55 results on '"Mizuuchi H"'
Search Results
2. A Case of Tension Pneumomediastinum Treated With Mediastinal Drainage Using a Semi-flexible Fiberscope via a Subxiphoid Approach.
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Matsumoto Y, Mizuuchi H, Honjo K, Hata M, and Shigenaga T
- Abstract
Tension pneumomediastinum with hemodynamic failure is a rare but life-threatening condition. Rapid decompression of the mediastinum by drainage is essential to save the patient's life. This report presents a case of tension pneumomediastinum that developed during conservative management of a pneumomediastinum associated with idiopathic pulmonary fibrosis. Endoscopically guided mediastinal drainage was successfully performed in the emergency situation of tension pneumomediastinum. Using the semi-flexible fiberscope inserted through a subxiphoid approach, the drainage catheter was easily and safely placed at the appropriate site in the mediastinum. Good mediastinal decompression was achieved, and the patient was out of this critical condition., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Matsumoto et al.)
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- 2024
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3. Advances in the Evaluation of Gastrointestinal Absorption Considering the Mucus Layer.
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Miyazaki K, Sasaki A, and Mizuuchi H
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Because of the increasing sophistication of formulation technology and the increasing polymerization of compounds directed toward undruggable drug targets, the influence of the mucus layer on gastrointestinal drug absorption has received renewed attention. Therefore, understanding the complex structure of the mucus layer containing highly glycosylated glycoprotein mucins, lipids bound to the mucins, and water held by glycans interacting with each other is critical. Recent advances in cell culture and engineering techniques have led to the development of evaluation systems that closely mimic the ecological environment and have been applied to the evaluation of gastrointestinal drug absorption while considering the mucus layer. This review provides a better understanding of the mucus layer components and the gastrointestinal tract's biological defense barrier, selects an assessment system for drug absorption in the mucus layer based on evaluation objectives, and discusses the overview and features of each assessment system.
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- 2023
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4. Liver metastases 2 years after resection of a very-low-risk duodenal gastrointestinal stromal tumor: a case report.
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Mita J, Tada K, Kuboyama Y, Hiroshige S, Nakamura S, Takahashi J, Sakata K, Mizuuchi H, Oba T, Yoshizumi F, Iwaki K, Takeuchi H, Kajiyama K, and Fukuzawa K
- Abstract
Background: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors, but are the most common mesenchymal tumors of the gastrointestinal tract. The risk classification of GISTs is based on the tumor size, mitotic index, tumor site, and presence of tumor rupture. Recurrence in the very-low-risk group is extremely rare. We herein report a case of liver metastases 2 years after resection of a very-low-risk duodenal GIST., Case Presentation: A 57-year-old woman presented to the hospital for evaluation of melena. Esophagogastroduodenoscopy showed bleeding from the exposed blood vessels at the top of a submucosal tumor approximately 20 mm in size located in the second (descending) part of the duodenum, and the bleeding was controlled with electrocoagulation. A GIST was suspected, and the patient underwent wedge resection of the duodenum. The resected specimen contained a 16- × 12-mm (< 20-mm) white submucosal tumor composed of spindle cells with a mitotic count of 4 per 50 high-power fields, and a histologically negative margin was achieved. Immunochemical analysis revealed positive tumor staining for c-kit protein and alpha-smooth muscle actin and negative staining for CD34, desmin, and S-100 protein. Therefore, the tumor was diagnosed as a very-low-risk duodenal GIST based on the Fletcher classification and modified Fletcher classification (Joensuu classification). The postoperative course was uneventful, and the patient was discharged on postoperative day 11. At the follow-up visit 2 years postoperatively, contrast-enhanced computed tomography revealed liver tumors in S8 and S6 measuring 26 × 24 and 10 × 10 mm, respectively. Both lesions showed peripheral dominant hyperenhancement with hypoenhancement inside, indicating tissue degeneration within the tumors. These imaging findings closely resembled those of the duodenal GIST. Hence, the patient was diagnosed with liver metastases of GIST 2 years postoperatively. She was subsequently started on treatment with 400 mg of imatinib. At the time of this writing (2 months after diagnosis), the patient was clinically well and asymptomatic and was continuing imatinib therapy., Conclusions: Recurrence of very-low-risk GISTs is extremely rare. Even a small GIST with low mitotic activity can never be considered completely benign, and long-term follow-up is necessary., (© 2022. The Author(s).)
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- 2022
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5. CD44 Facilitates Epithelial-to-Mesenchymal Transition Phenotypic Change at Acquisition of Resistance to EGFR Kinase Inhibitors in Lung Cancer.
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Suda K, Murakami I, Yu H, Kim J, Tan AC, Mizuuchi H, Rozeboom L, Ellison K, Rivard CJ, Mitsudomi T, and Hirsch FR
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- Antineoplastic Agents pharmacology, Biomarkers, Cell Line, Tumor, ErbB Receptors genetics, ErbB Receptors metabolism, Gene Expression Profiling, Gene Knockdown Techniques, Humans, Immunohistochemistry, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Phenotype, RNA Interference, Drug Resistance, Neoplasm genetics, Epithelial-Mesenchymal Transition drug effects, ErbB Receptors antagonists & inhibitors, Hyaluronan Receptors metabolism, Lung Neoplasms metabolism, Lung Neoplasms pathology, Protein Kinase Inhibitors pharmacology
- Abstract
Epithelial-to-mesenchymal transition (EMT) is one of the acquired resistance mechanisms to EGFR tyrosine kinase inhibitors (TKI) in lung cancers. Because EMT is related to tumor invasion, metastases, and resistance to various treatments, it is important to prevent the emergence of EMT. However, molecular mechanism(s) underlying EMT phenotypic changes, as well as biomarker(s) that predict the emergence of EMT in EGFR -mutated lung cancers, are unclear to date. Through the comparison of expression data between isogenic lung cancer cell lines that acquired resistance to EGFR-TKI(s), we identified that high CD44 expression is related to a mesenchymal phenotype and that shRNA-mediated knockdown of CD44 reversed the EMT change. High membranous CD44 expression was identified in lesions with mesenchymal phenotype that were obtained from lung cancer patients who developed acquired resistance to gefitinib or afatinib, whereas isogenic lesions without EMT change showed negative/weak staining for CD44. Immunohistochemistry for treatment-naïve lung cancer cell lines with EGFR mutations found those that acquire resistance to EGFR-TKIs via EMT (HCC4006 and H1975 cells) had strong membranous CD44 expression compared with non-EMT-transforming lines which demonstrated negative or weak staining (Fisher exact test P value = 0.036). shRNA-mediated CD44 knockdown in HCC4006 cells prevented the emergence of EMT after chronic exposure to osimertinib. These results suggest that upregulation of CD44 facilitates EMT-phenotypic change in lung cancers with EGFR mutations when treated with EGFR-TKIs. In addition, our results suggest that CD44 can be a useful biomarker to predict the emergence of EMT upon EGFR-TKI monotherapy. Mol Cancer Ther; 17(10); 2257-65. ©2018 AACR ., (©2018 American Association for Cancer Research.)
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- 2018
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6. Effect of dasatinib on EMT-mediated-mechanism of resistance against EGFR inhibitors in lung cancer cells.
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Sesumi Y, Suda K, Mizuuchi H, Kobayashi Y, Sato K, Chiba M, Shimoji M, Tomizawa K, Takemoto T, and Mitsudomi T
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- Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung pathology, Cell Line, Tumor metabolism, Drug Resistance, Neoplasm, Drug Therapy, Combination methods, Epithelial-Mesenchymal Transition genetics, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Erlotinib Hydrochloride, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mutation, Treatment Outcome, Carcinoma, Non-Small-Cell Lung drug therapy, Cell Line, Tumor drug effects, Dasatinib pharmacology, Epithelial-Mesenchymal Transition drug effects, Lung Neoplasms drug therapy, Protein Kinase Inhibitors pharmacology
- Abstract
Objective: The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells (Wilson et al., 2014). In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells, which tend to acquire resistance to EGFR-TKIs via EMT., Materials and Methods: Sensitivity to dasatinib in HCC4006 and HCC4006 erlotinib-resistant (ER) cells with an EMT phenotype was analyzed. HCC4006 cells acquired resistance against the combination of erlotinib and dasatinib (HCC4006EDR) following chronic treatment with these drugs. The expression of EMT markers and the resistance mechanism were analyzed., Results: Short-term or long-term treatment with dasatinib did not reverse EMT in HCC4006ER. In contrast, HCC4006EDR cells maintained an epithelial phenotype, and the mechanism underlying resistance to erlotinib plus dasatinib combination therapy was attributable to a T790M secondary mutation. HCC4006EDR cells, but not HCC4006ER cells, were highly sensitive to a third-generation EGFR-TKI, osimertinib., Conclusions: Although dasatinib monotherapy did not reverse EMT in HCC4006ER cells, preemptive combination treatment with erlotinib and dasatinib prevented the emergence of acquired resistance via EMT, and led to the emergence of T790M. Our results indicate that preemptive combination therapy may be a promising strategy to prevent the emergence of EMT-mediated resistance., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
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- 2017
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7. MEK inhibitors against MET-amplified non-small cell lung cancer.
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Chiba M, Togashi Y, Tomida S, Mizuuchi H, Nakamura Y, Banno E, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Mitsudomi T, and Nishio K
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- A549 Cells, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, Crizotinib, Diphenylamine pharmacology, ErbB Receptors genetics, Humans, Lung Neoplasms genetics, Phosphoinositide-3 Kinase Inhibitors, Proto-Oncogene Proteins c-met genetics, Pyrazoles pharmacology, Pyridines pharmacology, Antineoplastic Agents pharmacology, Benzamides pharmacology, Carcinoma, Non-Small-Cell Lung pathology, Diphenylamine analogs & derivatives, Lung Neoplasms pathology, MAP Kinase Kinase 1 antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyridones pharmacology, Pyrimidinones pharmacology
- Abstract
Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.
