during treatment with gefitinib. The DNA sequence of the EGFR gene in his tumor biopsy specimen at relapse revealed the presence of a second point mutation, resulting in threonine-to-methionine amino acid change at position 790 of EGFR. Structural modeling and biochemical studies showed that this second mutation led to gefitinib resistance.
3,812 citations
TL;DR: Gefitinib treatment decreased EGFR, ERK1/2, and Akt phosphorylation in EGFR mutant cell lines whereas cetuximab had relatively little effect, and EGFR mutations in NSCLC cells are associated with sensitivity to gefit inib but not to cetUXimab.
Abstract: BACKGROUND Many patients with non-small-cell lung cancer (NSCLC) who achieve radiographic responses to treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib have somatic mutations in the EGFR tyrosine kinase domain. However, little is known about the efficacy of cetuximab, an antibody against the EGFR extracellular domain, in EGFR mutant NSCLC. METHODS NSCLC cell lines carrying wild-type EGFR (A549, H441, and H1666) or mutant EGFR (H3255, DFCILU-011, PC-9, and HCC827) were treated with various dilutions of gefitinib or cetuximab relative to maximal achievable serum concentration. Cell growth was analyzed by the MTS assay, with differences between dose-response curves analyzed nonparametrically. Apoptosis was analyzed by propidium iodide staining and immunoblotting for PARP. Phosphorylation of EGFR and the downstream signaling components ERK1/2 and Akt were analyzed by immunoblotting. Statistical tests were two-sided. RESULTS Growth of NSCLC lines with wild-type EGFR was slightly (A549 and H441) or moderately (H1666) inhibited by gefitinib and cetuximab, and the effects of the two agents were similar. Both agents also induced no (H441) or moderate (H1666) apoptosis in NSCLC cells with wild-type EGFR. By contrast, gefitinib was statistically significantly more effective than cetuximab at inhibiting growth of EGFR mutant cells (H3255: P = .003, DFCILU-011: P = .011, and PC-9: P = .003), and gefitinib-treated EGFR mutant cells had higher levels of apoptosis than cetuximab-treated cells (mean fold increase in apoptosis by 1 microM of gefitinib and 10 microg/mL of cetuximab relative to control, H3255: 8.3 [95% confidence interval {CI} = 4.8 to 11.8] and 2.1 [95% CI = 2.0 to 2.2], respectively, P = .025; DFCILU-011: 5.7 [95% CI = 5.1 to 6.3] and. 0.9 [95% CI = 0.3 to 1.5], respectively, P < .001). Gefitinib treatment decreased EGFR, ERK1/2, and Akt phosphorylation in EGFR mutant cell lines whereas cetuximab had relatively little effect. Both gefitinib and cetuximab inhibited the growth of HCC827 cells, but gefitinib inhibited growth to a greater extent (P = .003). CONCLUSIONS EGFR mutations in NSCLC cells are associated with sensitivity to gefitinib but not to cetuximab.
303 citations
TL;DR: The ability of gefitinib to induce growth arrest and apoptosis in cells transfected with wild-type or L858R EGFR, whereas the T790M mutation leads to high-level functional resistance against gefithinib and erlotinib, support the notion that clinical investigations of compounds similar to CL-387,785 may be useful as a treatment strategy for patients with resistance to EGFR inhibitor therapy caused by the T797M mutation.
Abstract: Mutations of the epidermal growth factor receptor (EGFR) gene have been identified in non-small cell lung cancer specimens from patients responding to anilinoquinazoline EGFR inhibitors. However, clinical resistance to EGFR inhibitor therapy is commonly observed. Previously, we showed that such resistance can be caused by a second mutation of the EGFR gene, leading to a T790M amino acid change in the EGFR tyrosine kinase domain and also found that CL-387,785, a specific and irreversible anilinoquinazoline EGFR inhibitor, was able to overcome this resistance on the biochemical level. Here, we present the successful establishment of a stable Ba/F3 cell line model system for the study of oncogenic EGFR signaling and the functional consequences of the EGFR T790M resistance mutation. We show the ability of gefitinib to induce growth arrest and apoptosis in cells transfected with wild-type or L858R EGFR, whereas the T790M mutation leads to high-level functional resistance against gefitinib and erlotinib. In addition, CL-387,785 is able to overcome resistance caused by the T790M mutation on a functional level, correlating with effective inhibition of downstream signaling pathways. Similar data was also obtained with the use of the gefitinib-resistant H1975 lung cancer cell line. The systems established by us should prove useful for the large-scale screening of alternative EGFR inhibitor compounds against the T790M or other EGFR mutations. These data also support the notion that clinical investigations of compounds similar to CL-387,785 may be useful as a treatment strategy for patients with resistance to EGFR inhibitor therapy caused by the T790M mutation.
