66 results on '"Endo, Y."'
Search Results
2. Recurrence of gastric gastrointestinal stromal tumor 12 years after repeat hepatectomies for liver metastases: report of a case.
- Author
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Fujinaga A, Ohta M, Masuda T, Itai Y, Nakanuma H, Kawasaki T, Kawano Y, Hirashita T, Endo Y, and Inomata M
- Subjects
- Chemotherapy, Adjuvant, Child, Female, Hepatectomy, Humans, Neoplasm Recurrence, Local drug therapy, Antineoplastic Agents therapeutic use, Gastrointestinal Stromal Tumors drug therapy, Gastrointestinal Stromal Tumors surgery, Liver Neoplasms drug therapy, Liver Neoplasms surgery
- Abstract
No consensus has been reached on the postoperative treatment and follow-up duration for high-risk malignant gastrointestinal stromal tumor (GIST). We herein report a case of recurrent liver metastasis from gastric GIST in a patient who had been receiving adjuvant chemotherapy with imatinib mesylate for 10 years. A 78-year-old woman underwent local gastrectomy for a 20-cm gastric GIST with a mitotic index of 25/50 high-power fields (HPF) 17 years before. Partial hepatectomy for recurrent liver metastases was repeatedly performed 14 and 12 years before. After the second hepatectomy, postoperative adjuvant chemotherapy with imatinib mesylate was given for 10 years, during which no recurrence was observed. Two years after the completion of adjuvant chemotherapy, computed tomography revealed a 2-cm hepatic tumor; thus, laparoscopic partial hepatectomy was performed. Histopathological findings revealed a liver metastasis of gastric GIST with a mitotic count of 20/50 HPF and MIB-1 labeling index of 20%. Mutation analysis of the KIT gene revealed an exon 11 mutation. The patient is currently undergoing postoperative adjuvant chemotherapy with imatinib mesylate. The combination of surgery and long-term adjuvant chemotherapy for high-risk malignant GIST and liver metastases may be effective to achieve a good prognosis., (© 2021. Japanese Society of Gastroenterology.)
- Published
- 2021
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3. A case of metastatic eccrine porocarcinoma without actionable mutations treated with carboplatin and epirubicin chemotherapy.
- Author
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Tahara J, Ishida Y, Otsuka A, Komatsu-Fujii T, Yamamura K, Kaku Y, Endo Y, Nomura T, Irie H, and Kabashima K
- Subjects
- Aged, Eccrine Porocarcinoma diagnosis, Humans, Male, Mutation, Treatment Outcome, Antineoplastic Agents therapeutic use, Carboplatin therapeutic use, Eccrine Porocarcinoma drug therapy, Epirubicin therapeutic use
- Published
- 2021
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4. Structure-Activity Relationships of UTX-121 Derivatives for the Development of Novel Matrix Metalloproteinase-2/9 Inhibitors.
- Author
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Yamahana H, Komiya Y, Takino T, Endo Y, Yamada H, Asada C, and Uto Y
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Matrix Metalloproteinase Inhibitors chemical synthesis, Matrix Metalloproteinase Inhibitors chemistry, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Drug Development, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Matrix Metalloproteinase Inhibitors pharmacology
- Abstract
Celecoxib, a nonsteroidal anti-inflammatory drug, has been reported to have antitumor and antimetastatic activities, and it has potential for application in cancer treatments. The expression of matrix metalloproteinase (MMP)-2/9 is strongly correlated with cancer malignancy, and inhibition of these MMPs is believed to be effective in improving the antitumor and antimetastatic effects of drugs. We have previously revealed that UTX-121, which converted the sulfonamide of celecoxib to methyl ester, has more potent MMP-2/9 inhibitory activity than celecoxib. Based on these findings, we identified compounds with improved MMP inhibitory activity through a structure-activity relationship (SAR) study, using UTX-121 as a lead compound. Among them, compounds 9c and 10c, in which the methyl group of the p-tolyl group was substituted for Cl or F, showed significantly higher antitumor activity than UTX-121, and suppressed the expression of MMP-2/9 and activation of pro MMP-2. Our findings suggest that compounds 9c and 10c may be potent lead compounds for the development of more effective antitumor drugs targeting MMP.
- Published
- 2021
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5. Successful Management of Platinum-resistant Ovarian Cancer by Weekly Nedaplatin Followed by Olaparib: Three Case Reports.
- Author
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Soeda S, Watanabe T, Kamo N, Sato T, Okabe C, Ueda M, Endo Y, Manabu K, Nomura S, Furukawa S, Nishigori H, Takahashi T, and Fujimori K
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Biomarkers, Tumor, Biopsy, Combined Modality Therapy, Drug Administration Schedule, Female, Humans, Middle Aged, Neoplasm Grading, Neoplasm Staging, Organoplatinum Compounds therapeutic use, Ovarian Neoplasms diagnosis, Phthalazines administration & dosage, Piperazines administration & dosage, Positron Emission Tomography Computed Tomography, Tomography, X-Ray Computed, Treatment Outcome, Antineoplastic Agents administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm, Organoplatinum Compounds administration & dosage, Ovarian Neoplasms drug therapy
- Abstract
Background: Treatment for platinum-resistant ovarian cancer is difficult and challenging because available chemotherapeutic agents only offer short survival improvements. The efficacy of re-treatment with platinum-based agents including nedaplatin for platinum-resistant patients has not been fully investigated., Case Report: We describe herein three cases of heavily treated platinum-resistant ovarian cancer that were successfully treated with weekly nedaplatin followed by olaparib. After becoming platinum-resistant, the cases were treated with non-platinum chemotherapies. Following these regimens, weekly nedaplatin was introduced, followed by olaparib. At the time of writing, survival since the start of weekly nedaplatin was 30 months for case 1, 20 months for case 2, and 17 months for case 3, with all patients showing no evidence of disease., Conclusion: Weekly nedaplatin followed by olaparib might represent a good treatment option for platinum-resistant ovarian cancer and is a solid candidate for further evaluation., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2020
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6. Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma.
- Author
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Bolidong D, Domoto T, Uehara M, Sabit H, Okumura T, Endo Y, Nakada M, Ninomiya I, Miyashita T, Wong RW, and Minamoto T
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- Adult, Aged, Animals, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Biomarkers, Tumor, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Disease Models, Animal, Esophageal Neoplasms drug therapy, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Esophageal Squamous Cell Carcinoma drug therapy, Esophageal Squamous Cell Carcinoma genetics, Esophageal Squamous Cell Carcinoma pathology, Female, Gene Expression, Glycogen metabolism, Glycogen Synthase Kinase 3 beta genetics, Glycogen Synthase Kinase 3 beta metabolism, Humans, Male, Mice, Middle Aged, Molecular Targeted Therapy, Neoplasm Metastasis, Neoplasm Staging, Phosphorylation, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Esophageal Neoplasms metabolism, Esophageal Squamous Cell Carcinoma metabolism, Glycogen Synthase Kinase 3 beta antagonists & inhibitors
- Abstract
Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal cancer and is often refractory to current therapies. Development of efficient therapeutic strategies against ESCC presents a major challenge. Glycogen synthase kinase (GSK)3β has emerged as a multipotent therapeutic target in various diseases including cancer. Here we investigated the biology and pathological role of GSK3β in ESCC and explored the therapeutic effects of its inhibition. The expression of GSK3β and tyrosine (Y)216 phosphorylation-dependent activity was higher in human ESCC cell lines and primary tumors than untransformed esophageal squamous TYNEK-3 cells from an ESCC patient and tumor-adjacent normal esophageal mucosa. GSK3β-specific inhibitors and small interfering (si)RNA-mediated knockdown of GSK3β attenuated tumor cell survival and proliferation, while inducing apoptosis in ESCC cells and their xenograft tumors in mice. GSK3β inhibition spared TYNEK-3 cells and the vital organs of mice. The therapeutic effect of GSK3β inhibition in tumor cells was associated with G0/G1- and G2/M-phase cell cycle arrest, decreased expression of cyclin D1 and cyclin-dependent kinase (CDK)4 and increased expression of cyclin B1. These results suggest the tumor-promoting role of GSK3β is via cyclin D1/CDK4-mediated cell cycle progression. Consequently, our study provides a biological rationale for GSK3β as a potential therapeutic target in ESCC.
- Published
- 2020
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7. Effects of neoadjuvant chemotherapy on operative adverse events and chemotherapy and radiotherapy in patients undergoing immediate breast reconstruction.
- Author
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Adachi Y, Okumura S, Sawaki M, Hattori M, Yoshimura A, Gondo N, Kotani H, Iwase M, Kataoka A, Sugino K, Horisawa N, Ozaki Y, Endo Y, Sakamoto S, and Iwata H
- Subjects
- Antineoplastic Agents administration & dosage, Axilla, Breast pathology, Breast surgery, Breast Neoplasms pathology, Chemotherapy, Adjuvant adverse effects, Chemotherapy, Adjuvant methods, Chemotherapy, Adjuvant statistics & numerical data, Female, Humans, Lymph Node Excision adverse effects, Lymph Node Excision statistics & numerical data, Lymph Nodes pathology, Mammaplasty methods, Mastectomy adverse effects, Mastectomy methods, Middle Aged, Neoadjuvant Therapy methods, Postoperative Complications etiology, Radiotherapy, Adjuvant adverse effects, Radiotherapy, Adjuvant statistics & numerical data, Retrospective Studies, Risk Factors, Time Factors, Time-to-Treatment, Antineoplastic Agents adverse effects, Breast Neoplasms therapy, Mammaplasty adverse effects, Neoadjuvant Therapy adverse effects, Postoperative Complications epidemiology
- Abstract
Background: Immediate breast reconstruction (IBR) has been become a standard treatment for patients with breast cancer undergoing mastectomy. However, whether IBR is appropriate in patients undergoing neoadjuvant chemotherapy (NAC) is still unclear. Therefore, in this study we examined the rates of operative adverse events (AEs), risk factors for operative AEs, and effects on chemotherapy and radiotherapy of IBR with NAC., Methods: Between January 2012 and March 2018, 593 patients underwent IBR at the Aichi Cancer Center Hospital. We retrospectively obtained clinical data of all these patients from their medical records and identified 56 patients (65 breasts) who had received NAC (NAC group) and 537 patients (568 breasts) who had not (non-NAC group). We compared the rates of operative AEs, risk factors for operative AEs, chemotherapy-related AEs, and duration to radiotherapy between the NAC and non-NAC cohorts., Results: The rate of operative AEs was significantly higher in the NAC than the non-NAC group (35% vs. 22%, p < 0.05). However, axillary lymph node dissection was the most influential risk factor, and NAC was not identified as a risk factor for operative AEs in patients who had undergone IBR. Additionally, there were no statistically significant differences in chemotherapy-related AEs or interval between surgery and postoperative radiotherapy between the NAC and non-NAC groups., Conclusions: NAC remains likely to contribute to increased postoperative AEs in patients undergoing IBR; however, it does not affect postoperative treatment and IBR is appropriate for patients undergoing NAC.