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- 2016
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8. Functional Analyses of Mutations in Receptor Tyrosine Kinase Genes in Non-Small Cell Lung Cancer: Double-Edged Sword of DDR2.
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Terashima M, Togashi Y, Sato K, Mizuuchi H, Sakai K, Suda K, Nakamura Y, Banno E, Hayashi H, De Velasco MA, Fujita Y, Tomida S, Mitsudomi T, and Nishio K
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- A549 Cells, Animals, Cell Line, Cell Line, Tumor, Cell Proliferation genetics, ErbB Receptors genetics, HEK293 Cells, Humans, Mice, NIH 3T3 Cells, Receptor Protein-Tyrosine Kinases genetics, Carcinoma, Non-Small-Cell Lung genetics, Discoidin Domain Receptor 2 genetics, Lung Neoplasms genetics, Mutation genetics, Phosphatidylinositol 3-Kinases genetics, Receptor Protein-Tyrosine Kinases metabolism
- Abstract
Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets., Experimental Design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro, Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growth-suppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor., Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen. Clin Cancer Res; 22(14); 3663-71. ©2016 AACR., (©2016 American Association for Cancer Research.)
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- 2016
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9. Clinical, Pathological, and Molecular Features of Lung Adenocarcinomas with AXL Expression.
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Sato K, Suda K, Shimizu S, Sakai K, Mizuuchi H, Tomizawa K, Takemoto T, Nishio K, and Mitsudomi T
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- Adenocarcinoma genetics, Adenocarcinoma surgery, Aged, Anaplastic Lymphoma Kinase, Antineoplastic Agents therapeutic use, Cadherins biosynthesis, Down-Regulation, ErbB Receptors genetics, Female, Gefitinib, Humans, Hyaluronan Receptors biosynthesis, Immunohistochemistry, Kaplan-Meier Estimate, Lung drug effects, Lung surgery, Lung Neoplasms genetics, Lung Neoplasms surgery, Male, Multivariate Analysis, Mutation, Outcome Assessment, Health Care methods, Outcome Assessment, Health Care statistics & numerical data, Prognosis, Proportional Hazards Models, Proto-Oncogene Proteins p21(ras) genetics, Quinazolines therapeutic use, Receptor Protein-Tyrosine Kinases genetics, Axl Receptor Tyrosine Kinase, Adenocarcinoma metabolism, Lung metabolism, Lung Neoplasms metabolism, Proto-Oncogene Proteins biosynthesis, Receptor Protein-Tyrosine Kinases biosynthesis
- Abstract
The receptor tyrosine kinase AXL is a member of the Tyro3-Axl-Mer receptor tyrosine kinase subfamily. AXL affects several cellular functions, including growth and migration. AXL aberration is reportedly a marker for poor prognosis and treatment resistance in various cancers. In this study, we analyzed clinical, pathological, and molecular features of AXL expression in lung adenocarcinomas (LADs). We examined 161 LAD specimens from patients who underwent pulmonary resections. When AXL protein expression was quantified (0, 1+, 2+, 3+) according to immunohistochemical staining intensity, results were 0: 35%; 1+: 20%; 2+: 37%; and 3+: 7% for the 161 samples. AXL expression status did not correlate with clinical features, including smoking status and pathological stage. However, patients whose specimens showed strong AXL expression (3+) had markedly poorer prognoses than other groups (P = 0.0033). Strong AXL expression was also significantly associated with downregulation of E-cadherin (P = 0.025) and CD44 (P = 0.0010). In addition, 9 of 12 specimens with strong AXL expression had driver gene mutations (6 with EGFR, 2 with KRAS, 1 with ALK). In conclusion, we found that strong AXL expression in surgically resected LADs was a predictor of poor prognosis. LADs with strong AXL expression were characterized by mesenchymal status, higher expression of stem-cell-like markers, and frequent driver gene mutations.
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- 2016
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10. Oncogene swap as a novel mechanism of acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor in lung cancer.
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Mizuuchi H, Suda K, Murakami I, Sakai K, Sato K, Kobayashi Y, Shimoji M, Chiba M, Sesumi Y, Tomizawa K, Takemoto T, Sekido Y, Nishio K, and Mitsudomi T
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- Acrylamides administration & dosage, Cell Line, Tumor, ErbB Receptors antagonists & inhibitors, Gefitinib, Humans, Lung Neoplasms genetics, Lung Neoplasms pathology, Mutation, Oncogenes, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage, Quinazolines administration & dosage, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, Lung Neoplasms drug therapy, Proto-Oncogene Proteins c-met genetics
- Abstract
Mutant selective epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), such as rociletinib and AZD9291, are effective for tumors with T790M secondary mutation that become refractory to first-generation EGFR-TKI. However, acquired resistance to these prospective drugs is anticipated considering the high adaptability of cancer cells and the mechanisms remain largely obscure. Here, CNX-2006 (tool compound of rociletinib) resistant sublines were established by chronic exposure of HCC827EPR cells harboring exon 19 deletion and T790M to CNX-2006. Through the analyses of these resistant subclones, we identified two resistant mechanisms accompanied by MET amplification. One was bypass signaling by MET amplification in addition to T790M, which was inhibited by the combination of CNX-2006 and MET-TKI. Another was loss of amplified EGFR mutant allele including T790M while acquiring MET amplification. Interestingly, MET-TKI alone was able to overcome this resistance, suggesting that oncogenic dependence completely shifted from EGFR to MET. We propose describing this phenomenon as an "oncogene swap." Furthermore, we analyzed multiple lesions from a patient who died of acquired resistance to gefitinib, then found a clinical example of an oncogene swap in which the EGFR mutation was lost and a MET gene copy was gained. In conclusion, an "oncogene swap" from EGFR to MET is a novel resistant mechanism to the EGFR-TKI. This novel mechanism should be considered in order to avoid futile inhibition of the original oncogene., (© 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
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- 2016
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11. Impact of bevacizumab in combination with erlotinib on EGFR-mutated non-small cell lung cancer xenograft models with T790M mutation or MET amplification.
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Furugaki K, Fukumura J, Iwai T, Yorozu K, Kurasawa M, Yanagisawa M, Moriya Y, Yamamoto K, Suda K, Mizuuchi H, Mitsudomi T, and Harada N
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- Animals, Bevacizumab administration & dosage, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, ErbB Receptors genetics, Erlotinib Hydrochloride administration & dosage, Humans, Immunoblotting, Lung Neoplasms genetics, Male, Mice, Mice, Inbred BALB C, Mutation, Polymerase Chain Reaction, Xenograft Model Antitumor Assays, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma, Non-Small-Cell Lung pathology, Gene Amplification, Genes, erbB-1, Lung Neoplasms pathology, Proto-Oncogene Proteins c-met genetics
- Abstract
Erlotinib (ERL), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, shows notable efficacy against non-small cell lung cancer (NSCLC) harboring EGFR mutations. Bevacizumab (BEV), a humanized monoclonal antibody to vascular endothelial cell growth factor (VEGF), in combination with ERL (BEV+ERL) significantly extended progression-free survival in patients with EGFR-mutated NSCLC compared with ERL alone. However, the efficacy of BEV+ERL against EGFR-mutated NSCLC harboring T790M mutation or MET amplification, is unclear. Here, we examined the antitumor activity of BEV+ERL in four xenograft models of EGFR-mutated NSCLC (three harboring ERL resistance mutations). In the HCC827 models (exon 19 deletion: DEL), ERL significantly inhibited tumor growth by blocking EGFR signal transduction. Although there was no difference between ERL and BEV+ERL in maximum tumor growth inhibition, BEV+ERL significantly suppressed tumor regrowth during a drug-cessation period. In the HCC827-EPR model (DEL+T790M) and HCC827-vTR model (DEL+MET amplification), ERL reduced EGFR signal transduction and showed less pronounced but still significant tumor growth inhibition than in the HCC827 model. In these models, tumor growth inhibition was significantly stronger with BEV+ERL than with each single agent. In the NCI-H1975 model (L858R+T790M), ERL did not inhibit growth or EGFR signal transduction, and BEV+ERL did not inhibit growth more than BEV. BEV alone significantly decreased microvessel density in each tumor. In conclusion, addition of BEV to ERL did not enhance antitumor activity in primarily ERL-resistant tumors with T790M mutation; however, BEV+ERL enhanced antitumor activity in T790M mutation- or MET amplification-positive tumors as long as their growth remained significantly suppressed by ERL., (© 2015 UICC.)
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- 2016
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12. Heterogeneity in resistance mechanisms causes shorter duration of epidermal growth factor receptor kinase inhibitor treatment in lung cancer.