251 citations
TL;DR: Antimycin A9 is the first antimycin having an aromatic 8-acyl residue and showed potent nematocidal and insecticidal activities against Caenorhabditis elegans and Artemia salina.
Abstract: A new antimycin group antibiotic, antimycin A9, was isolated from a cultured broth of Streptomyces sp. K01-0031 together with antimycins A3a, A3b, A4, and A7, and flazin methyl ester. Antimycin A9 is the first antimycin having an aromatic 8-acyl residue. It showed potent nematocidal and insecticidal activities against Caenorhabditis elegans and Artemia salina, respectively. It inhibited bovine heart NADH oxidase at nanomolar level like other known antimycins.
57 citations
TL;DR: It is concluded that monoacetylcurcumin is a selective inhibitor of pol lambda and could be used as a chromatographic ligand to purify pol lambda.
27 citations
TL;DR: The peptide was immobilized peptide on a sensor chip and showed a dissociation constant (KD) of approximately 0.1 microM against CPT in QCM and SPR experiments.
23 citations
TL;DR: A biotinylated derivative of the anti-tumor agent camptothecin (CPT) was synthesized and used in a phage display assay to identify drug-binding sequences, and a NSSQSARR-binding sequence was identified.
15 citations
TL;DR: Of the resins tested, TentaGel was the most effective at purifying pol beta and at resisting nonspecific absorption of proteins and the batch affinity purification of pol beta from a protein mixture using these resins was examined.
14 citations
TL;DR: In this paper, a 1,3- or 1,5-rearrangement of N,O-acetals in dichloromethane was described, and crossover experiments indicated that the reaction proceeded through an ion pair intermediate.
8 citations
TL;DR: Antimycin A9 as discussed by the authors is the first antimycin having an aromatic 8-acyl residue and showed potent nematocidal and insecticidal activities against Caenorhabditis elegans and Artemia salina, respectively.
Abstract: A new antimycin group antibiotic, antimycin A9, was isolated from a cultured broth of Streptomyces sp. K01-0031 together with antimycins A3a, A3b, A4, and A7, and flazin methyl ester. Antimycin A9 is the first antimycin having an aromatic 8-acyl residue. It showed potent nematocidal and insecticidal activities against Caenorhabditis elegans and Artemia salina, respectively. It inhibited bovine heart NADH oxidase at nanomolar level like other known antimycins.
6 citations
TL;DR: In this paper, a functionalized spiro[4.5]decane framework was synthesized by the Claisen rearrangement of 4-substituted bicyclic dihydropyrans in a highly stereoselective fashion.
Abstract: A functionalized spiro[4.5]decane framework was synthesized by the Claisen rearrangement of 4-substituted bicyclic dihydropyrans in a highly stereoselective fashion.
TL;DR: In this paper, a highly regio-and diastereoselective TiCl4-mediated Mukaiyama aldol reaction using the chiral vinylketene silyl N,O-acetal has been developed.
Abstract: A highly regio- and diastereoselective TiCl4-mediated vinylogous Mukaiyama aldol reaction using the chiral vinylketene silyl N,O-acetal has been developed. The present vinylogous Mukaiyama aldol reaction provides a unique and effective means of controlling remote asymmetric induction. The methyl group at the alpha-position is important in achieving a high level of stereoselectivity. From a synthetic point of view, this methodology can provide a one-step construction of delta-hydroxy-alpha,gamma-dimethyl-alpha,beta-unsaturated carbonyl unit that is seen in many natural polyketide products.