- Published
- 2020
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8. Pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil administration after major hepatectomy in a rat model.
- Author
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Tada K, Iwashita Y, Shiraiwa K, Uchida H, Oshima Y, Sato Y, Nakanuma H, Hirashita T, Masuda T, Endo Y, Takeuchi Y, Ohta M, Itoh H, and Inomata M
- Subjects
- Animals, Dihydrouracil Dehydrogenase (NADP) metabolism, Disease Models, Animal, Female, Hepatectomy methods, Liver metabolism, Liver Regeneration drug effects, Male, Rats, Rats, Wistar, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Fluorouracil pharmacokinetics, Fluorouracil toxicity, Liver drug effects
- Abstract
Background: Chemotherapy after hepatectomy for colorectal liver metastasis has not been established, due to the toxic side effects, which are likely related to impaired drug clearance during liver regeneration. We investigated the pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil (5-FU) during liver regeneration after major hepatectomy in a rat model., Methods: Thirty-six male Wistar rats were divided into control (C), control with chemotherapy (CC), hepatectomy (H), and hepatectomy with chemotherapy (HC) groups. The CC and HC groups were administered 5-FU for 4 days. Plasma 5-FU, liver weight, and liver dihydropyrimidine dehydrogenase (DPD) were measured. The ileal villous height was measured to determine adverse effects., Results: The area under the curve and maximum plasma concentration of 5-FU increased by up to 51% and 32%, respectively, in the HC group compared to the CC group. The liver regeneration rate was significantly lower in the HC group than in the H group (67.3 ± 7.4 vs 33.0 ± 5.7%, p < 0.001). The HC group had a significantly lower liver DPD than the CC group (4.4 ± 1.1 mg vs 6.9 ± 1.1 mg, p < 0.01). The HC group had a significantly lower ileal villous height than the CC group (253 ± 40 μm vs. 318 ± 36 μm, p < 0.05)., Conclusions: Reduction of the total liver DPD following major hepatectomy caused increased plasma 5-FU levels and 5-FU-associated toxicity.
- Published
- 2020
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9. Interstitial Lung Disease Onset and Its Risk Factors in Japanese Patients With ALK-Positive NSCLC After Treatment With Crizotinib.
- Author
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Gemma A, Kusumoto M, Kurihara Y, Masuda N, Banno S, Endo Y, Houzawa H, Ueno N, Ohki E, and Yoshimura A
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- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung pathology, Child, Child, Preschool, Crizotinib pharmacology, Female, Humans, Japan, Lung Diseases, Interstitial pathology, Lung Neoplasms pathology, Male, Middle Aged, Risk Factors, Young Adult, Antineoplastic Agents adverse effects, Carcinoma, Non-Small-Cell Lung chemically induced, Crizotinib adverse effects, Lung Diseases, Interstitial chemically induced, Lung Neoplasms chemically induced
- Abstract
Introduction: The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting., Methods: Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists., Results: The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema-like shadows with or without diffuse alveolar damage pattern were observed in crizotinib-associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2-4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD., Conclusions: Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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10. Anti-cancer activity of m-carborane-containing trimethoxyphenyl derivatives through tubulin polymerization inhibition.
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Kaise A, Endo Y, and Ohta K
- Subjects
- Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Drug Design, Drug Screening Assays, Antitumor, Female, Humans, Structure-Activity Relationship, Tubulin metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Boranes chemistry, Boranes pharmacology, Tubulin Modulators chemistry, Tubulin Modulators pharmacology
- Abstract
m-Carborane-containing compound 1a was identified as a cell growth inhibitor from a random screening of a boron compound library. As 1a is a mixture of diastereomers due to the presence of two chiral carbons, we designed achiral derivatives 2-4 and studied the structure-activity relationships of the methoxy groups on the benzene ring. 3,4,5-Trimethoxybenzyl derivative 2a and 3,4,5-trimethoxybenzoyl derivative 3a showed more potent anti-cancer activity against the human breast cancer cell line MDA-MB-453 than lead compound 1a. Compound 3a inhibited tubulin polymerization in a dose-dependent manner., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
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11. Efficacy and Safety of Amrubicin in Non-Small-Cell Lung Cancer Patients Beyond Third-Line Therapy.
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Saigusa M, Asada K, Akamatsu T, Tanaka Y, Endo Y, Yamamoto A, Morita S, and Shirai T
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- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Treatment Outcome, Anthracyclines therapeutic use, Antineoplastic Agents therapeutic use, Carcinoma, Non-Small-Cell Lung drug therapy, Lung Neoplasms drug therapy
- Abstract
Background: There are no standard cytotoxic treatments for non-small-cell lung cancer (NSCLC) patients beyond third-line therapy. The purpose of this study was to evaluate the efficacy and safety of amrubicin in pretreated NSCLC patients., Methods: The records of NSCLC patients who received amrubicin monotherapy as a third or later line of chemotherapy at Shizuoka General Hospital between April 2007 and March 2015 were retrospectively reviewed. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 3.0., Results: Overall, 69 patients were enrolled in this study; 16 patients were female and the median age was 67 years. The median number of treatment cycles was 3. The response rate was 7.2%, and the disease control rate was 63.8%. The median progression-free survival was 2.8 months. The median overall survival was 7.7 months. Hematological toxicities of ≥ grade 3 included leukopenia (59.4%) and neutropenia (62.3%). Non-hematological toxicities of ≥ grade 2 included anorexia (27.5%) and fatigue (24.6%)., Conclusion: Although hematological toxicities were severe, these results suggested that amrubicin in NSCLC patients beyond third-line therapy shows sufficient clinical benefit., (© 2018 S. Karger AG, Basel.)
- Published
- 2019
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12. Real-world use of sunitinib in Japanese patients with pancreatic neuroendocrine tumors: results from a post-marketing surveillance study.
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Sato K, Toyoshima Y, Moriyama S, Endo Y, Ito T, and Ohki E
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- Adult, Aged, Antineoplastic Agents adverse effects, Female, Follow-Up Studies, Humans, Incidence, Japan epidemiology, Male, Middle Aged, Neoplasm Metastasis, Neuroendocrine Tumors pathology, Prognosis, Antineoplastic Agents therapeutic use, Drug-Related Side Effects and Adverse Reactions epidemiology, Neuroendocrine Tumors drug therapy, Product Surveillance, Postmarketing, Sunitinib therapeutic use
- Abstract
Background: Sunitinib is approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced or metastatic disease. Safety and efficacy data in Japanese patients are limited. We report outcomes from a post-marketing surveillance study of sunitinib treatment in Japanese patients., Methods: Sunitinib 37.5 mg once daily was orally administered in Japanese patients aged ≥ 15 years with pNETs. The primary endpoints included adverse events (AEs) occurring during the observation period of 168 days and objective response rate (ORR)., Results: Sunitinib was administered in 62 patients with pNETs. The median duration of treatment was 165 days. At 168 days from the start of treatment, 31 patients were still receiving sunitinib treatment and treatment continuation rate was 50.0%. Of the 31 patients who discontinued treatment, 18 (58.1%) discontinued because of AEs and 16 (51.6%) patients discontinued due to insufficient clinical effect. Of the 18 patients who discontinued due to AEs, 10 did so within 42 days of treatment initiation. The most common all-grade AEs were platelet count decreased (33.9%), diarrhea (29.0%), neutrophil count decreased (27.4%), hypertension (24.2%), and palmar-plantar erythrodysesthesia syndrome (24.2%). In the 51 patients eligible for the efficacy analysis, ORR was 13.7% (95% confidence interval, 5.7-26.3) and clinical benefit rate was 70.6%., Conclusions: There were no new safety concerns in real-world use of sunitinib in Japanese patients with pNETs. The short treatment duration likely led to low tumor response. Appropriate AEs management through dose interruption/reduction is essential for sunitinib treatment success in this patient population.
- Published
- 2019
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13. Anti-tumour effect of lapatinib in canine transitional cell carcinoma cell lines.
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Sakai K, Maeda S, Saeki K, Nakagawa T, Murakami M, Endo Y, Yonezawa T, Kadosawa T, Mori T, Nishimura R, and Matsuki N
- Subjects
- Animals, Blotting, Western veterinary, Carcinoma, Transitional Cell drug therapy, Cell Line, Tumor, Cell Proliferation drug effects, Dogs, ErbB Receptors metabolism, Female, Lapatinib, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation veterinary, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, Urinary Bladder Neoplasms drug therapy, Antineoplastic Agents therapeutic use, Carcinoma, Transitional Cell veterinary, Dog Diseases drug therapy, Quinazolines therapeutic use, Urinary Bladder Neoplasms veterinary
- Abstract
Transitional cell carcinoma (TCC) accounts for >90% of canine malignant tumours occurring in urinary bladder, and the prognosis is poor. Our previous study, using RNA sequencing, showed that human epidermal growth factor 2 (HER2) was the most activated upstream regulator related to carcinogenesis in canine TCC. The aim of this study was to examine the anti-tumour effect of lapatinib, a tyrosine kinase inhibitor of HER2, on canine TCC cell lines in vitro and in vivo. Five canine TCC cell lines (TCCUB, Love, Sora, LCTCC, and MCTCC) were used. Western blotting showed that HER2 protein expression was observed in all of the canine TCC cell lines. Lapatinib inhibited phosphorylation of HER2 and cell growth in a dose-dependent manner. Cell cycle analyses using flow cytometry showed that lapatinib significantly increased the sub-G
1 and G0 /G1 phase fractions and significantly decreased the S and G2 /M phase fractions in the cell lines (Sora and TCCUB). For the in vivo experiments, the canine TCC cells (Sora) were subcutaneously injected into nude mice. Six days after inoculation, lapatinib (100 mg/kg) or vehicle was administered daily via intraperitoneal administration for 14 days. Tumour volume was significantly smaller in the lapatinib group compared with the vehicle control group. Histologically, lapatinib significantly increased necrotic areas in the tumour tissues. These findings suggest that lapatinib exerts anti-tumour effects on canine TCC cells by inhibiting HER2 signalling and inducing cell cycle arrest., (© 2018 John Wiley & Sons Ltd.)- Published
- 2018
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14. T-DM1-resistant cells gain high invasive activity via EGFR and integrin cooperated pathways.