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Suda K, Murakami I, Sakai K, Tomizawa K, Mizuuchi H, Sato K, Nishio K, and Mitsudomi T
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- Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Cohort Studies, Drug Administration Schedule, Drug Resistance, Neoplasm, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Gefitinib, Gene Dosage, Genes, erbB-1, Genetic Heterogeneity, Humans, Lung Neoplasms enzymology, Lung Neoplasms pathology, Male, Middle Aged, Molecular Targeted Therapy, Mutation, Proto-Oncogene Proteins c-met genetics, Quinazolines administration & dosage, Survival Analysis, Time-to-Treatment trends, Treatment Failure, ErbB Receptors antagonists & inhibitors, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Protein Kinase Inhibitors administration & dosage
- Abstract
Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are used as a first line therapy for metastatic lung cancer harboring somatic EGFR mutation. However, acquisition of resistance to these drugs is almost inevitable. T790M (threonine to methionine substitution at codon 790 of the EGFR gene) and MET amplification are well-known resistance mechanisms, and we previously demonstrated that three of six autopsied patients showed inter-tumor heterogeneity in resistance mechanisms by analyzing T790M and MET gene copy number (Suda et al., 2010). To further elucidate the role of heterogeneity in acquired resistance, here we performed further analyses including additional five patients., Materials and Methods: We analyzed somatic mutations in 50 cancer-related genes for 26 EGFR-TKI refractory lesions from four autopsied patients using target sequencing. MET and ERBB2 copy numbers were analyzed by real-time PCR. Data for additional one patient was obtained from our recent study (Suda et al., 2015). Relationship between heterogeneity in resistance mechanism(s) and time to treatment failure (TTF) of EGFR-TKI and post-progression survival (PPS) were analyzed., Results and Conclusion: We observed heterogeneity of resistance mechanisms in two of four patients analyzed (T790M+MET gene copy number gain, and mutant EGFR loss+unknown). We also identified quantitative heterogeneity in EGFR T790M mutation ratio among EGFR-TKI refractory lesions. In analyzing patient outcomes, we found that patients who developed multiple resistance mechanisms had shorter TTF compared with those who developed single resistance mechanism (p=0.022). PPS after EGFR-TKI treatment failure was compatible between these two groups (p=0.42). These findings further our understanding of acquired resistance mechanisms to EGFR-TKIs, and may lead to better treatment strategies after acquisition of resistance to first generation EGFR-TKIs in lung cancer patients with EGFR mutations., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
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- 2016
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13. MET gene exon 14 deletion created using the CRISPR/Cas9 system enhances cellular growth and sensitivity to a MET inhibitor.
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Togashi Y, Mizuuchi H, Tomida S, Terashima M, Hayashi H, Nishio K, and Mitsudomi T
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- Base Sequence, Cell Line, Tumor, Cell Proliferation, Computational Biology methods, Databases, Genetic, HEK293 Cells, Humans, Lung Neoplasms drug therapy, Lung Neoplasms genetics, Molecular Sequence Data, Mutation, Proto-Oncogene Proteins c-met chemistry, RNA Splice Sites, RNA, Guide, CRISPR-Cas Systems, Sequence Analysis, DNA, CRISPR-Cas Systems, Drug Resistance, Neoplasm genetics, Exons, Gene Targeting, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-met genetics, Sequence Deletion
- Abstract
Background: MET splice site mutations resulting in an exon 14 deletion have been reported to be present in about 3% of all lung adenocarcinomas. Patients with lung adenocarcinoma and a MET splice site mutation who have responded to MET inhibitors have been reported. The CRISPR/Cas9 system is a recently developed genome-engineering tool that can easily and rapidly cause small insertions or deletions., Materials and Methods: We created an in vitro model for MET exon 14 deletion using the CRISPR/Cas9 system and the HEK293 cell line. The phenotype, which included MET inhibitor sensitivity, was then investigated in vitro. Additionally, MET splice site mutations were analyzed in several cancers included in The Cancer Genome Atlas (TCGA) dataset., Results: An HEK293 cell line with a MET exon 14 deletion was easily and rapidly created; this cell line had a higher MET protein expression level, enhanced MET phosphorylation, and prolonged MET activation. In addition, a direct comparison of phenotypes using this system demonstrated enhanced cellular growth, colony formation, and MET inhibitor sensitivity. In the TCGA dataset, lung adenocarcinomas had the highest incidence of MET exon 14 deletions, while other cancers rarely carried such mutations. Approximately 10% of the lung adenocarcinoma samples without any of driver gene alterations carried the MET exon 14 deletion., Conclusions: These findings suggested that this system may be useful for experiments requiring the creation of specific mutations, and the present experimental findings encourage the development of MET-targeted therapy against lung cancer carrying the MET exon 14 deletion., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)
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- 2015
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14. EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs.
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Kobayashi Y, Togashi Y, Yatabe Y, Mizuuchi H, Jangchul P, Kondo C, Shimoji M, Sato K, Suda K, Tomizawa K, Takemoto T, Hida T, Nishio K, and Mitsudomi T
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- Afatinib, Animals, Cell Line, Tumor, DNA Mutational Analysis, Databases, Genetic, Drug Resistance, Neoplasm genetics, ErbB Receptors chemistry, Gene Expression, Gene Frequency, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Male, Mice, Middle Aged, Models, Molecular, Molecular Conformation, Mutation Rate, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Quinazolines chemistry, Quinazolines pharmacology, Quinazolines therapeutic use, Quinolines chemistry, Quinolines pharmacology, Quinolines therapeutic use, Structure-Activity Relationship, Transfection, Treatment Outcome, ErbB Receptors genetics, Exons, Lung Neoplasms genetics, Mutation
- Abstract
Purpose: Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18., Experimental Design: Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined., Results: Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼ 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature., Conclusions: Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations., (©2015 American Association for Cancer Research.)
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- 2015
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15. Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer.
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Suda K, Murakami I, Sakai K, Mizuuchi H, Shimizu S, Sato K, Tomizawa K, Tomida S, Yatabe Y, Nishio K, and Mitsudomi T
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- Aged, Amino Acid Substitution, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Codon, DNA Copy Number Variations, Drug Resistance, Neoplasm genetics, Female, Humans, Lung Neoplasms drug therapy, Neoplasm Metastasis, Neoplasm Staging, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-met genetics, Small Cell Lung Carcinoma drug therapy, Cell Transformation, Neoplastic genetics, ErbB Receptors genetics, Lung Neoplasms genetics, Lung Neoplasms pathology, Mutation, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology
- Abstract
Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre- and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.
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- 2015
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16. An activating ALK gene mutation in ALK IHC-positive/FISH-negative nonsmall-cell lung cancer.
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Togashi Y, Mizuuchi H, Kobayashi Y, Hayashi H, Terashima M, Sakai K, Banno E, Mizukami T, Nakamura Y, de Velasco MA, Fujita Y, Tomida S, Mitsudomi T, and Nishio K
- Subjects
- Aged, Anaplastic Lymphoma Kinase, Carcinoma, Non-Small-Cell Lung metabolism, HEK293 Cells, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Lung Neoplasms metabolism, Male, Middle Aged, Mutation, Receptor Protein-Tyrosine Kinases metabolism, Carcinoma, Non-Small-Cell Lung genetics, Lung Neoplasms genetics, Receptor Protein-Tyrosine Kinases genetics
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- 2015
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17. Collateral chemoresistance to anti-microtubule agents in a lung cancer cell line with acquired resistance to erlotinib.
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Mizuuchi H, Suda K, Sato K, Tomida S, Fujita Y, Kobayashi Y, Maehara Y, Sekido Y, Nishio K, and Mitsudomi T
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- ATP Binding Cassette Transporter, Subfamily B antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B genetics, ATP Binding Cassette Transporter, Subfamily B metabolism, Cadherins antagonists & inhibitors, Cadherins genetics, Cadherins metabolism, Cell Line, Tumor, Epithelial-Mesenchymal Transition drug effects, ErbB Receptors metabolism, Gene Expression Regulation, Neoplastic drug effects, Humans, Lung Neoplasms metabolism, Lung Neoplasms pathology, Neoplastic Stem Cells cytology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, RNA Interference, RNA, Small Interfering metabolism, Cell Proliferation drug effects, Drug Resistance, Neoplasm drug effects, Erlotinib Hydrochloride toxicity, Protein Kinase Inhibitors toxicity, Tubulin Modulators toxicity
- Abstract
Various alterations underlying acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been described. Although treatment strategies specific for these mechanisms are under development, cytotoxic agents are currently employed to treat many patients following failure of EGFR-TKIs. However, the effect of TKI resistance on sensitivity to these cytotoxic agents is mostly unclear. This study investigated the sensitivity of erlotinib-resistant tumor cells to five cytotoxic agents using an in vitro EGFR-TKI-resistant model. Four erlotinib-sensitive lung adenocarcinoma cell lines and their resistant derivatives were tested. Of the resistant cell lines, all but one showed a similar sensitivity to the tested drugs as their parental cells. HCC4006ER cells with epithelial mesenchymal transition features acquired resistance to the three microtubule-targeting agents, docetaxel, paclitaxel and vinorelbine, but not to cisplatin and gemcitabine. Gene expression array and immunoblotting demonstrated that ATP-binding cassette subfamily B, member 1 (ABCB1) was up-regulated in HCC4006ER cells. ABCB1 knockdown by siRNA partially restored sensitivity to the anti-microtubule agents but not to erlotinib. Moreover, the histone deacetylase inhibitor entinostat sensitized HCC4006ER cells to anti-microtubule agents through ABCB1 suppression. Our study indicates that sensitivity of tumor cells to cytotoxic agents in general does not change before and after failure of EGFR-TKIs. However, we describe that two different molecular alterations confer acquired resistance to EGFR-TKIs and cytotoxic agents, respectively. This phenomenon should be kept in mind in selection of subsequent therapy after failure of EGFR-TKIs.
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- 2015
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18. Solitary pulmonary metastasis from malignant melanoma of the bulbar conjunctiva presenting as a pulmonary ground glass nodule: Report of a case.
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Mizuuchi H, Suda K, Kitahara H, Shimamatsu S, Kohno M, Okamoto T, and Maehara Y
- Abstract
We herein report a case of solitary pulmonary metastasis from malignant melanoma that presented as a pulmonary ground glass nodule. A 57-year-old man who had undergone resection of a malignant melanoma of the right bulbar conjunctiva at the age of 51 was referred to our hospital for management of ground glass opacity in his left lung. Because radiological examination suggested the nodule was an adenocarcinoma in situ, computed tomography (CT) follow-up was planned. CT examination performed nine months later showed that the nodule had grown from 6 mm to 8 mm. Moreover, CT performed one and a half years after first detection revealed that the nodule had grown up to 10 mm. The patient, therefore, underwent partial resection of the lung for diagnosis and treatment. Pathological examination of the resected specimen revealed atypical cells with melanin granules proliferating in a lepidic-like fashion. The cells were positive on S-100 staining, indicating a pulmonary metastasis from malignant melanoma. Thus, metastatic tumors from malignant melanoma can present as ground glass opacities.