Journal Article•
TL;DR: A novel, in vivo occurring mutation of the EGFR conferring gefitinib resistance is identified and described, believed to be the first resistance mutation in an oncogenic tyrosine kinase in a common epithelial cancer.
Abstract: 2637 Mutations of the epidermal growth factor receptor gene conferring sensitivity to anilinoquinazoline EGFR inhibitors have recently been identified. Despite the typical dramatic tumor responses to such inhibitors, patients will eventually relapse with time and the mechanism of relapse has not been identified. A patient with advanced lung adenocarcinoma with a del747-752 EGFR mutation treated with gefitinib had a durable remission, but relapsed after 24 months of treatment. The DNA sequencing of exons 18-21 of his original specimen as well as his biopsy on relapse demonstrated persistence of the 747-752 deletion. The DNA sequence of his tumor biopsy from his relapse revealed a new, secondary C-to-T base pair change leading to a Thr-Met amino acid substitution at position 790. This amino acid change corresponds to one of the common bcr-abl kinase mutations conferring STI-571 resistance. Structural modeling suggested that this change would lead to the introduction of a bulkier amino acid side chain into a hydrophobic pocket of the ATP-binding site of the EGFR molecule. Further modeling also suggested that this substitution would lead to likely steric hindrance of either erlotinib or gefitinib binding due to the juxtaposition of the methionine side chain and the acetylene or chloride side chain of the anilino group of the respective inhibitor. Plasmid constructs were generated introducing this amino acid change into wild-type, L858R mutant, del747-753insS as well as del747-752 constructs. In transient transfection experiments, equal expression as well as phosphoprotein generation upon EGF stimulation between all the corresponding construct pairs (primary versus resistance mutant) was seen. While gefitinib completely inhibited EGF-stimulated phospho-EGFR generation of the non-resistance mutant constructs at concentrations of 2-20 nM, all four constructs carrying the Thr-Met substitution showed high level resistance to gefitinib with sustained EGFR phosphorylation at concentrations as high as 2 μM. A screen of commercially available EGFR inhibitors demonstrated that one of the screened inhibitors, CL-387,785, inhibited both the del747-752 as well as the del747-752 plus resistance mutant constructs with nearly the same potency with full inhibition observed at a concentration as low as 30nM. CL-387,785 is an irreversible, anilinoquinazoline inhibitor of EGFR. In summary, we have identified a novel, in vivo occurring mutation of the EGFR conferring gefitinib resistance and thereby describe the first resistance mutation in an oncogenic tyrosine kinase in a common epithelial cancer. We also demonstrate an alternative compound which can inhibit this mutant receptor, suggesting that drugs of this class might be useful in patients who relapse while on treatment with gefitinib.
TL;DR: HBe抗体陽性B型肝炎ウイルス (HBV) キャリア状態にあり, 64歳時に 肝切除を施行, 切�’��’本より慢性�”疾患を母地と
Abstract: 高分化型肝細胞癌切除18年後に残肝再発を確認した男性症例を経験した. 初発時はHBe抗体陽性B型肝炎ウイルス (HBV) キャリア状態にあり, 64歳時に肝切除を施行. 切除標本より慢性肝疾患を母地としない肝S4の4cm大の高分化型肝細胞癌であった. 輸血後肝炎と考えられる急性肝炎状態となり, 3年後に沈静化する間にHBs抗体陽転化を示した. その後C型肝炎ウイルス (HCV) 持続感染が判明し, 80歳頃よりトランスアミナーゼ上昇が持続したが, 血中HBV DNAは持続陰性であった. 外来にて経過観察中, 78歳頃より肝S7に小結節性病変が検出され緩徐に増大, 82歳時に動脈血流に富む1.7cm大の肝細胞癌と診断し, 加療した. 非癌部肝組織は慢性肝炎で, 組織中HBV DNAも検出されなかった. 本症例は初発時には慢性肝疾患なく, 発癌にはHBVの直接的関与が, 再発時にはHCV感染持続による慢性肝炎を背景とした発癌が考えられた.
TL;DR: In conclusion, CDDO leads to granulocytic differentiation and translational induction of CEBPA protein, and may provide a novel treatment approach for patients with acute myeloid leukemia.