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Endo Y, Shen Y, Youssef LA, Mohan N, and Wu WJ
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- Ado-Trastuzumab Emtansine, Cell Line, Tumor, Cell Movement, Drug Resistance, Neoplasm genetics, Female, Humans, Integrin alpha5beta1 genetics, Integrin alpha5beta1 metabolism, Integrin alphaVbeta3 metabolism, Maytansine therapeutic use, Neoplasm Invasiveness, RNA, Small Interfering genetics, Receptor Cross-Talk, Receptor, ErbB-2 genetics, Signal Transduction, Antineoplastic Agents therapeutic use, Breast Neoplasms drug therapy, Carcinoma, Ductal drug therapy, Maytansine analogs & derivatives, Trastuzumab therapeutic use
- Abstract
Ado-trastuzumab emtansine (Kadcyla®; T-DM1) is an antibody-drug conjugate developed to treat trastuzumab-resistant disease. Despite initial favorable outcomes, most patients eventually cease to respond due to developing acquired resistance to T-DM1. Currently, there is no targeted therapy to treat T-DM1-resistant disease. To explore novel therapeutic targets to improve therapeutic efficacy of T-DM1, we generated T-DM1-resistant cells using trastuzumab-resistant JIMT1 cells. We found that the loss of human epidermal growth factor receptor 2 confers T-DM1 resistance, which in turn activates a compensatory mechanism that increases epidermal growth factor receptor (EGFR) expression. Upregulation of EGFR increases the protein levels of α5β1 and αVβ3 integrins, resulting in enhanced motility and invasion of T-DM1-resistant cells. This study delineates previously unappreciated relationships between α5β1 and αVβ3 and suggests that specific integrins should be carefully selected as therapeutic targets to treat T-DM1-resistant disease. Specifically, silencing β1 integrin expression by siRNA in T-DM1-resistant cells destabilizes α5, but increases expression of αV, a critical integrin mediating the invasion and metastases in many different cancers. As a consequence, T-DM1-resistant cells gain metastatic potential and become more invasive. This finding is underscored by the fact that β1 integrin blockage induced by an inhibitory antibody, MAB 13, significantly increases invasion of T-DM1-resistant cells. However, the increased cell invasion induced by β1 integrin blockage can be significantly reduced by either EGFR inhibitor or specific siRNA against αV integrin. The discovery of functional cooperation between EGFR and αV integrin in regulating cell growth and invasion provides an opportunity to develop novel therapeutic strategy by dual-targeting EGFR and specific integrin to overcome T-DM1 resistance.
- Published
- 2018
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15. Design and synthesis of p-carborane-containing sulfamates as multitarget anti-breast cancer agents.
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Kaise A, Ohta K, Shirata C, and Endo Y
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- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Boranes chemical synthesis, Boranes chemistry, Breast Neoplasms pathology, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Female, Humans, Microtubules drug effects, Microtubules metabolism, Molecular Structure, Structure-Activity Relationship, Sulfonic Acids chemical synthesis, Sulfonic Acids chemistry, Antineoplastic Agents pharmacology, Boranes pharmacology, Breast Neoplasms drug therapy, Drug Design, Sulfonic Acids pharmacology
- Abstract
The development of multitarget anticancer agents is of high interest to medicinal chemists in terms of overcoming drug resistance and preventing cancer-cell migration. Based on the structure of the potent carborane-containing estrogen BE120, non-steroidal multitarget anti-breast cancer agent candidates 1a-1j were designed and synthesized. Compound 1f shows potent STS-inhibitory activity (IC
50 = 1.8 μM), cell-growth-inhibitory (CGI) activity against 39 human cancer cell lines (MG-MID = 2.8 μM), and tubulin-polymerization-inhibitory (TPI) activity. An analysis of the DNA content for MDA-MB-453 breast cancer cells revealed that 1f arrests the cell cycle in the G2/M phase and induces apoptosis. Accordingly, 1f should be a promising therapeutic agent for hormone-dependent breast cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)- Published
- 2017
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16. Novel p-carborane-containing multitarget anticancer agents inspired by the metabolism of 17β-estradiol.
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Kaise A, Ohta K, and Endo Y
- Subjects
- 2-Methoxyestradiol, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Boranes chemical synthesis, Boranes chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Estradiol chemistry, Estradiol pharmacology, Humans, Molecular Structure, Polymerization drug effects, Steryl-Sulfatase antagonists & inhibitors, Steryl-Sulfatase metabolism, Structure-Activity Relationship, Tubulin metabolism, Antineoplastic Agents pharmacology, Boranes pharmacology, Enzyme Inhibitors pharmacology, Estradiol analogs & derivatives, Estradiol metabolism
- Abstract
The female hormone 17 β-estradiol (E2) is synthesized from estrone by steroid sulfatase (STS), and metabolized into 2-methoxyestradiol (2-ME), whereby the biological activity of the latter is substantially different from that of E2. Based on the metabolic pathways of E2, a carborane-containing 2-ME mimic (1c) and its derivatives (1 and 2) were designed and synthesized as novel multitarget anticancer agents. Bissulfamate 1f exhibited potent STS-inhibitory activity and tubulin-polymerization-inhibitory activity. Moreover, the cell-growth-inhibitory (CGI) activity of 1f was similar to that of 2-ME in a panel screening against 39 human cancer cell lines. Accordingly, 1f should be a promising perspective therapeutic agent for hormone-dependent breast tissue., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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17. Rapid regression of metastatic brain tumours in a melanoma patient after dabrafenib/trametinib therapy.
- Author
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Komori T, Otsuka A, Kusuba N, Taniguchi K, Endo Y, Honda T, and Kabashima K
- Subjects
- Aged, Brain Neoplasms secondary, Humans, Imidazoles administration & dosage, Male, Melanoma secondary, Oximes administration & dosage, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Pyridones administration & dosage, Pyrimidinones administration & dosage, Remission Induction, Skin Neoplasms pathology, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Brain Neoplasms drug therapy, Melanoma drug therapy
- Published
- 2017
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18. Design and synthesis of iodocarborane-containing ligands with high affinity and selectivity toward ERβ.
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Ohta K, Ogawa T, and Endo Y
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Ligands, MCF-7 Cells, Molecular Structure, Phenols chemical synthesis, Phenols chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Drug Design, Estrogen Receptor beta agonists, Phenols pharmacology
- Abstract
The selectivity and the binding affinity of previously reported carborane-containing ligands 2 and 3 toward ERβ remains to be optimized. To improve their biological profiles, a series of iodinated carboranyl phenol derivatives (4-6) were designed and synthesized as prospective ERβ-selective ligands with high affinity. Several iodinated carboranyl phenols showed high relative binding affinity (RBA) values for both ERs, and especially for ERβ, due to suitable hydrophobic interactions of the iodine atoms with the hydrophobic amino acid residues of the ERβ ligand-binding domains. Among these derivatives, 9,10-diiodo-m-carborane 5f exhibited a more than 100% increase of the RBA values toward ERβ, a 14-fold increased selectivity for ERβ over ERα, and ER-agonistic activity in MCF-7 cell proliferation assays., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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19. Effects of toceranib phosphate (Palladia) monotherapy on multidrug resistant lymphoma in dogs.
- Author
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Yamazaki H, Miura N, Lai YC, Takahashi M, Goto-Koshino Y, Yasuyuki M, Nakaichi M, Tsujimoto H, Setoguchi A, and Endo Y
- Subjects
- Animals, Cell Line, Tumor, Dogs, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Female, Lymphoma drug therapy, Male, Antineoplastic Agents therapeutic use, Dog Diseases drug therapy, Indoles therapeutic use, Lymphoma veterinary, Pyrroles therapeutic use
- Abstract
We examined whether multidrug resistant (MDR) canine lymphoma increases gene expression for platelet-derived growth factor receptor α (PDGFRα), vascular endothelial growth factor receptor 2 (VEGFR2), and c-KIT, and whether toceranib phosphate (TOC) has potential as a treatment for MDR canine lymphoma. The clinical data showed that PDGFRα expression was higher in canine subjects with MDR T-cell lymphoma than in those with untreated T-cell lymphoma, and that c-KIT expression was greater in subjects with T-cell lymphoma than in those with B-cell lymphoma. TOC monotherapy was well tolerated without serious adverse effects, and two of the five subjects that received TOC exhibited partial responses. The data presented here could contribute to the assessment of TOC-based therapy for dogs with MDR or T-cell lymphoma.
- Published
- 2017
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20. Design and Synthesis of Novel Anti-metastatic Hypoxic Cytotoxin TX-2137 Targeting AKT Kinase.
- Author
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Shiba I, Kouzaki R, Yamada H, Endo Y, Takino T, Sato H, Kitazato K, Kageji T, Nagahiro S, and Uto Y
- Subjects
- A549 Cells, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Hypoxia drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Chick Embryo, Drug Design, Humans, Liver Neoplasms secondary, Matrix Metalloproteinase 9 metabolism, Mice, Neoplasm Metastasis, Phosphorylation drug effects, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Xenograft Model Antitumor Assays, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemical synthesis, Liver Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemical synthesis, Proto-Oncogene Proteins c-akt antagonists & inhibitors
- Abstract
Background: The hypoxic microenvironment plays a crucial role in the malignant progression of tumor cells. Moreover, AKT, a serine/threonine kinase, is activated by various extracellular growth factors and is important for cell growth, survival, and motility of leukocytes, fibroblasts, endothelial cells, and tumor cells. Therefore, we aimed to design an anti-metastatic hypoxic cytotoxin which has inhibitory effects on AKT., Results: TX-2137 was designed and synthesized based on the structural similarity of a preexisting AKT1/2 kinase inhibitor and a hypoxic cytotoxin tirapazamine. TX-2137 effectively reduced the expression of phosphorylated AKT and matrix metalloproteinase 9 (MMP9) and showed strong inhibition of the proliferation of B16-F10, HT-1080, and MKN-45 cells. In addition, TX-2137 exhibited hypoxia-selective cytotoxicity towards A549 cells and inhibited liver metastasis of B16-F10 cells in a xenograft chick embryo model in the same way as doxorubicin., Conclusion: TX-2137 may be a potent lead compound in the development of a novel anti-metastatic AKT kinase inhibitor., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)
- Published
- 2017
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21. Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a spotlight on trastuzumab.