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- 2015
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19. Recent evidence, advances, and current practices in surgical treatment of lung cancer.
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Suda K, Sato K, Mizuuchi H, Kobayashi Y, Shimoji M, Tomizawa K, Takemoto T, Iwasaki T, Sakaguchi M, and Mitsudomi T
- Subjects
- Adenocarcinoma diagnosis, Adenocarcinoma genetics, Adenocarcinoma pathology, Chemotherapy, Adjuvant, Combined Modality Therapy, Humans, Lung Neoplasms diagnosis, Lung Neoplasms genetics, Lung Neoplasms pathology, Lymphatic Metastasis, Minimally Invasive Surgical Procedures methods, Molecular Targeted Therapy, Neoplasm Recurrence, Local, Neoplasm Staging, Precision Medicine trends, Pulmonary Surgical Procedures methods, Radiotherapy, Adjuvant, Small Cell Lung Carcinoma diagnosis, Small Cell Lung Carcinoma genetics, Small Cell Lung Carcinoma pathology, Thoracic Surgery, Video-Assisted, Adenocarcinoma surgery, Lung Neoplasms surgery, Minimally Invasive Surgical Procedures trends, Pulmonary Surgical Procedures trends, Small Cell Lung Carcinoma surgery
- Abstract
In the last 10-15 years, strategies and modalities of lung cancer treatment have changed dramatically. Meanwhile, the treatment objectives, the lung cancers themselves, have also changed, probably owing to early detection by computed tomography and aging of the population. In particular, the proportions of smaller lung cancers, lung adenocarcinomas with ground-glass opacity, and lung cancers in older patients are increasing. Along with these changes, surgeons have innovated and evaluated novel procedures for pulmonary resection. These include the application of minimally invasive surgical techniques, such as video-assisted thoracoscopic surgery (VATS) and robotic surgery, and sub-lobar resection, such as wedge resection and segmentectomy, for small peripheral lung cancers. Currently, VATS has gained wide acceptance and several institutions in Japan have started using robotic surgery for lung cancers. Two important clinical trials of sub-lobar resection for small peripheral lung cancers are now underway in Japan. In addition, surgery itself is of growing importance in lung cancer treatment. In particular, recent evidence supports the use of surgery in strictly selected patients with locally advanced disease, lung cancers with N2 lymph node metastases, small cell lung cancers, recurrent oligo-metastasis after pulmonary resection, or relapsed tumors after drug treatment. Surgical treatment also provides abundant tumor samples for molecular analysis, which can be used for drug selection in the adjuvant setting or after disease relapse. In the era of personalized treatment, surgery is still one of the most important treatment modalities to combat lung cancer., (Copyright © 2014 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)
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- 2014
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20. The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor.
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Suda K, Mizuuchi H, Sato K, Takemoto T, Iwasaki T, and Mitsudomi T
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- Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor drug effects, Cell Proliferation, Dose-Response Relationship, Drug, Erlotinib Hydrochloride, Humans, Mutation, Phosphorylation, RNA, Small Interfering metabolism, Drug Resistance, Neoplasm, ErbB Receptors genetics, Lung Neoplasms genetics, Lung Neoplasms pathology, Quinazolines pharmacology, Receptor, IGF Type 1 metabolism
- Abstract
Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy often provides a dramatic response in lung cancer patients with EGFR mutations. In addition, moderate clinical efficacy of the EGFR-TKI, erlotinib, has been shown in lung cancer patients with the wild-type EGFR. Numerous molecular mechanisms that cause acquired resistance to EGFR-TKIs have been identified in lung cancers with the EGFR mutations; however, few have been reported in lung cancers with the wild-type EGFR. We used H358 lung adenocarcinoma cells lacking EGFR mutations that showed modest sensitivity to erlotinib. The H358 cells acquired resistance to erlotinib via chronic exposure to the drug. The H358 erlotinib-resistant (ER) cells do not have a secondary EGFR mutation, neither MET gene amplification nor PTEN downregulation; these have been identified in lung cancers with the EGFR mutations. From comprehensive screening of receptor tyrosine kinase phosphorylation, we observed increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) in H358ER cells compared with parental H358 cells. H358ER cells responded to combined therapy with erlotinib and NVP-AEW541, an IGF1R-TKI. Our results indicate that IGF1R activation is a molecular mechanism that confers acquired resistance to erlotinib in lung cancers with the wild-type EGFR., (© 2014 UICC.)
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- 2014
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21. CRKL amplification is rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation.
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Suda K, Mizuuchi H, Murakami I, Uramoto H, Tanaka F, Sato K, Takemoto T, Iwasaki T, Sekido Y, Yatabe Y, and Mitsudomi T
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- Aged, Aged, 80 and over, Female, Gene Dosage, Humans, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Lung Neoplasms pathology, Male, Middle Aged, Neoplasm Staging, Prognosis, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-met genetics, Risk Factors, Adaptor Proteins, Signal Transducing genetics, Drug Resistance, Neoplasm genetics, ErbB Receptors genetics, Gene Amplification, Lung Neoplasms genetics, Mutation, Nuclear Proteins genetics
- Abstract
Objectives: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs., Materials and Methods: We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined., Results and Conclusion: In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)
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- 2014
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22. Genetic and Prognostic Differences of Non-small Cell Lung Cancer between Elderly Patients and Younger Counterparts.
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Suda K, Tomizawa K, Mizuuchi H, Ito S, Kitahara H, Shimamatsu S, Kohno M, Yoshida T, Okamoto T, Maehara Y, Yatabe Y, and Mitsudomi T
- Abstract
Many elderly patients suffer from lung cancers, but it is not clear if their lung cancers differ from those of younger patients. In this study, we compared genetic and prognostic characteristics of lung cancers of patients aged ≥75 years with those of patients aged ≤ 64 years. In the genetic analysis, we explored 292 surgically treated non-squamous cell lung cancers with known mutational status of epidermal growth factor (EGFR) and anaplastic lymphoma kinase (ALK). In the prognostic analysis, we retrospectively analyzed 405 surgically treated non-small cell lung cancers (NSCLCs) before the era of routine clinical application of post-surgical adjuvant chemotherapy. Postsurgical recurrence-free survival (RFS) was compared between elderly patients and younger counterparts. The genetic analysis showed elderly non-squamous cell lung cancer patients to have higher prevalence of EGFR mutations (53.1 % vs 42.0%, P = 0.15) and lower prevalence of the ALK translocation (0 % vs 4.5%, P = 0.23) than their younger counterparts. The prognostic analysis showed postsurgical RFS was similar between the elderly NSCLC patients and the younger patients. However in multivariate analysis, adjusting for gender, smoking status, pathological stage, and histology, elderly patients had significantly worse prognoses (HR 1.57, 95% CI, 1.08-2.29; P = 0.02) compared with younger patients. These results suggest differences in genetic and prognostic aspects between elderly lung cancer patients and younger lung cancer patients.
- Published
- 2012
23. Acquired resistance mechanisms to tyrosine kinase inhibitors in lung cancer with activating epidermal growth factor receptor mutation--diversity, ductility, and destiny.
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Suda K, Mizuuchi H, Maehara Y, and Mitsudomi T
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Drug Resistance, Neoplasm, Epithelial-Mesenchymal Transition, ErbB Receptors antagonists & inhibitors, Hepatocyte Growth Factor genetics, Humans, Lung Neoplasms genetics, Nuclear Proteins genetics, PTEN Phosphohydrolase genetics, Proto-Oncogene Proteins c-met genetics, ErbB Receptors genetics, Lung Neoplasms drug therapy, Mutation, Protein Kinase Inhibitors therapeutic use
- Abstract
Lung cancers that harbor somatic activating mutations in the gene for the epidermal growth factor receptor (EGFR) depend on mutant EGFR for their proliferation and survival; therefore, lung cancer patients with EGFR mutations often dramatically respond to orally available EGFR tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. To elucidate and overcome this acquired resistance, multidisciplinary basic and clinical investigational approaches have been applied, using in vitro cell line models or samples obtained from lung cancer patients treated with EGFR-TKIs. These efforts have revealed several acquired resistance mechanisms and candidates, including EGFR secondary mutations (T790M and other rare mutations), MET amplification, PTEN downregulation, CRKL amplification, high-level HGF expression, FAS-NFκB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer. Interestingly, cancer cells harbor potential destiny and ductility together in acquiring resistance to EGFR-TKIs, as shown in in vitro acquired resistance models. Molecular mechanisms of "reversible EGFR-TKI tolerance" that occur in early phase EGFR-TKI exposure have been identified in cell line models. Furthermore, others have reported molecular markers that can predict response to EGFR-TKIs in clinical settings. Deeper understanding of acquired resistance mechanisms to EGFR-TKIs, followed by the development of molecular target drugs that can overcome the resistance, might turn this fatal disease into a chronic disorder.
- Published
- 2012
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24. Current-stimulated release of solutes solubilized in water-immiscible room temperature ionic liquids (RTILs).
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Jaitely V, Mizuuchi H, and Florence AT
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- Animals, Biological Transport, Dexamethasone pharmacokinetics, Electric Stimulation methods, Hydrophobic and Hydrophilic Interactions, Rats, Solubility, Solvents chemistry, Sucrose pharmacokinetics, Surface Tension, Temperature, Viscosity, Water chemistry, Dexamethasone chemistry, Imidazoles chemistry, Ionic Liquids chemistry, Sucrose chemistry
- Abstract
Room temperature ionic liquids (RTILs), salts which are liquid at room temperature, may be water-soluble or water immiscible, depending on the combination of cation and anion. They are efficient solvents for a wide range of solutes including drugs. The water-immiscible RTILs studied in this paper (the 1-butyl, hexyl and octyl 3-methyl imidazolium (BMIM, HMIM, and OMIM) hexafluorophosphate (PF(6)(-)) salts) can act as drug reservoirs. Passage of an electric current through these immiscible liquids can enhance the release of some solutes into an aqueous medium. Current flow (over the range 1-5 mA) increased the release rate of a solubilized hydrophilic solute, (3)H-sucrose, and of a model hydrophobic drug, (3)H-dexametasone. A threefold increase in the release rate of both sucrose and dexamethasone into water was observed under some conditions although the effect of application of current was not always linear. OMIM[PF(6)] was the most responsive liquid. Some measurable physical properties of the ionic liquids change on the application of current. For example, the surface tension of the three RTILs studied decreased significantly on application of current for 15 min (from 47.8 mNm(-1) to 36.2 mNm(-1) for BMIM) but the effect on the surface tension of the OMIM salt was small. Only a small decrease in the viscosity of RTILs was observed. Although the mechanisms of the enhanced release are not yet elucidated, RTILs are potentially interesting depots for electrically controlled drug delivery.
- Published
- 2010
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25. Topics on transporter-mediated renal excretion and drug-drug interaction.
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Mizuuchi H
- Subjects
- Glomerular Filtration Rate, Humans, Kidney Tubules metabolism, Drug Design, Drug Interactions, Kidney metabolism, Organic Anion Transporters physiology, Organic Cation Transport Proteins physiology, Pharmaceutical Preparations metabolism
- Published
- 2010
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26. Room temperature ionic liquids and their mixtures: potential pharmaceutical solvents.
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Mizuuchi H, Jaitely V, Murdan S, and Florence AT
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- Albendazole chemistry, Danazol chemistry, Molecular Structure, Solubility, Temperature, Imidazoles chemical synthesis, Imidazoles chemistry, Ionic Liquids chemical synthesis, Ionic Liquids chemistry, Pharmaceutic Aids chemical synthesis, Pharmaceutic Aids chemistry, Solvents chemical synthesis, Solvents chemistry
- Abstract
Room temperature ionic liquids (RTILs) are organic salts which are liquids at ambient temperature. Composed of relatively large asymmetric organic cations and inorganic or organic anions, they have generated interest as 'green' solvents. Here we report on the solvency of alkyl imidazolium salts (PF(6)(-)Br(-)Cl(-)) for poorly water-soluble model drugs, albendazole and danazol, indicating their potential application as pharmaceutical solvents/cosolvents. The solubility of albendazole, for example, is increased by more than 10,000 times by 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF(6)(-)). Ionic liquids can be water-miscible or water-immiscible. The aqueous miscibility of a poorly water-miscible RTIL such as of [bmim]PF(6)(-) can be improved by the inclusion of a second more miscible RTIL (e.g. 1-hexyl-3-methylimidazolium bromide ([hmim]Br(-))). The extent of improvement in water miscibility was found to correlate with the hydrophilicity of the second RTIL. This ability to modulate RTILs' aqueous miscibility increases their usefulness as pharmaceutical solvents.
- Published
- 2008
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27. Intramuscular absorption and biodistribution of dexamethasone from non-aqueous emulsions in the rat.
- Author
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Suitthimeathegorn O, Turton JA, Mizuuchi H, and Florence AT
- Subjects
- Absorption, Animals, Emulsions chemistry, Injections, Intramuscular, Kidney metabolism, Liver metabolism, Oils, Rats, Rats, Sprague-Dawley, Tissue Distribution, Dexamethasone administration & dosage, Dexamethasone pharmacokinetics, Emulsions therapeutic use
- Abstract
Non-aqueous or oil-in-oil emulsions may be used as reservoirs to deliver lipophilic or hydrolytically unstable drugs. Emulsions of castor oil-in-silicone oil (co/so) release drugs slowly in vitro. To investigate the potential use of such formulations as depot preparations in vivo, drug absorption and distribution from an intramuscular injection site to various organs in the rat was studied. (3)H-dexamethasone (0.1mg/kg) was incorporated into the castor oil (disperse phase) of co/so emulsions and in castor oil-in-water (co/w) emulsions, the latter serving as control. (3)H-dexamethasone was absorbed after intramuscular injection of co/w emulsions, reaching a plasma C(max) of 0.078 microg/ml at 2.0 h (T(max)). For co/so emulsions, a lower C(max) (0.048 microg/ml) was observed with a longer T(max) (4.0 h). No significant difference was found between the two formulations in the area under the plasma concentration-time curve (AUC(infinity)), or in clearance (CL). Administration of (3)H-dexamethasone in the co/so emulsion improved the mean residence time (MRT) and the elimination half-life (t(1/2)) in comparison to the co/w emulsion. The clearance of (3)H-dexamethasone from the co/so emulsions at the injection site was also slower and at 4.0 h post-injection the amount of drug remaining in the muscle was found to be eight times higher than with the co/w emulsions. For both formulations, a high uptake of (3)H-dexamethasone was identified in the liver and kidneys whereas smaller amounts were found in other tissues. Non-aqueous emulsions could be considered as depot formulations for sustained release drug delivery, but further studies on the choice of the continuous phase are necessary to optimize effects.
- Published
- 2007
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28. A study of clinical features of cough variant asthma.
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Okada C, Horiba M, Matsumoto H, Torigoe R, Mizuuchi H, Murao M, Soda R, Takahashi K, Kimura G, and Tanimoto Y
- Subjects
- Asthma immunology, Blood Proteins metabolism, Bronchial Hyperreactivity diagnosis, Eosinophil Granule Proteins, Eosinophilia diagnosis, Female, Humans, Male, Middle Aged, Respiratory Function Tests, Sputum immunology, Asthma diagnosis, Cough diagnosis, Ribonucleases
- Abstract
Patients with cough variant asthma (CVA) and classic asthma are frequently among subjects who present at clinics complaining of a chronic persistent cough. To reveal the features of CVA, we examined the differences in the clinical appearance between CVA and classic asthma. Ten CVA subjects and 11 classic asthmatics were enrolled in the study; they were recruited among patients who presented at the National Minamiokayama Hospital complaining of a chronic cough. The number of eosinophils in peripheral blood was 256 +/- 45.8/microl in CVA and 400 +/- 123/microl in classic asthma. Eosinophils represented 67% of the cells of sputum in CVA and 82% in classic asthma. Bronchial responsiveness to methacholine was Dmin 1.37 +/- 0.56 U in CVA and 0.71 +/- 0.46 U in classic asthma. There was no significant difference in these three parameters. There was only a significant difference in V25 between CVA and classic asthma, 80.0 +/- 6.9 and 52.2 +/- 10.0%, respectively. Eosinophil inflammation was almost the same in both CVA and classic asthma., (Copyright 2001 S. Karger AG, Basel)
- Published
- 2001
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29. Transport of procainamide via H(+)/tertiary amine antiport system in rabbit intestinal brush-border membrane.
- Author
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Katsura T, Mizuuchi H, Hashimoto Y, and Inui KI
- Subjects
- Amines pharmacology, Animals, Biological Transport drug effects, Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone pharmacology, Cimetidine pharmacology, Ethylamines pharmacology, Guanidine pharmacology, Hydrogen-Ion Concentration, Intestine, Small, Kinetics, Male, Mannitol pharmacokinetics, Microvilli drug effects, Potassium metabolism, Rabbits, Sodium metabolism, Amines metabolism, Intestinal Mucosa physiology, Microvilli physiology, Procainamide pharmacokinetics
- Abstract
Transport characteristics of procainamide in the brush-border membrane isolated from rabbit small intestine were studied by a rapid-filtration technique. Procainamide uptake by brush-border membrane vesicles was stimulated by an outward H(+) gradient (pH(in) = 6.0, pH(out) = 7.5) against a concentration gradient (overshoot phenomenon), and this stimulation was reduced when the H(+) gradient was subjected to rapid dissipation by the presence of a protonophore, FCCP. An outward H(+) gradient-dependent procainamide uptake was not caused by H(+) diffusion potential. The initial uptake of procainamide was inhibited by other tertiary amines with N-dimethyl or N-diethyl moieties in their structures, such as triethylamine, dimethylaminoethyl chloride, and diphenhydramine, but not by tetraethylammonium and thiamine. Furthermore, procainamide uptake was stimulated by preloading the vesicles with these tertiary amines (trans-stimulation effect), indicating the existence of a specific transport system for tertiary amines. These findings indicate that procainamide transport in the intestinal brush-border membrane is mediated by the H(+)/tertiary amine antiport system that recognizes N-dimethyl or N-diethyl moieties in the structures of tertiary amines.
- Published
- 2000
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30. Transepithelial transport of diphenhydramine across monolayers of the human intestinal epithelial cell line Caco-2.
- Author
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Mizuuchi H, Katsura T, Hashimoto Y, and Inui K
- Subjects
- Algorithms, Caco-2 Cells, Chlorpheniramine pharmacology, Chromatography, High Pressure Liquid, Drug Interactions, Humans, Hydrogen-Ion Concentration, Intestinal Mucosa cytology, Intestinal Mucosa metabolism, Diphenhydramine metabolism, Epithelial Cells metabolism, Histamine H1 Antagonists metabolism
- Abstract
Purpose: The transepithelial transport characteristics of the antihistamine, diphenhydramine, were studied in human intestinal Caco-2 cell monolayers to elucidate the mechanisms of its intestinal absorption., Methods: The transepithelial transport and the cellular accumulation of diphenhydramine were measured using Caco-2 cell monolayers grown in Transwell chambers., Results: The transepithelial transport of diphenhydramine from the apical to basolateral side was saturable, and the flux and cellular accumulation of diphenhydramine were dependent on the apical extracellular pH (pH 7.4 > 6.5 > 5.5). Transport and accumulation of diphenhydramine from the apical side were inhibited by another antihistamine, chlorpheniramine, while typical substrates for the renal organic cation transport system such as tetraethylammonium, cimetidine and guanidine had no effect. The transepithelial transport and cellular accumulation of diphenhydramine from the basolateral side were also pH-dependent and inhibited by chlorpheniramine. In addition, intracellular diphenhydramine preloaded was preferentially effluxed to the apical side, suggesting the involvement of the secretory pathway in diphenhydramine transport. Furthermore, diphenhydramine uptake from both the apical and basolateral sides was stimulated by preloading monolayers with chlorpheniramine (trans-stimulation effect)., Conclusions: Transepithelial transport of diphenhydramine across Caco-2 cells is mediated by pH-dependent, specific transport systems that exist in both the apical and basolateral membranes.