- Author
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Dokmanovic M, King KE, Mohan N, Endo Y, and Wu WJ
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Cardiotoxicity physiopathology, Drug Design, Drug Evaluation, Preclinical methods, Female, Humans, Molecular Targeted Therapy, Receptor, ErbB-2 antagonists & inhibitors, Stomach Neoplasms drug therapy, Stomach Neoplasms pathology, Trastuzumab administration & dosage, Trastuzumab pharmacology, Antineoplastic Agents adverse effects, Cardiotoxicity etiology, Trastuzumab adverse effects
- Abstract
Introduction: Trastuzumab, a therapeutic monoclonal antibody directed against ErbB2, is often noted as a successful example of targeted therapy. Trastuzumab improved outcomes for many patients with ErbB2-positive breast and gastric cancers, however, cardiac side effects [e.g., left ventricular dysfunction and congestive heart failure (CHF)] were reported in the early phase clinical studies. This finding, subsequently corroborated by multiple clinical studies, raised concerns that the observed cardiotoxicity induced by trastuzumab might adversely impact the clinical development of other therapeutics targeting ErbB family members. Areas covered: In this review we summarize both basic research and clinical findings regarding trastuzumab-induced cardiotoxicity and assess if there has been an impact of trastuzumab-induced cardiotoxicity on the development of other agents targeting ErbB family members. Expert opinion: There are a number of scientific gaps that are critically important to address for the continued success of HER2-targeted agents. These include: 1) elucidating the molecular mechanisms contributing to cardiotoxicity; 2) developing relevant preclinical testing systems for predicting cardiotoxicity; 3) developing clinical strategies to identify patients at risk of cardiotoxicity; and 4) enhancing management of clinical symptoms of cardiotoxicity.
- Published
- 2017
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22. Hypoxia-activated prodrug TH-302 decreased survival rate of canine lymphoma cells under hypoxic condition.
- Author
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Yamazaki H, Lai YC, Tateno M, Setoguchi A, Goto-Koshino Y, Endo Y, Nakaichi M, Tsujimoto H, and Miura N
- Subjects
- ATP-Binding Cassette Transporters genetics, Animals, Cell Hypoxia, Cell Line, Tumor, Dogs, Gene Expression Regulation, Neoplastic drug effects, Hypoxia drug therapy, Hypoxia genetics, Hypoxia pathology, Lymphoma genetics, Lymphoma pathology, Platelet-Derived Growth Factor genetics, Up-Regulation drug effects, Vascular Endothelial Growth Factor A genetics, Antineoplastic Agents pharmacology, Cell Survival drug effects, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Lymphoma drug therapy, Nitroimidazoles pharmacology, Phosphoramide Mustards pharmacology, Prodrugs pharmacology
- Abstract
We tested the hypotheses that hypoxic stimulation enhances growth potentials of canine lymphoma cells by activating hypoxia-inducible factor 1α (HIF-1α), and that the hypoxia-activated prodrug (TH-302) inhibits growth potentials in the cells. We investigated how hypoxic culture affects the growth rate, chemoresistance, and invasiveness of canine lymphoma cells and doxorubicin (DOX)-resistant lymphoma cells, and influences of TH-302 on survival rate of the cells under hypoxic conditions. Our results demonstrated that hypoxic culture upregulated the expression of HIF-1α and its target genes, including ATP-binding cassette transporter B1 (ABCB1), ATP-binding cassette transporter G2 (ABCG2), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and survivin, and enhanced the growth rate, DOX resistance, and invasiveness of the cells. Additionally, TH-302 decreased the survival rate of the cells under hypoxic condition. Our studies suggest that hypoxic stimulation may advance the tumorigenicity of canine lymphoma cells, favoring malignant transformation. Therefore, the data presented may contribute to the development of TH-302-based hypoxia-targeting therapies for canine lymphoma.
- Published
- 2017
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23. Targeting Cancer with PCPA-Drug Conjugates: LSD1 Inhibition-Triggered Release of 4-Hydroxytamoxifen.
- Author
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Ota Y, Itoh Y, Kaise A, Ohta K, Endo Y, Masuda M, Sowa Y, Sakai T, and Suzuki T
- Subjects
- Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Liberation drug effects, Drug Screening Assays, Antitumor, Epithelial Cells, Histone Demethylases metabolism, Humans, MCF-7 Cells, Molecular Structure, Prodrugs chemistry, Structure-Activity Relationship, Tranylcypromine chemistry, Antineoplastic Agents pharmacology, Histone Demethylases antagonists & inhibitors, Prodrugs pharmacology, Tranylcypromine pharmacology
- Abstract
Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2016
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24. Upregulation of granzyme B and interferon-γ mRNA in responding lesions by treatment with nivolumab for metastatic melanoma: a case report.
- Author
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Anegawa H, Otsuka A, Kaku Y, Nonomura Y, Fujisawa A, Endo Y, and Kabashima K
- Subjects
- Aged, Humans, Male, Melanoma pathology, Neoplasm Metastasis, Nivolumab, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Granzymes genetics, Interferon-gamma genetics, Melanoma drug therapy, RNA, Messenger genetics, Up-Regulation
- Published
- 2016
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- View/download PDF
25. Design, synthesis, and anti-proliferative activity of 1-(4-methoxyphenyl)-12-hydroxymethyl-p-carborane derivatives.
- Author
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Kaise A, Ohta K, and Endo Y
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Apoptosis drug effects, Binding, Competitive, Boranes chemistry, Boranes metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Chemistry Techniques, Synthetic, Drug Screening Assays, Antitumor, Estrogen Receptor alpha metabolism, Humans, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Boranes chemical synthesis, Boranes pharmacology, Drug Design
- Abstract
1-(4-Methoxyphenyl)-12-hydroxymethyl-p-carborane (2a), which is a precursor to the previously developed potent carborane-containing ER agonist BE120, exhibited weak cell growth inhibitory activity against four human cancer cell lines (MCF-7, MDA-MB-453, LNCaP, and PC-3). The biological evaluation of a series of derivatives of 2a revealed that an increased number of methoxy groups on the benzene ring of 2a enhanced the cell growth inhibitory activity. Trimethoxyphenyl derivative 2g afforded the most potent cell growth inhibitory activity (mean GI50 value: 5.8 μM) in a panel screening using 39 human cancer cell lines. Moreover, 2g induced for MDA-MB-453 breast cancer cell lines an arrest of the cell cycle in the G2/M phase and apoptosis mediated by caspase-3/7., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Published
- 2016
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26. 5-Aminolevulinic Acid Enhances Ultrasound-mediated Antitumor Activity via Mitochondrial Oxidative Damage in Breast Cancer.
- Author
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Shimamura Y, Tamatani D, Kuniyasu S, Mizuki Y, Suzuki T, Katsura H, Yamada H, Endo Y, Osaki T, Ishizuka M, Tanaka T, Yamanaka N, Kurahashi T, and Uto Y
- Subjects
- Animals, Apoptosis, Cell Line, Tumor, Drug Screening Assays, Antitumor, Female, Humans, Mice, Mice, Inbred BALB C, Mitochondria drug effects, Mitochondria metabolism, Neoplasm Transplantation, Oxidation-Reduction, Reactive Oxygen Species metabolism, Ultrasonic Waves, Aminolevulinic Acid administration & dosage, Antineoplastic Agents administration & dosage, Breast Neoplasms drug therapy, Mammary Neoplasms, Experimental drug therapy
- Abstract
Background/aim: 5-Aminolevulinic acid (5-ALA), a precursor of protoporphyrin IX (PpIX), is now used for photodynamic therapy (PDT) of pre-cancers of the skin and photodynamic diagnosis (PDD) of brain tumors. Sonodynamic therapy (SDT) of cancers with ultrasound has been studied using 5-ALA as a sonosensitizer. In this article, we evaluated the sonosensitizing activity and mode of action of 5-ALA/PpIX by using mouse mammary tumor EMT6 cells., Results: 5-ALA-SDT showed significant antitumor effects toward EMT6 cells in vitro and in vivo. The fluorescence of MitoSOX Red, an indicator specific for mitochondrial superoxide, was significantly increased by 5-ALA-SDT. Moreover, the fluorescence derived from JC-1, an indicator of mitochondrial membrane potential, was also significantly increased by 5-ALA-SDT. These findings suggest that mitochondria are one of the target organelles of 5-ALA-SDT. PpIX enhanced reactive oxygen species (ROS) production from tert-butyl hydroperoxide (tBHP), suggesting that PpIX might stabilize or promote ROS generation from tBHP., Conclusion: 5-ALA-SDT showed an antitumor effect in mouse mammary tumor EMT6 cells through oxidation of the mitochondrial membrane via ROS production., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2016
27. Pyomyositis at the surgical site in a patient with chronic myeloid leukemia: a case report and literature review.
- Author
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Takebayashi K, Sonoda H, Shimizu T, Ohta H, Minamiguchi H, Ishida M, Mekata E, Endo Y, Tani T, and Tani M
- Subjects
- Aged, Combined Modality Therapy, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Male, Neoplasm Staging, Prognosis, Pyomyositis pathology, Antineoplastic Agents adverse effects, Imatinib Mesylate adverse effects, Leukemia, Myelogenous, Chronic, BCR-ABL Positive complications, Leukemia, Myelogenous, Chronic, BCR-ABL Positive surgery, Pyomyositis etiology
- Abstract
Background: Pyomyositis is a rare, subacute, deep pyogenic infection of the muscle tissue. This disease has been previously described in patients that were immunocompromised due to a hematological malignancy., Case Presentation: A 68-year-old man with a history of chronic myeloid leukemia was treated with imatinib. He was diagnosed with ascending colon cancer and underwent curative surgery. His postoperative course was uneventful, and he was healthy at 6 months after surgery, allowing for reinitiation of imatinib therapy. After the reinitiation of therapy, a computed tomography (CT) scan revealed a mass shadow in the right iliopsoas muscle. This lesion was clinically diagnosed as recurrent colon cancer with an abscess, which was resected surgically. A pathological examination uncovered both edema and inflammation. Two months after the second surgery, imatinib therapy was reinitiated; however, he again developed painful swelling and erythema in his right thigh. A CT scan revealed a similar shadow as described previously. He was then diagnosed with pyomyositis; he underwent incisional drainage and was administered linezolid. Following the treatment for pyomyositis, there was no cancer recurrence or evidence of any recurrent pyomyositis., Conclusions: Findings from this case suggest that both undergoing surgery and receiving imatinib therapy may modulate an individual's immune response, whereby the surgical site becomes more prone to infection and may predispose an individual to pyomyositis. The case report is followed by a discussion of the literature regarding this disease, including potential risk factors and the underlying pathogenesis.