- Published
- 2000
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31. Diphenhydramine transport by pH-dependent tertiary amine transport system in Caco-2 cells.
- Author
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Mizuuchi H, Katsura T, Ashida K, Hashimoto Y, and Inui K
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Amines pharmacology, Biological Transport physiology, Caco-2 Cells, Humans, Hydrogen-Ion Concentration drug effects, Intracellular Membranes metabolism, Amines metabolism, Diphenhydramine pharmacokinetics, Histamine H1 Antagonists pharmacokinetics, Hydrogen metabolism
- Abstract
Substrate specificity and pH dependence of the transport system for diphenhydramine were investigated in Caco-2 cell monolayers. Diphenhydramine uptake was not affected by any typical substrate for the renal organic cation transport system except procainamide. Along with procainamide, tertiary amine compounds with N-dimethyl or N-diethyl moieties in their structures inhibited the diphenhydramine uptake. Moreover, accumulation of diphenhydramine was stimulated by preloading the Caco-2 cells with these tertiary amines (trans-stimulation effect), indicating the existence of the specific transport system for tertiary amines with N-dimethyl or N-diethyl moieties. Efflux of diphenhydramine from monolayers was enhanced by medium acidification. In addition, intracellular acidification resulted in marked stimulation of diphenhydramine accumulation. ATP depletion of the cells caused an enhancement of diphenhydramine accumulation, suggesting the involvement of an active secretory pathway. However, P-glycoprotein did not mediate the diphenhydramine transport. These findings indicate that a novel pH-dependent tertiary amine transport system that recognizes N-dimethyl or N-diethyl moieties is involved in diphenhydramine transport in Caco-2 cells.
- Published
- 2000
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32. Transport characteristics of diphenhydramine in human intestinal epithelial Caco-2 cells: contribution of pH-dependent transport system.
- Author
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Mizuuchi H, Katsura T, Saito H, Hashimoto Y, and Inui KI
- Subjects
- Biological Transport, Active, Caco-2 Cells, Cations, Chlorpheniramine pharmacology, Chromatography, High Pressure Liquid, Humans, Hydrogen-Ion Concentration, Kinetics, Membrane Potentials drug effects, Spectrophotometry, Ultraviolet, Stereoisomerism, Diphenhydramine metabolism, Histamine H1 Antagonists metabolism, Intestinal Absorption physiology
- Abstract
Transport characteristics of diphenhydramine, an antihistamine, were studied in cultured human intestinal Caco-2 cell monolayers to elucidate the mechanisms of its intestinal absorption. Diphenhydramine accumulation in the monolayers increased rapidly and was influenced by extracellular pH (pH 7.4 > 6.5 > 5.5). Diphenhydramine uptake was temperature dependent, saturable, and not potential sensitive. Kinetic analysis revealed that the apparent Km values were constant (0.8-1.0 mM) in all pH conditions tested, whereas Vmax values decreased at the lower pH. The initial uptake of diphenhydramine was competitively inhibited by another antihistamine, chlorpheniramine, with a Ki value of 1.3 mM. On the other hand, cimetidine and tetraethylammonium, typical substrates for the renal organic cation transport system, had no effect. Moreover, biological amines and neurotransmitters, such as histamine, dopamine, serotonin, and choline, also had no effect on the diphenhydramine accumulation. Finally, diphenhydramine uptake was stimulated by preloading monolayers with chlorpheniramine (trans-stimulation effect). These findings indicate that diphenhydramine transport in Caco-2 cells is mediated by a specific transport system. This pH-dependent transport system may contribute to the intestinal absorption of diphenhydramine.
- Published
- 1999
33. Preferential salivary-type hypoamylasemia in obese children.
- Author
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Mizuuchi H and Taketa K
- Subjects
- Adolescent, Child, Female, Humans, Isoamylase classification, Male, Reference Values, Weight Loss physiology, Amylases blood, Isoamylase blood, Obesity enzymology, Saliva enzymology
- Abstract
Serum levels of total amylase, pancreatic type (P-type) isoamylase, and salivary type (S-type) isoamylase were measured in obese children (153 subjects; mean age, 10.1 years old; 86 boys and 67 girls) before and after weight reduction therapy. Serum amylase activities were determined using p-nitrophenylmaltoheptaoside as a substrate, with or without an antibody added to inhibit the S-type isoamylase. Serum levels of total amylase, P-type isoamylase and S-type isoamylase activities were significantly decreased in obese children with an obesity index more than 50%. S-type and P-type isoamylases showed negative correlation with the obesity index, the correlation coefficient being slightly larger in S-type than in P-type isoamylase. Analysis of the serum amylase activities in obese children who underwent weight reduction treatments showed a negative correlation only between the differences in S-type isoamylase activity and the differences in the obesity index. It may be concluded that the S-type isoamylase activity in serum of obese children is decreased and that it can be increased by reducing their body weight.
- Published
- 1999
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34. Effects of corticotropin-releasing factor on feeding and pancreatic polypeptide response in the dog.
- Author
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Okita M, Inui A, Inoue T, Mizuuchi H, Banno K, Baba S, and Kasuga M
- Subjects
- Animals, Atropine pharmacology, Blood Glucose metabolism, Dogs, Injections, Intraventricular, Pancreatic Polypeptide blood, Parasympatholytics pharmacology, Stimulation, Chemical, Corticotropin-Releasing Hormone pharmacology, Eating drug effects, Pancreatic Polypeptide metabolism, Parasympathetic Nervous System drug effects
- Abstract
We have previously reported that corticotropin-releasing factor (CRF) is a potent stimulator of adrenocorticotropic hormone and cortisol secretion in the dog. Therefore, in the present study, we investigated the extrahypophysiotropic actions of CRF in this species. When CRF was injected into the third cerebral ventricle, it failed to inhibit food intake significantly at doses of 1.19, 3.57, and 11.9 nmol. This is in sharp contrast with the results in rodents. At the 3.57 and 11.9 nmol doses, CRF markedly stimulated the secretion of pancreatic polypeptide (PP), a hormone under vagal control, and at the highest dose CRF increased plasma glucose levels. These results suggest species differences in the feeding response to CRF and activation of the parasympathetic nervous system in the dog.
- Published
- 1998
- Full Text
- View/download PDF
35. Antitumor effect of carboplatin combined with radiation on tumors in mice.
- Author
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Aratani Y, Yoshiga K, Mizuuchi H, Jo A, Tanimoto K, and Sakurai K
- Subjects
- Animals, Combined Modality Therapy, Dose-Response Relationship, Drug, Dose-Response Relationship, Radiation, Male, Mice, Mice, Inbred Strains, Carboplatin administration & dosage, Carcinoma, Ehrlich Tumor drug therapy, Carcinoma, Ehrlich Tumor radiotherapy
- Abstract
The antitumor effect of cis-diammine-1, 1-cyclobutane dicarboxylate platinum(II) (CBDCA, Carboplatin) and radiation on Ehrlich ascites tumors was evaluated in CD-1 mice. A single dose of CBDCA was combined with a single dose of radiation. The antitumor effect was evaluated by tumor volume. Inhibition of tumor growth by the combination of CBDCA and radiation was greater than by CBDCA and radiation alone. The most effective condition was the simultaneous combination of CBDCA with radiation. Further, we examined the radiation influence on the concentration of platinum in tumor tissue. We found that when CBDCA was administered after irradiation, the concentration of platinum in tumor tissue decreased proportionally with time.
- Published
- 1997
36. Enhancement of antitumor effects of new analogue of platinum, cis-diammine (glycolato) platinum (254-S) combined with hyperthermia in vivo.
- Author
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Jo A, Sakurai K, Tsumura M, Mizuuchi H, Yoshiga K, and Takada K
- Subjects
- Animals, Carcinoma, Ehrlich Tumor drug therapy, Carcinoma, Ehrlich Tumor metabolism, Male, Mice, Mice, Inbred Strains, Neoplasm Transplantation, Platinum analysis, Platinum pharmacokinetics, Antineoplastic Agents pharmacology, Carcinoma, Ehrlich Tumor therapy, Hyperthermia, Induced, Organoplatinum Compounds pharmacology
- Abstract
Cis-diammine (glycolato) platinum (254-S) is a second generation platinum complex with reduced nephrotoxicity. In this study the antitumor effect of 254-S combined with hyperthermia in vivo in mice was studied. On the 6th day after inoculation of the Ehrlich ascites tumour cells, 254-S (15mg/kg) was administered intraperitoneally (i.p.) and hyperthermia was induced by using a circulating water bath at 42.5 degrees C for 45 min. The antitumour effect was evaluated by relative tumour volume. Furthermore, platinum concentration in tumour tissue was determined by using atomic absorption spectrophotometry. The most effective condition was found to be the combination of 254-S with hyperthermia. A significantly higher concentration of platinum in the tumour tissue was observed when treatment with 254-S was combined with hyperthermia, than with treatment using 254-S alone. Our study suggested that the accumulation of 254-S in the tumour tissue, and its retention at a high concentration within the tumour tissue long term was one of the reasons for the enhancement of antitumour effect of 254-S treatment when combined with hyperthermia.