- Published
- 2016
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28. Ado-Trastuzumab Emtansine Targets Hepatocytes Via Human Epidermal Growth Factor Receptor 2 to Induce Hepatotoxicity.
- Author
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Yan H, Endo Y, Shen Y, Rotstein D, Dokmanovic M, Mohan N, Mukhopadhyay P, Gao B, Pacher P, and Wu WJ
- Subjects
- Ado-Trastuzumab Emtansine, Animals, Antibodies, Monoclonal, Humanized adverse effects, Antineoplastic Agents adverse effects, Biomarkers, Cell Membrane metabolism, Cell Proliferation drug effects, Gene Expression, Humans, Immunohistochemistry, Inflammation drug therapy, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Liver drug effects, Liver metabolism, Liver pathology, Maytansine adverse effects, Maytansine pharmacology, Membrane Potential, Mitochondrial drug effects, Mice, Microtubules metabolism, Mitochondrial Membranes metabolism, Mitochondrial Membranes pathology, Mitochondrial Membranes ultrastructure, Models, Animal, Necrosis drug therapy, Necrosis pathology, Receptor, ErbB-2 genetics, Trastuzumab, Tubulin Modulators pharmacology, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents pharmacology, Hepatocytes drug effects, Hepatocytes metabolism, Maytansine analogs & derivatives, Receptor, ErbB-2 metabolism
- Abstract
Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2-positive metastatic breast cancer. It consists of trastuzumab, a humanized mAb directed against HER2, and a microtubule inhibitor, DM1, conjugated to trastuzumab via a thioether linker. Hepatotoxicity is one of the serious adverse events associated with T-DM1 therapy. Mechanisms underlying T-DM1-induced hepatotoxicity remain elusive. Here, we use hepatocytes and mouse models to investigate the mechanisms of T-DM1-induced hepatotoxicity. We show that T-DM1 is internalized upon binding to cell surface HER2 and is colocalized with LAMP1, resulting in DM1-associated cytotoxicity, including disorganized microtubules, nuclear fragmentation/multiple nuclei, and cell growth inhibition. We further demonstrate that T-DM1 treatment significantly increases the serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase in mice and induces inflammation and necrosis in liver tissues, and that T-DM1-induced hepatotoxicity is dose dependent. Moreover, the gene expression of TNFα in liver tissues is significantly increased in mice treated with T-DM1 as compared with those treated with trastuzumab or vehicle. We propose that T-DM1-induced upregulation of TNFα enhances the liver injury that may be initially caused by DM1-mediated intracellular damage. Our proposal is underscored by the fact that T-DM1 induces the outer mitochondrial membrane rupture, a typical morphologic change in the mitochondrial-dependent apoptosis, and mitochondrial membrane potential dysfunction. Our work provides mechanistic insights into T-DM1-induced hepatotoxicity, which may yield novel strategies to manage liver injury induced by T-DM1 or other ADCs., (©2015 American Association for Cancer Research.)
- Published
- 2016
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29. Idiopathic thrombocytopenic purpura induced by nivolumab in a metastatic melanoma patient with elevated PD-1 expression on B cells.
- Author
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Kanameishi S, Otsuka A, Nonomura Y, Fujisawa A, Endo Y, and Kabashima K
- Subjects
- Aged, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, B-Lymphocytes metabolism, Female, Humans, Immunoglobulins, Intravenous therapeutic use, Lung Neoplasms drug therapy, Lung Neoplasms secondary, Melanoma drug therapy, Melanoma pathology, Nivolumab, Platelet Transfusion, Prednisolone therapeutic use, Programmed Cell Death 1 Receptor metabolism, Receptors, Fc therapeutic use, Recombinant Fusion Proteins therapeutic use, Thrombopoietin therapeutic use, Antibodies, Monoclonal adverse effects, Antineoplastic Agents adverse effects, Programmed Cell Death 1 Receptor antagonists & inhibitors, Purpura, Thrombocytopenic, Idiopathic chemically induced, Purpura, Thrombocytopenic, Idiopathic therapy
- Published
- 2016
- Full Text
- View/download PDF
30. Successful surgical approach for a patient with encapsulating peritoneal sclerosis after hyperthermic intraperitoneal chemotherapy: a case report and literature review.
- Author
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Takebayashi K, Sonoda H, Shimizu T, Ohta H, Ishida M, Mekata E, Endo Y, Tani T, and Tani M
- Subjects
- Adult, Antineoplastic Agents therapeutic use, Follow-Up Studies, Humans, Injections, Intraperitoneal, Male, Peritoneal Fibrosis diagnosis, Peritoneal Fibrosis etiology, Peritoneum pathology, Tomography, X-Ray Computed, Antineoplastic Agents adverse effects, Digestive System Surgical Procedures methods, Hyperthermia, Induced adverse effects, Peritoneal Fibrosis surgery, Sigmoid Neoplasms therapy
- Abstract
Background: Encapsulating peritoneal sclerosis (EPS) is a rare surgical complication that can occur after intraperitoneal treatment. It is also a serious and potentially fatal complication of continuous ambulatory peritoneal dialysis. The present report describes a case of surgically treated EPS that probably occurred as a complication of hyperthermic intraperitonal chemotherapy (HIPEC)., Case Presentation: A 39-year-old man required sigmoidectomy for serosal invasive advanced sigmoid colon cancer. HIPEC with oxaliplatin, 5-fluorouracil and mitomycin C were given as adjuvant therapy. Subsequently, intestinal obstruction developed at 15 months postoperatively, and the patient was hospitalized. Abdominal computed tomography showed a dilated small intestine enveloped by a thickened membrane. We found no evidence of peritoneal recurrence, but exploratory surgery revealed EPS, probably caused by HIPEC. We peeled the capsule off of the intestine. The patient's postoperative course was uneventful, and sufficient nutritional intake after surgery was noted. Seven months after surgery, he is well with no recurrence., Conclusion: The surgical treatment via peritonectomy and enterolysis for postoperative EPS appears safe and effective. A diagnosis of EPS should be considered when intestinal obstruction does not show improvement with conservative treatment in patients who have undergone HIPEC, provided the possibility of peritoneal cancer recurrence is excluded.
- Published
- 2014
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31. Novel estrogen receptor (ER) modulators containing various hydrophobic bent-core structures.
- Author
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Ohta K, Ogawa T, Kaise A, and Endo Y
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Estrogen Receptor Modulators chemistry, Humans, Hydrophobic and Hydrophilic Interactions, MCF-7 Cells, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Estrogen Receptor Modulators pharmacology, Estrogen Receptor alpha agonists
- Abstract
We previously discovered m-carborane-containing estrogen receptor (ER) modulator 4, which exhibits weak ER-agonistic and antagonistic activities in transactivation assays. With the aim of developing novel ER partial agonists, we designed and synthesized various analogues of 4 with a bent-core structure, that is, pseudo cyclic structure (5), tetrahydropyrimidinone (6), m-benzene (7), adamantane (8), and 9,10-dimethyl-m-carborane (9), in place of the m-carborane moiety. Compound 9 showed greater binding affinity than 4 in ER-binding assay using [6,7-(3)H]-17β-estradiol and was a more effective partial agonist than 4 in MCF-7 cell proliferation assay. It appears to be a promising candidate as a selective ER modulator (SERM)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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32. Phase I dose-escalation study of nimustine in tumor-bearing dogs.
- Author
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Takahashi M, Goto-Koshino Y, Fukushima K, Kanemoto H, Nakashima K, Fujino Y, Ohno K, Endo Y, and Tsujimoto H
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Dogs, Dose-Response Relationship, Drug, Japan, Maximum Tolerated Dose, Neutropenia chemically induced, Nimustine therapeutic use, Time Factors, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Neoplasms drug therapy, Nimustine administration & dosage, Nimustine adverse effects
- Abstract
Nimustine (ACNU) is an alkylating agent of the nitrosourea and can be an antineoplastic agent in dogs. But, there has been no report on its dose-limiting toxicity (DLT) in dogs. This study was a phase I dose-escalation clinical trial to determine the maximum tolerated dose (MTD) and DLT of ACNU in tumor-bearing dogs. The starting dosage was 25 mg/m(2), and subsequent dosages were administered in increments of 5 mg/m(2) in cohort of 3 dogs. Eight dogs were included, the MTD was determined to be 25 mg/m(2), DLT was neutropenia, and the optimal interval was considered to be 21 days. The data herein provide a basis for the subsequent phase II trial of ACNU in dogs.
- Published
- 2014
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33. Improvement in telangiectatic rosacea as a side-effect of monthly docetaxel therapy.
- Author
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Tokunaga M, Endo Y, Fujisawa A, Tanioka M, Nomura T, and Miyachi Y
- Subjects
- Aged, Docetaxel, Humans, Incidental Findings, Male, Middle Aged, Nose, Recurrence, Remission, Spontaneous, Antineoplastic Agents therapeutic use, Facial Dermatoses drug therapy, Nose Diseases drug therapy, Rosacea drug therapy, Taxoids therapeutic use, Telangiectasis drug therapy
- Published
- 2014
- Full Text
- View/download PDF
34. A new treatment for human malignant melanoma targeting L-type amino acid transporter 1 (LAT1): a pilot study in a canine model.
- Author
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Fukumoto S, Hanazono K, Fu DR, Endo Y, Kadosawa T, Iwano H, and Uchide T
- Subjects
- Amino Acids, Cyclic pharmacology, Animals, Cell Line, Tumor, Cell Proliferation drug effects, Dogs, Dose-Response Relationship, Drug, Humans, Inhibitory Concentration 50, Melphalan pharmacology, Neoplasm Metastasis, Pilot Projects, Antineoplastic Agents therapeutic use, Gene Expression Regulation, Neoplastic, Large Neutral Amino Acid-Transporter 1 metabolism, Melanoma drug therapy, Melanoma metabolism
- Abstract
L-type amino acid transporter 1 (LAT1), an isoform of amino acid transport system L, transports branched or aromatic amino acids essential for fundamental cellular activities such as cellular growth, proliferation and maintenance. This amino acid transporter recently has received attention because of its preferential and up-regulated expression in a variety of human tumors in contrast to its limited distribution and low-level expression in normal tissues. In this study, we explored the feasibility of using LAT1 inhibitor as a new therapeutic agent for human malignant melanomas (MM) using canine spontaneous MM as a model for human MM. A comparative study of LAT expression was performed in 48 normal tissues, 25MM tissues and five cell lines established from MM. The study observed LAT1 mRNA levels from MM tissues and cell lines that were significantly (P<0.01) higher than in normal tissues. Additionally, MM with distant metastasis showed a higher expression than those without distant metastasis. Functional analysis of LAT1 was performed on one of the five cell lines, CMeC-1. [(3)H]l-Leucine uptake and cellular growth activities in CMeC-1 were inhibited in a dose-dependent manner by selective LAT1 inhibitors (2-amino-2-norbornane-carboxylic acid, BCH and melphalan, LPM). Inhibitory growth activities of various conventional anti-cancer drugs, including carboplatin, cyclophosphamide, dacarbazine, doxorubicin, mitoxantrone, nimustine, vinblastine and vincristine, were significantly (P<0.05) enhanced by combination use with BCH or LPM. These findings suggest that LAT1 could be a new therapeutic target for MM., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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35. Clinical potential of the anticancer drug sensitivity test for patients with synchronous stage IV colorectal cancer.
- Author
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Takebayashi K, Mekata E, Sonoda H, Shimizu T, Endo Y, and Tani T
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma pathology, Adenocarcinoma secondary, Adult, Aged, Aged, 80 and over, Antineoplastic Agents therapeutic use, Collagen Type I metabolism, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Feasibility Studies, Female, Follow-Up Studies, Gels, Humans, Liver Neoplasms drug therapy, Liver Neoplasms metabolism, Liver Neoplasms pathology, Liver Neoplasms secondary, Male, Middle Aged, Neoplasm Staging, Retrospective Studies, Survival Analysis, Tumor Cells, Cultured, Tumor Stem Cell Assay, Adenocarcinoma drug therapy, Antineoplastic Agents pharmacology, Colorectal Neoplasms surgery, Drug Resistance, Multiple, Drug Resistance, Neoplasm
- Abstract
Purpose: We retrospectively evaluated the clinical efficacy and feasibility of a collagen gel droplet-embedded culture drug sensitivity test (CD-DST) to guide therapy for patients with stage IV colorectal cancer (CRC)., Methods: We investigated 38 patients with stage IV CRC. All patients were younger than 85 years and had untreated evaluable metastatic lesions. The primary tumors were surgically resected, and the tissue samples were investigated by CD-DST. Patients treated with in vitro sensitive drugs were defined as Group A (n = 14), while those treated with in vitro non-sensitive drugs were defined as Group B (n = 24). We evaluated response rate (RR), progression-free survival (PFS), and overall survival (OS)., Results: RR was 85.71 % in Group A and 41.67 % in Group B (p = 0.0079). The median PFS was 696.5 days in Group A and 297.5 days in Group B (p = 0.0326). The median OS was 1,023.4 days in Group A and 518.5 days in Group B (p = 0.0061)., Conclusions: The CD-DST can define chemoresistant and chemosensitive tumors. The use of CD-DST might be one of the tools to supplement informed consent prior to initiation of therapy.
- Published
- 2013
- Full Text
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36. [A case of advanced hepatocellular carcinoma with portal vein invasion successfully treated by sorafenib].
- Author
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Endo Y, Miyamoto M, Koujima T, Watanabe Y, Kawai T, Toda K, Nobuhisa T, Watanabe T, Matsumoto Y, Watanabe N, Kai K, and Sato S
- Subjects
- Aged, Carcinoma, Hepatocellular blood supply, Carcinoma, Hepatocellular etiology, Carcinoma, Hepatocellular pathology, Hepatitis C, Chronic complications, Humans, Liver Neoplasms blood supply, Liver Neoplasms etiology, Male, Neoplasm Invasiveness, Niacinamide analogs & derivatives, Phenylurea Compounds, Sorafenib, Antineoplastic Agents therapeutic use, Benzenesulfonates therapeutic use, Carcinoma, Hepatocellular therapy, Liver Neoplasms drug therapy, Portal Vein pathology, Pyridines therapeutic use
- Abstract
A 73-year-old man was followed up for HCV-associated chronic hepatitis and hepatocellular carcinoma (HCC), developed in segment 8 of the liver. Radiofrequency ablation (P-RFA) was used to treat the tumor in June 2004. Afterwards, the patient underwent repetitive transcatheter arterial chemoembolization (TACE) against recurrent tumors 5 times. An abdominal computed tomogram (CT) showed an infiltrative mass in the left liver with tumor thrombus invading into the umbilical portion. Transarterial infusion (TAI) therapy of cisplatin (CDDP) was performed 2 times, in January and June of 2010. The size of the main tumor was decreased according to CT, and tumor marker levels such as AFP and PIVKA-II also decreased, but tumor thrombus of the portal vein developed into the main trunk (Vp4). We started therapy with sorafenib in July, 2010. Two months later, an abdominal CT revelaed further reduction of the main tumor and a shrunken tumor thrombus of the portal vein back to the left lobe. The therapeutic effect of sorafenib against HCC with tumor thrombus of the portal vein continued for 9 months.
- Published
- 2012
37. Influence of cytidine deaminase on antitumor activity of 2'-deoxycytidine analogs in vitro and in vivo.
- Author
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Yoshida T, Endo Y, Obata T, Kosugi Y, Sakamoto K, and Sasaki T
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Blotting, Western, Cell Line, Tumor, Cell Survival drug effects, Cytidine Deaminase genetics, Deoxycytidine therapeutic use, Female, Humans, Mice, Mice, Nude, Neoplasms, Experimental drug therapy, Neoplasms, Experimental enzymology, Neoplasms, Experimental metabolism, Recombinant Proteins genetics, Recombinant Proteins metabolism, Substrate Specificity, Transfection, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacokinetics, Cytidine Deaminase metabolism, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacokinetics
- Abstract
Antitumor 2'-deoxycytidine (dCyd) analogs such as gemcitabine (dFdC), cytarabine (Ara-C), and 2'-C-cyano-2'-deoxy-1-β-d-arabinofuranosylcytosine (CNDAC) are activated by dCyd kinase, whereas cytidine deaminase (CDA) inactivates them by conversion to their uracil forms. To elucidate the relationship between the chemosensitivity to antitumor dCyd nucleosides and CDA expression, we established a stable line of human gastric carcinoma TMK-1 cells constitutively overexpressing CDA (TMK-1/CDA) and examined its chemosensitivity to antitumor dCyd analogs in vitro and in vivo. We observed comparable reactivity for dFdC and Ara-C, and the substrate reactivity of CNDAC to recombinant human CDA was more than 10 times less efficient than those of Ara-C and dFdC. Next, we examined the in vitro chemosensitivity of TMK-1/CDA and observed a marked decrease in the sensitivity of TMK-1/CDA to Ara-C, dFdC, and CNDAC compared with mock-transfected cells. In addition, we transplanted TMK-1/CDA cells into a nude mouse xenograft model and examined their in vivo chemosensitivity to CNDAC. The in vivo antitumor effect of CNDAC on TMK-1/CDA cells was substantially reduced compared with that of mice transplanted with mock-transfected cells. These results indicate that CDA could play an important role in regulating susceptibility to antitumor dCyd analogs in vitro and in vivo. In addition, the expression level of CDA was found to affect the antitumor activity of CNDAC, even though the substrate reactivity of CNDAC to CDA is relatively low.
- Published
- 2010
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38. Cytoreduction and intraperitoneal chemotherapy for carcinomatosis from gastric cancer.
- Author
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Yonemura Y, Bando E, Kawamura T, Ito H, Endo Y, Miura M, Kiyosaki K, and Sasaki T
- Subjects
- Carcinoma diagnosis, Carcinoma secondary, Combined Modality Therapy, Female, Humans, Male, Middle Aged, Minimally Invasive Surgical Procedures, Peritoneal Neoplasms diagnosis, Peritoneal Neoplasms secondary, Peritoneum surgery, Survival Rate, Treatment Outcome, Antineoplastic Agents administration & dosage, Carcinoma drug therapy, Infusions, Parenteral methods, Peritoneal Neoplasms drug therapy, Stomach Neoplasms pathology
- Published
- 2007
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- View/download PDF
39. Development of an antitumor adenosine analog, 3''-ethynyladenosine.
- Author
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Endo Y, Obata T, Nomura M, Fukushima M, Yamada Y, Matsuda A, and Sasaki T
- Subjects
- Adenosine chemistry, Adenosine pharmacology, Adenosine Deaminase metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cell Proliferation drug effects, Deamination drug effects, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Humans, Adenosine analogs & derivatives, Adenosine chemical synthesis, Antineoplastic Agents chemical synthesis
- Abstract
3'-ethynyladenosine (EAdo) was an adenosine analog with potent antitumor activity against various human tumor cells in vitro. However, EAdo was enzymatically inactivated by adenosine deaminase (ADA) in vitro and in vivo. Therefore, we synthesized two ADA-resistant EAdo derivatives (2-F-EAdo and EAdo-5'-monophosphate, EAMP) and examined their antitumor activities.
- Published
- 2007
- Full Text
- View/download PDF
40. Enhanced antitumor efficacy of telomerase-selective oncolytic adenoviral agent OBP-401 with docetaxel: preclinical evaluation of chemovirotherapy.