- Published
- 1996
37. Antitumor effect of carboplatin combined with hyperthermia on Ehrlich-ascites tumor in vivo.
- Author
-
Mizuuchi H, Yoshiga K, Sakurai K, Tsumura M, and Takada K
- Subjects
- Animals, Carcinoma, Ehrlich Tumor drug therapy, Carcinoma, Ehrlich Tumor pathology, Combined Modality Therapy, Drug Administration Schedule, Mice, Mice, Inbred Strains, Platinum blood, Antineoplastic Agents pharmacology, Carboplatin pharmacology, Carcinoma, Ehrlich Tumor therapy, Hyperthermia, Induced
- Abstract
We examined the optimal timing for the enhancement of antitumor effects of CDDP analogues, cis- diammine-1,1- cyclobutane dicarboxylate platinum (II); CBDCA combined with hyperthermia against the CD-1 mice bearing Ehrlich ascites tumor (EAT) cells in vivo. The prolonged tumor doubling time was observed when two modalities were combined. The longest tumor doubling time was obtained by simultaneous administration of CBDCA combined with hyperthermia. The findings indicated that the most effective condition was the simultaneous combination of CBDCA with hyperthermia. An increase in intratumoral platinum concentration was observed by the treatment of CBDCA simultaneous combined with hyperthermia.
- Published
- 1996
38. [Is CA125 useful in the management of recurrence of endometrial carcinoma?].
- Author
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Sato K, Mizuuchi H, Mori Y, Okamura N, Endo T, Ito E, and Kudo R
- Subjects
- Aged, Aged, 80 and over, Carcinoma, Squamous Cell diagnosis, Female, Humans, Middle Aged, Adenocarcinoma diagnosis, Biomarkers, Tumor blood, CA-125 Antigen blood, Endometrial Neoplasms diagnosis, Neoplasm Recurrence, Local diagnosis
- Abstract
It has been considered that there is no useful serum tumor marker to diagnose endometrial cancer. But recently several reports describe how the serum CA125 value decreases in patients who have received bilateral oophorectomy and in postmenopausal women. In this study, we therefore determined a new cutoff level for serum CA125 and examined the usefulness of serum CA125 in the assessment of recurrence in 42 endometrial cancer cases. These cases were divided into 3 groups: one of 22 low risk cases, 10 moderate risk cases and 10 high risk cases cased by prognosis 1) In the low risk group, 5 cases had a higher serum CA125 level within 1 month after operation than before. 2) In 151 measurements, the mean CA125 value was 9.7 +/- 3.6U/ml, so we considered that 17 U/ml is the cutoff value for determining recurrence. 3) In the low risk group, the CA125 value was either lower than 17U/ml or it has not continued to increase. 4) We divided the high risk group into 3 subgroups into those who had died within 6 months, those who died within 13-14 months and those who died 2-5 years after the initial treatment. In the group who died 13-14 months after the initial treatment, the seurm CA125 level had continued to be high and there was no change in the value after the initial treatment. In the group who died 2-5 years after the initial treatment, the mean +/- S.D. for serum CA125 was 157.3 +/- 158.3U/ml, the maximum was 377U/ml and the minimum was 28U/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1995
39. High incidence of point mutation in K-ras codon 12 in carcinoma of the fallopian tube.
- Author
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Mizuuchi H, Mori Y, Sato K, Kamiya H, Okamura N, Nasim S, Garrett CT, and Kudo R
- Subjects
- Adenocarcinoma pathology, Adenocarcinoma therapy, Base Sequence, Combined Modality Therapy, Fallopian Tube Neoplasms pathology, Fallopian Tube Neoplasms therapy, Female, Humans, Hysterectomy, Incidence, Molecular Sequence Data, Outcome Assessment, Health Care, Polymerase Chain Reaction, Prognosis, Adenocarcinoma genetics, Fallopian Tube Neoplasms genetics, Genes, ras genetics, Point Mutation
- Abstract
Background: Adenocarcinoma of the fallopian tube is a rare tumor with a poor prognosis. Whether these carcinomas possess any genetic changes that contribute to their malignant behavior is unknown and to date few studies regarding the molecular pathogenesis of these tumors have been reported. In adenocarcinoma of the endometrium, mutations in the first exon of K-ras, although relatively infrequent, were observed to be an independent risk factor for poor clinical outcome., Methods: Eight patients with adenocarcinoma of the fallopian tube were examined for mutations in the 12th codon of K-ras. DNA was obtained from single sections of paraffin embedded tumor tissue and the first exon of K-ras was amplified by the polymerase chain reaction. Point mutations were assayed using a nonradioactive restriction fragment length polymorphism technique., Results: The eight patients in this study varied in clinical stage from I-IV and were all treated with surgery and chemotherapy. Six of eight of the patients died and one of the surviving patients had metastases in the vertebrae. K-ras point mutations were detected at codon 12 in seven of the eight tumors (87.5%)., Conclusions: K-ras mutations occurred with high frequency in this series of eight patients with fallopian tube carcinoma, suggesting that mutations of this protooncogene could play an important role in the molecular pathogenesis of this lesion.
- Published
- 1995
- Full Text
- View/download PDF
40. [A report of two endometrial cancer cases in that low-dose aspirin was effective for hypercoagulopathy caused by medroxyprogesterone acetate].
- Author
-
Sato K, Mori Y, Okamura N, and Mizuuchi H
- Subjects
- Adult, Female, Humans, Middle Aged, Adenocarcinoma drug therapy, Aspirin administration & dosage, Cystadenocarcinoma, Serous drug therapy, Endometrial Neoplasms drug therapy, Medroxyprogesterone Acetate adverse effects, Thrombosis chemically induced, Thrombosis drug therapy
- Published
- 1995
41. [Primary clear cell carcinoma arising in cystic adenomyosis of the uterus--a case report].
- Author
-
Mori Y, Inoue Y, Sakai K, Koizumi M, Okamura N, Sato K, and Mizuuchi H
- Subjects
- Female, Humans, Middle Aged, Adenocarcinoma, Clear Cell pathology, Cysts pathology, Endometriosis pathology, Uterine Diseases pathology, Uterine Neoplasms pathology
- Published
- 1994
42. [Management of the uterine endometrial cancer cases whose cytological and histologic specimens cannot be obtained from the uterine cavity--assessment by CA125 or vaginal ultrasonography].
- Author
-
Sato K, Mizuuchi H, Mori Y, Okamura N, Endo T, Kudo R, and Tsukamoto K
- Subjects
- Aged, Aged, 80 and over, Cytodiagnosis, Female, Humans, Middle Aged, Prognosis, Retrospective Studies, Ultrasonography methods, Uterine Neoplasms pathology, Vaginal Smears, Antigens, Tumor-Associated, Carbohydrate blood, Cervix Uteri diagnostic imaging, Postmenopause, Uterine Neoplasms diagnosis
- Abstract
An examination for endometrial cancer has been done by cytology. However, cytology is sometimes not possible because of closed or narrow cervix of postmenopausal woman. We did a retrospective study regarding the usefulness of CA125 or transvaginal ultrasonography in postmenopausal cases. The mean +/- S.D. of CA125 in normal menopausal women was 10.3 +/- 3.0 U/ml. The value of mean +/- 2S.D., the finding of Relative Operating Characteristic curve and the purpose that false positive was 0%, so we set 17 U/ml as the cut off value for CA125. In 46 cases with postmenopausal endometrial carcinoma, 23 cases were screened; and in 30 cases with surgical stage I, 10 cases were screened with this cut off value. The echoic patterns for uterine cavities which were observed by transvaginal ultrasonography were divided into 4 patterns (type I: anechoic pattern, type II: linear pattern, type III: clear mass pattern, type IV: unclear mass pattern). In 20 cases with postmenopausal endometrial cancer, 19 cases had type III or IV. In 41 normal postmenopausal women, 26 cases showed an anechoic pattern and 14 cases showed a linear pattern. It was found that 97.5% of cases with anechoic or linear patterns were normal endometrium. The screening by transvaginal ultrasonography was more useful than CA125. However CA125 was more useful than transvaginal ultrasonography in detecting lymph node metastasis.
- Published
- 1994
43. [The factors involved in invasive ability of endometrial carcinoma cells].
- Author
-
Mori Y, Mizuuchi H, Sato K, Okamura N, and Kudo R
- Subjects
- Cadherins genetics, Carcinoma, Endometrioid genetics, Female, Humans, Metalloendopeptidases genetics, Tumor Cells, Cultured, Uterine Neoplasms genetics, Carcinoma, Endometrioid pathology, Genes, ras, Neoplasm Invasiveness genetics, Point Mutation, Uterine Neoplasms pathology
- Abstract
The in vitro invasive ability, the expression of cell adhesion molecule E-cadherin, activity of matrix metalloproteinase (MMP) and K-ras point mutation were investigated in eight human endometrial carcinoma cell lines. 1) In vitro invasive abilities of endometrial carcinoma cell lines depend on the degree of cell differentiation and the origin of cell lines. A poorly-differentiated carcinoma cell line (NUE-1) and a cell line derived from metastatic lymph node (SNG-M) were more invasive than moderately-(HEC-1A, HEC-1BE) and well-differentiated (HEC-6, Ishikawa) cell lines. 2) Immunohistochemically, less or non-invasive cell lines expressed E-cadherin strongly, whereas a highly invasive cell line (NUE-1) expressed E-cadherin weakly. 3) When cultured on Matrigel-coated dishes, the tumor cells derived from moderately- and well-differentiated carcinoma aggregated with each other and did not invade Matrigel in the invasion assay. The aggregated cells expressed E-cadherin more strongly when cultured on Matrigel. 4) 72-kD gelatinase (MMP-2) was secreted in serum-free conditioned medium of all cell lines. In an invasive cell line (NUE-1,SNG-M), the activity of MMP-2 was stronger than in other cell lines. And the activity of 92-kDa gelatinase (MMP-9) was detected in most invasive cell line (NUE-1). 5) Point mutation of K-ras codon 12 was detected in four of eight (50%) cell lines by the PCR-RFLP method. The changes in the DNA sequence were identified, but K-ras point mutation was not correlated with in vitro invasiveness of the tumor cells.