- Author
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Fujiwara T, Kagawa S, Kishimoto H, Endo Y, Hioki M, Ikeda Y, Sakai R, Urata Y, Tanaka N, and Fujiwara T
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carcinoma drug therapy, Carcinoma, Non-Small-Cell Lung drug therapy, Cell Line, Tumor, Colorectal Neoplasms drug therapy, Docetaxel, Drug Carriers, Esophageal Neoplasms drug therapy, Feasibility Studies, Gene Expression Regulation, Neoplastic, Green Fluorescent Proteins drug effects, Green Fluorescent Proteins metabolism, Humans, Lung Neoplasms drug therapy, Mice, Mice, Nude, Neoplasms enzymology, Polymerase Chain Reaction, Stomach Neoplasms drug therapy, Taxoids pharmacology, Transplantation, Heterologous, Vinblastine analogs & derivatives, Vinblastine pharmacology, Vinorelbine, Adenoviridae genetics, Antineoplastic Agents pharmacology, Neoplasms drug therapy, Telomerase drug effects
- Abstract
Oncolytic adenoviruses are being developed as novel anticancer therapeutics and currently undergoing clinical trials. We previously demonstrated that telomerase-specific replication-competent adenovirus (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) promoter regulates viral replication, efficiently killed human tumor cells. We further constructed OBP-401 (Telomelysin-GFP) that expresses the green fluorescent protein (GFP) reporter gene under the control of the cytomegalovirus promoter in the E3 region to monitor viral distribution. Here, we examined the feasibility of a single-agent therapy with OBP-401 as well as of combining OBP-401 with chemotherapeutic agents. Infection of OBP-401 alone or followed by the treatment of a chemotherapeutic drug, docetaxel (Taxotere), resulted in a profound in vitro cytotoxicity and GFP expression in various human cancer cell lines originating from different organs (lung, colon, esophagus, stomach, liver and prostate), although the magnitude of antitumor effect varied among the cell types. Other chemotherapeutic drugs such as vinorelbine (Navelbine) and SN38 (the potent active metabolite of irinotecan) combined with OBP-401 also inhibited the growth of human cancer cells. Quantitative real-time PCR analysis demonstrated that docetaxel did not affect viral replication. For in vivo evaluation, nu/nu mice xenografted with H1299 human lung tumor received intratumoral injection of OBP-401 and intraperitoneal administration of docetaxel. Analysis of growth of implanted tumors showed a significant, therapeutic synergism, although OBP-401 alone and docetaxel alone showed modest inhibition of tumor growth. Thus, OBP-401 in combination with docetaxel efficiently enhances the antitumor efficacy both in vitro and in vivo, and the outcome has important implications for tumor-specific oncolytic chemovirotherapies for human cancers., (2006 Wiley-Liss, Inc.)
- Published
- 2006
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41. [Thymidylate synthase and dihydropyrimidine dehydrogenase expression and histological effects of preoperative UFT in gastric cancer patients].
- Author
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Uyama R, Yoshizawa Y, Tajiri T, Endo Y, Mitsuya T, and Sanada Y
- Subjects
- Aged, Drug Combinations, Female, Humans, Lymph Nodes pathology, Lymphatic Metastasis, Male, Middle Aged, Neoadjuvant Therapy, Neoplasm Staging, Stomach Neoplasms enzymology, Antineoplastic Agents administration & dosage, Dihydrouracil Dehydrogenase (NADP) metabolism, Stomach Neoplasms drug therapy, Stomach Neoplasms pathology, Tegafur administration & dosage, Thymidylate Synthase metabolism, Uracil administration & dosage
- Abstract
Unlabelled: During DNA synthesis in tumors, fluoropyrimidine anticancer agents target thymidylate synthase (TS) that catalyze the synthesis of dTMP from dUMP and are metabolized by dihydropyrimidine dehydrogenase (DPD). We administered UFT to patients with gastric cancer preoperatively to prevent cancers from advancing while they await surgery or down staging., Patients and Methods: We administered UFT to 24 gastric cancer patients at 360 mg/m(2)/day for longer than 3 weeks as a preoperative chemotherapy. TS and DPD expression in the tumor were measured by immunohistochemistry staining before and after (during surgery) chemotherapy and compared with the results of histological assessment., Results: TS and DPD expression decreased significantly after UFT administration (p<0.05). Histological assessment showed Grade 1 b or 2 in 11 of 24 patients (46%). Eight of 15 patients with high DPD (53.3%) exhibited Grade 1 b or 2., Conclusions: Histological assessment revealed the efficacy of UFT, through a DPD-inhibitory fluoropyrimidine (DIF) effect, in patients with high DPD. This suggests that preoperative administration of UFT can be a useful clinical measure.
- Published
- 2006
42. Effective treatment of a case of refractory mycosis fungoides with imatinib.
- Author
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Oka S, Yokote T, Hara S, Akioka T, Kobayashi K, Hirata Y, Yamano T, Endo Y, Tsuji M, and Hanafusa T
- Subjects
- Benzamides, Humans, Imatinib Mesylate, Male, Middle Aged, Mycosis Fungoides pathology, Skin Neoplasms pathology, Antineoplastic Agents therapeutic use, Mycosis Fungoides drug therapy, Piperazines therapeutic use, Pyrimidines therapeutic use, Skin Neoplasms drug therapy
- Published
- 2006
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- View/download PDF
43. A crucial role of uridine/cytidine kinase 2 in antitumor activity of 3'-ethynyl nucleosides.
- Author
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Murata D, Endo Y, Obata T, Sakamoto K, Syouji Y, Kadohira M, Matsuda A, and Sasaki T
- Subjects
- Cell Line, Tumor, Dose-Response Relationship, Drug, Humans, Point Mutation, Uridine Kinase genetics, Antineoplastic Agents pharmacology, Cytidine analogs & derivatives, Cytidine pharmacology, Uridine analogs & derivatives, Uridine pharmacology, Uridine Kinase physiology
- Abstract
The antitumor 3'-ethynyl nucleosides, 1-(3-C-ethynyl-beta-D-ribopentofuranosyl)cytosine (ECyd) and 1-(3-C-ethynyl-beta-D-ribopentofuranosyl)uridine (EUrd), are potent inhibitors of RNA polymerases and show excellent antitumor activity against various human solid tumors in xenograft models. ECyd is being investigated in phase I clinical trials as a novel anticancer drug possessing a unique antitumor action. ECyd and EUrd require the activity of uridine/cytidine kinase (UCK) to produce the corresponding active metabolite. The UCK family consists of two members, UCK1 and UCK2, and both UCKs are expressed in many tumor cells. It was unclear, however, whether UCK1 or UCK2 is responsible for the phosphorylation of the 3'-ethynyl nucleosides. We therefore established cell lines that are highly resistant to the 3'-ethynyl nucleosides from human fibrosarcoma HT-1080 and gastric carcinoma NUGC-3. All the resistant cell lines showed a high cross-resistance to ECyd and EUrd. As a result of cDNA sequence analysis, we found that UCK2 mRNA expressed in EUrd-resistant HT-1080 cells has a 98-base pair deletion of exon 5, whereas EUrd-resistant NUGC-3 cells were harboring the point mutation at nucleotide position 484 (C to T) within exon 4 of UCK2 mRNA. This mutation was confirmed by genome sequence analysis of the UCK2 gene. Moreover, the expression of UCK2 protein was decreased in these resistant cells. In contrast, no mutation in the mRNA or differences in protein expression levels of UCK1 were shown in the EUrd-resistant HT-1080 and NUGC-3 cells. These results suggest that UCK2 is responsible for the phosphorylation and activation of the antitumor 3'-ethynyl nucleosides.
- Published
- 2004
- Full Text
- View/download PDF
44. Modified rice bran beneficial for weight loss of mice as a major and acute adverse effect of Cisplatin.
- Author
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Endo Y and Kanbayashi H
- Subjects
- Administration, Oral, Animals, Antibodies, Enzyme-Linked Immunosorbent Assay, Female, Infusions, Parenteral, Mice, Mice, Inbred BALB C, Plant Extracts administration & dosage, Plant Extracts immunology, Plant Extracts therapeutic use, Antineoplastic Agents adverse effects, Cisplatin adverse effects, Oryza, Phytotherapy, Weight Loss drug effects
- Published
- 2003
- Full Text
- View/download PDF
45. The molecular targets of antitumor 2'-deoxycytidine analogues.
- Author
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Obata T, Endo Y, Murata D, Sakamoto K, and Sasaki T
- Subjects
- Animals, Antineoplastic Agents metabolism, Carrier Proteins drug effects, Carrier Proteins metabolism, Deoxycytidine metabolism, Deoxycytidine Kinase metabolism, Drug Resistance, Neoplasm, Humans, Antineoplastic Agents pharmacology, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology
- Abstract
Most antitumor 2'-deoxycytidine (dCyd) analogues, such as Ara-C (1-beta-arabinofuranosylcytosine) and gemcitabine (2'-deoxy-2',2'-difluolo-cytidine), have common antitumor mechanisms and metabolic pathways. These nucleosides are transported into tumor cells via specific nucleoside transporters (NT), and then phosphorylated toward each monophosphate form by dCyd kinase. Finally, tri-phosphate forms are enzymatically produced and efficiently inhibit DNA synthesis. It is believed that dCyd kinase is a very important activator of antitumor 2'-dCyd analogues and an attractive molecular target for biochemical modulation. Resistant cells established by continuous exposure to 2'-dCyd analogues in vitro have extremely high resistance as compared with parental cells, and their resistance indexes are sometimes increased between several hundred to thousand times. Such high resistance is generally attributed to deficiency of dCyd kinase activity, but the clinical resistance index of Ara-C-resistant patients is estimated to be increased a maximum of 20 times compared with non-treated patients. The differences between experimental and clinical resistances may be caused by different mechanisms of resistance. To clarify such resistance mechanisms, we carried out research focused on NT and dCyd kinase. Our results show that earlier resistant cells, that exhibited a 20 times lower resistance index, had a reduced NT activity but retained dCyd kinase activity. In contrast, dCyd kinase activity was deficient in later resistant cells that showed maximum resistance. Both NT and dCyd kinase activities are important for the acquisition of resistance and are useful as molecular targets for biochemical modulation or the development of novel antitumor 2'-dCyd analogues. These results suggest that NT activity is likely to be responsible for clinical resistance.
- Published
- 2003
- Full Text
- View/download PDF
46. Potent antitumor effect of 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine on peritoneal dissemination models of gastrointestinal cancers.