- Published
- 1994
44. [Usefulness of CA125 determination in the diagnosis of lymph node metastasis in post menopausal uterine endometrial carcinoma].
- Author
-
Sato K, Mizuuchi H, Mori Y, Okamura N, and Kudo R
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Middle Aged, Antigens, Tumor-Associated, Carbohydrate blood, Endometrial Neoplasms pathology, Lymph Nodes pathology, Lymphatic Metastasis diagnosis, Menopause
- Abstract
It has been difficult to diagnose all but advanced cases of lymph node metastases with CT or MRI. It has been reported that the serum value of CA125 rises with the stage of endometrial cancer. This level is lower in the postmenopausal period than before menopause. In this study, we have examined the usefulness of CA125 for the assessment of lymph node metastasis in 43 postmenopausal endometrial cancer cases. There were significant differences in the CA125 level between lymph node metastasis positive cases and negative cases, between cancers occupying > or = 1/2 and < 1/2 of the uterine cavity, between lesions of > or = 1/3 and < 1/3 depth, and between surgical stages I, and III and IV. There was no significant correlation between serum CA125 levels and histological type. The serum CA125 value (mean +/- S.D., U/ml) was 179.0 +/- 291.0 (N = 6) in cases with lymph node metastasis and 15.8 +/- 8.5 (N = 37) in cases without metastasis (p < 0.001). We concluded that 32U/ml, which equals the mean + 2S.D., is a useful cut off value for suspicion of lymph node metastasis. The sensitivity and specificity of this cut off value were 100 (6/6) and 91.9% (34/37), respectively. This standard seems likely to considerably increase the accuracy of diagnosis of lymph node metastasis when taken in combination with the several factors already known to predict this. It may also be useful to diagnose lymph node metastasis in the preoperative period. Although the number of cases in this study was small, the data seem very promising for planning therapy for individual cases.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1994
45. Clinical implications of K-ras mutations in malignant epithelial tumors of the endometrium.
- Author
-
Mizuuchi H, Nasim S, Kudo R, Silverberg SG, Greenhouse S, and Garrett CT
- Subjects
- Base Sequence, Endometrial Neoplasms pathology, Epithelium pathology, Exons genetics, Female, Humans, Lymph Nodes pathology, Lymph Nodes surgery, Molecular Sequence Data, Multivariate Analysis, Mutation, Polymerase Chain Reaction, Prognosis, Proportional Hazards Models, Endometrial Neoplasms genetics, Genes, ras genetics
- Abstract
Tumorigenesis in humans and experimental animals appears to involve the activation of ras protooncogenes for a number of organ systems and seems to be important to the development of the metastatic phenotype in several model systems. Clinically, the presence of activated ras protooncogenes has been reported to be a negative prognostic factor in the myelodysplastic syndrome and in adenocarcinoma of the lung. In the present study we examined 49 cases of endometrial carcinoma for mutations in the first exon of K-ras using the polymerase chain reaction and direct sequencing. Mutations in codon 12 or 13 of K-ras were detected in 6 of 49 cases (12.2%). These six cases consisted of five endometrioid endometrial carcinomas, each of which had a mutation in codon 12, and one case of clear cell carcinoma, which had a mutation in codon 13. In our study the presence of mutations in K-ras appeared to be an unfavorable prognostic factor. Three of six patients with the mutation died during follow-up, while only 7% of the 43 patients without K-ras mutations expired during this same period. In multivariate analysis using the Cox proportional hazard model, K-ras activation appeared to be an independent risk factor when compared with clinical stage, depth of myometrial invasion, and patient age. Thus, our findings support the hypothesis that K-ras protooncogene activation plays an important role in determining the aggressiveness of endometrial carcinoma.
- Published
- 1992
46. [Significance of 5-S-cysteinyldopa on primary malignant melanoma of the female genital organs].
- Author
-
Takehara M, Mizuuchi H, Ito E, Hayakawa O, Takashima S, Nei H, Kudo R, Horikoshi T, and Ito S
- Subjects
- Biomarkers, Tumor urine, Combined Modality Therapy, Cysteinyldopa urine, Female, Genital Neoplasms, Female therapy, Humans, Melanoma therapy, Biomarkers, Tumor blood, Cysteinyldopa blood, Genital Neoplasms, Female diagnosis, Melanoma diagnosis
- Published
- 1992
47. Peritoneal washing cytology at second-look laparotomy in cisplatin-treated ovarian cancer patients.
- Author
-
Kudo R, Takashina T, Ito E, Mizuuchi H, Sagae S, Moriwaka O, and Tamagawa A
- Subjects
- Female, Follow-Up Studies, Humans, Laparotomy, Neoplasm Staging, Ovarian Neoplasms drug therapy, Cisplatin therapeutic use, Ovarian Neoplasms pathology, Peritoneal Lavage methods
- Abstract
The use of peritoneal washing cytology during second-look laparotomy in 58 cisplatin-treated ovarian cancer patients was evaluated. Washing was performed for the 41 patients who showed no gross evidence of persistent disease. Peritoneal washing cytology was positive in 8 of 18 cases with histologically identified residual disease and in 4 of 23 cases without residual disease. However, three of the four cytologically positive patients without other evidence of disease later died of recurrences. The five-year survival rate of the 23 patients who showed no residual carcinomas macroscopically was 60.9%; when their washing cytologies were negative, there was a 73.7% five-year survival rate. These findings indicate that, despite its limitations, a peritoneal washing cytology at the time of second-look laparotomy is important to assess the response to treatment and to evaluate the prognosis of patients with ovarian cancer.
- Published
- 1990
48. A case-control study of uterine endometrial cancer in Japanese and Finn.
- Author
-
Kudo R, Punnonen R, Mizuuchi H, Teisala K, and Kanemoto T
- Subjects
- Adult, Age Factors, Asian People, Case-Control Studies, Female, Finland epidemiology, Humans, Japan epidemiology, Labor, Obstetric, Middle Aged, Obesity, Pregnancy, Risk Factors, White People, Uterine Neoplasms epidemiology
- Abstract
The difference between the endometrial cancer incidence in Japanese and Finnish women (lower and higher incidence, respectively), was evaluated on the basis of data from cases of endometrial cancer, cervical cancer and benign gynecological disease in both countries. The comparison took into account the various personal and clinical characteristics of these cases. In endometrial cancer, Japanese and Finnish women had similar characteristics except for the age at first delivery, the age at last delivery and obesity. However, obesity in postmenopausal women in the two countries was similar. Common factors in the two countries included few pregnancies and deliveries, nullipara and single women. In cervical cancer, no difference between the characteristics of Japanese and Finnish women was found except that Japanese women had a higher frequency of pregnancy. In benign diseases, characteristics were similar to those of endometrial cancer in Finnish women, but this was not the case in Japanese women. These facts may indicate the number of Finnish women with endometrial cancer risk factors is greater than the number of Japanese women with these risk factors. This was thought to account for the difference in the incidence of endometrial cancer.
- Published
- 1990
49. Ultrastructural and immunohistochemical study of infiltration in microinvasive carcinoma of the uterine cervix.
- Author
-
Kudo R, Sato T, and Mizuuchi H
- Subjects
- Actin Cytoskeleton ultrastructure, Carcinoma in Situ analysis, Female, Humans, Immunohistochemistry, Microscopy, Electron, Microtubules ultrastructure, Uterine Cervical Neoplasms analysis, Carcinoma in Situ ultrastructure, Fibronectins analysis, Neoplasm Invasiveness, Uterine Cervical Neoplasms ultrastructure
- Abstract
Carcinoma in situ and microinvasive cancer of the cervix were compared by transmission electron microscopy to examine ultrastructural features of the locally infiltrating lesion of microinvasive cancer. Many pseudopod-like cytoplasmic protrusions of the cancer cells and abundant microfilaments parallel to the direction of the protrusion were seen. Concomitant with the disappearance of part of the basal lamina, many vesicles 70-90 nm in diameter were observed, suggesting a role for these vesicles in cancer infiltration. With the immunoperoxidase method, the distribution of fibronectin around the invasive lesion also was examined. Fibronectin is a component of extracellular matrices and presumably, in view of its action on cell adhesion, is a resistant factor against cancer cell infiltration. Fibronectin decreased in the transitional area between the cancer nest and the stroma during the stage of microinvasion.
- Published
- 1990
- Full Text
- View/download PDF
50. Minimal-deviation adenocarcinoma (adenoma malignum) of the uterine cervix; four case reports.
- Author
-
Kudo R, Sagae S, Kusanagi T, Mizuuchi H, Hayakawa O, and Hashimoto M
- Subjects
- Adenocarcinoma ultrastructure, Adult, Female, Humans, Microscopy, Electron, Middle Aged, Uterine Cervical Neoplasms ultrastructure, Adenocarcinoma pathology, Uterine Cervical Neoplasms pathology
- Abstract
Four cases of minimal-deviation adenocarcinoma (adenoma malignum) of the uterine cervix are analysed in this clinicopathological study. Four patients, one Ib, two IIb and one IIIb stage, showed poor prognosis, which included three patients who died within 36 months, because of diagnostic delays of 5 years, 6 months and 1 year due to cytohistologically benign appearances. Cytologically, the nuclei were somewhat more irregular in size and shape than those of normal columnar epitherial cells. Slightly multilayered cell clusters were arranged as honeycombs, palisades or sheets with glandular openings. The characteristic histological features were the presence of sharp points projecting from the glands and marked variation in the size and shape of the glands. Ultrastructurally, intestinal metaplastic cells containing both microvilli with core filaments and rootlets, and secretary granules in the same cell were present in the specimens of two evaluable patients. These features indicate a disorder of differentiation. In order to diagnose this tumor accurately, comprehensive analysis should be required concerning the clinical features, cytohistological findings and ultrastructural findings.
- Published
- 1990
- Full Text
- View/download PDF
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