- Author
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Miura S, Endo Y, Yoshimura Y, Endo M, Yonemura Y, and Sasaki T
- Subjects
- Adenocarcinoma secondary, Administration, Oral, Animals, Antimetabolites, Antineoplastic pharmacology, Body Weight drug effects, Cell Division drug effects, Colonic Neoplasms pathology, Disease Models, Animal, Female, Floxuridine pharmacology, Fluorouracil pharmacology, Humans, Mice, Mice, Nude, Neoplasm Transplantation, Peritoneal Neoplasms secondary, Stomach Neoplasms pathology, Survival Rate, Tumor Cells, Cultured, Adenocarcinoma drug therapy, Antineoplastic Agents therapeutic use, Colonic Neoplasms drug therapy, Cytarabine analogs & derivatives, Cytarabine therapeutic use, Peritoneal Neoplasms drug therapy, Stomach Neoplasms drug therapy
- Abstract
We investigated the antitumor activity of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine (4'-thio-FAC) in peritoneal dissemination models of gastrointestinal cancers. Oral administration of 4'-thio-FAC showed a marked effect on the development of ascites and on the survival of nude mice implanted with the highly metastatic MKN-45-P gastric cancer cells into the peritoneal cavity. The toxic effect was observed at a dose of 15 mg/kg, however, no toxicity was observed at a dose of 10 mg/kg with excellent antitumor activity. We established another highly metastatic cell line HCT-15-P by serial intraperitoneal passage of the colon cancer cell line HCT-15. In the HCT-15-P model, 4'-thio-FAC showed an inhibitory effect of peritoneal dissemination and an increase in the life span at a dose of 10 mg/kg. On the other hand, oral administration of 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-DFUR) did not show an increase in the life span of mice at a dose of 10 mg/kg. In conclusion, 4'-thio-FAC is a promising therapeutic agent for use against peritoneal dissemination of gastrointestinal cancers.
- Published
- 2002
47. Multifunctional anti-angiogenic activity of the cyclic peroxide ANO-2 with antitumor activity.
- Author
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Arakawa K, Endo Y, Kimura M, Yoshida T, Kitaoka T, Inakazu T, Nonami Y, Abe M, Masuyama A, Nojima M, and Sasaki T
- Subjects
- Air Sacs blood supply, Angiogenesis Inhibitors chemical synthesis, Animals, Antineoplastic Agents chemical synthesis, Carcinoma, Lewis Lung prevention & control, Cathepsin B antagonists & inhibitors, Chick Embryo, Female, Humans, Lung Neoplasms prevention & control, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Naphthalenes chemical synthesis, Oxepins chemical synthesis, RNA, Messenger metabolism, Ribonuclease, Pancreatic metabolism, Sarcoma blood supply, Sarcoma prevention & control, Umbilical Veins cytology, Urokinase-Type Plasminogen Activator antagonists & inhibitors, Urokinase-Type Plasminogen Activator genetics, Urokinase-Type Plasminogen Activator urine, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors pharmacology, Antineoplastic Agents pharmacology, Carcinoma, Lewis Lung blood supply, Lung Neoplasms blood supply, Naphthalenes pharmacology, Neovascularization, Pathologic drug therapy, Oxepins pharmacology
- Abstract
Our focus was to develop an anti-angiogenic drug possessing the inhibitory activity of urokinase-type plasminogen activator (u-PA) production. During preliminary screening, the effects of 13 ozonides on the inhibition of u-PA production in human fibrosarcoma HT-1080 cells and on the inhibition of angiogenesis on chicken embryonic chorioallantoic membranes were determined. Of the ozonides tested, 9 inhibited in vitro u-PA production of HT-1080 cells and 7 of these 9 exhibited strong anti-angiogenic activity. Interestingly, 6 of the 13 ozonides also inhibited cathepsin B activity. 1-Phenyl-1, 4-epoxy-1H,4H-naphtho[1,8-de][1, 2]dioxepin (ANO-2) potently inhibited cathepsin B (IC(50) = 0.47 microM) as well as u-PA production. Consequently, ANO-2 was selected for further study. ANO-2 inhibited tube formation by human umbilical vein endothelial cells cultured on Matrigel while exhibiting no cytotoxicity. Additionally, in vivo administration of ANO-2 inhibited angiogenesis induced by mouse Sarcoma-180 cells tested using the mouse dorsal air sac assay. Moreover, ANO-2 also suppressed primary tumor growth and reduced the number of pulmonary metastases caused by Lewis lung carcinoma cells in mice. These in vitro and in vivo activities indicate that ANO-2 has considerable potential as a new and potent anti-angiogenic drug that inhibits both u-PA production and enzymatic activity of cathepsins, indicating that ANO-2 may be a multifunctional inhibitor of angiogenesis., (Copyright 2002 Wiley-Liss, Inc.)
- Published
- 2002
- Full Text
- View/download PDF
48. Antimetastatic and antitumor effects of 2,4-diamino-6-(pyridine-4-yl)-1,3,5-triazine (4PyDAT) on the high lung metastatic colon 26 tumor in mice.
- Author
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Maeda M, Ligo M, Tsuda H, Fujita H, Yonemura Y, Nakagawa K, Endo Y, and Sasaki T
- Subjects
- Animals, Colonic Neoplasms blood supply, Colonic Neoplasms enzymology, Colonic Neoplasms pathology, Drug Screening Assays, Antitumor, Female, Lung Neoplasms blood supply, Lung Neoplasms enzymology, Matrix Metalloproteinase Inhibitors, Mice, Neoplasm Transplantation, Neovascularization, Pathologic prevention & control, Tumor Cells, Cultured drug effects, Urokinase-Type Plasminogen Activator antagonists & inhibitors, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, Lung Neoplasms prevention & control, Lung Neoplasms secondary, Pyridines pharmacology, Triazines pharmacology
- Abstract
The therapeutic potential of a diaminotriazine, 2,4-diamino-6-(pyridine-4-yl)-1,3,5-triazine (4PyDAT), was investigated in a metastatic model using the mouse colon 26 carcinoma variant (Co26Lu), which preferentially metastasizes to the lung of mouse. The compound had a moderate antimetastatic activity as well as antitumor activity, without toxicity to the host, when administered orally. In the cytotoxicity test in vitro, 4PyDAT showed very weak direct cytotoxicity against the Co26Lu cell line, Co26Lu(F55) (IC50 < or = 1000 microM). Less microcapiral formation on tumors were observed for the treated group with a hemorrhage than the control group under microscopy. 4PyDAT significantly inhibited the production of urokinase-type plasminogen activator (u-PA) in Co26Lu(F55) cells. These results suggest that the antimetastatic and antitumor activities of 4PyDAT are due in part to inhibition of angiogenesis, rather than direct antiproliferative action on the tumor cells. 4PyDAT may become a lead compound to develop antitumor triazine derivatives based on antiangiogenic action.
- Published
- 2000
49. Determinants in chemosensitivity of oncogene-transformed NIH3T3 cells to 2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine.
- Author
-
Zhang M, Endo Y, and Sasaki T
- Subjects
- 3T3 Cells, Animals, Antineoplastic Agents metabolism, Cell Division drug effects, Cell Transformation, Neoplastic, Chick Embryo, Cytarabine metabolism, Cytarabine pharmacology, Cytidine Deaminase metabolism, Deoxycytidine Kinase metabolism, Mice, Mice, Nude, Neoplasm Transplantation, Neoplasms, Experimental enzymology, Neoplasms, Experimental metabolism, Neoplasms, Experimental pathology, Oncogenes, Transformation, Genetic, Tritium, Antineoplastic Agents pharmacology, Cytarabine analogs & derivatives
- Abstract
2'-C-Cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine (CNDAC) is a novel 2'-deoxycytidine (dCyd) analogue with potent antitumor activity. To elucidate the determinants of chemosensitivity to CNDAC, the intracellular accumulation of CNDAC and the activities of dCyd kinase and cytidine deaminase were investigated in transformed NIH 3T3 cells with different genetic bases. The results indicate that the primary determinants of chemosensitivity to CNDAC are different in each cell type, but membrane transportation and the enzyme activities of dCyd kinase and cytidine deaminase are critical factors underlying the antitumor action of CNDAC. Moreover, the expression or function of these factors appears to be influenced by the activation of various oncogenes.
- Published
- 1999
50. Studies of effects of anticancer agents in combination with/without hyperthermia on metastasized human bladder cancer cells in chick embryos using the polymerase chain reaction technique.
- Author
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Uchibayashi T, Lee SW, Kunimi K, Ohkawa M, Endo Y, Noguchi M, and Sasaki T
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Base Sequence, Carboplatin pharmacology, Cell Division drug effects, Cell Transplantation, Chick Embryo, Cisplatin pharmacology, DNA Primers chemistry, DNA, Neoplasm chemistry, Doxorubicin pharmacology, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic genetics, Globins genetics, Humans, Liver chemistry, Liver metabolism, Liver Neoplasms drug therapy, Mitomycin pharmacology, Molecular Sequence Data, Polymerase Chain Reaction, Tumor Cells, Cultured, Urinary Bladder Neoplasms pathology, Urinary Bladder Neoplasms therapy, Antineoplastic Agents pharmacology, Hyperthermia, Induced, Liver Neoplasms secondary, Urinary Bladder Neoplasms drug therapy
- Abstract
Cultivated T24 cells derived from a human bladder cancer were inoculated into the chorioallantoic membrane vein of chick embryos. Hyperthermic treatment was performed following injection of anticancer agents 3 days after the inoculation of the T24 cells. DNA samples were obtained from the livers of the chick embryos, and the polymerase chain reaction technique was used to amplify a DNA fragment specific to the human beta-globin gene. The Southern hybridization method was used to evaluate the inhibitory effects of anticancer agents in combination with/without hyperthermia on T24 cells metastasized to the liver. The hyperthermia exerted an inhibitory effect on the growth of the T24 cells in the livers of the chick embryos, and this was dependent on the thermal dose. The antitumor effects of hyperthermia performed at 42.5 degrees C for 20 min and at 43.0 degrees C for 10 min were evidenced by 69.2% an 82.0% inhibition of the growth of the metastasized T24 cells, respectively, as compared with the growth of untreated T24 cell. Hyperthermia performed at 42.5 degrees C for 10 min alone produced 26.7% tumor growth inhibition, and these conditions for hyperthermia were subsequently used as a criterion for evaluating the effects of its combination with various anticancer agents. Adriamycin (20 micrograms/egg) alone, mitomycin C (10 micrograms/egg) alone, carboplatin (10 micrograms/egg) alone, and cisplatin (10 micrograms/egg) alone produced 13.5%, 58.9%, 27.3%, and 29.1% tumor growth inhibition, respectively. Adriamycin and mitomycin C applied in combination with hyperthermia showed additive inhibitory effects on the growth of the metastasized T24 cells in this chick embryo model.
- Published
- 1994
- Full Text
- View/download PDF
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