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61.
Sung Yeon Kim Y R Santosh Laxmi Naomi Suzuki Kenichiro Ogura Tadashi Watabe Michael W Duffel Shinya Shibutani 《Drug metabolism and disposition》2005,33(11):1673-1678
Tamoxifen (TAM) is used as the standard endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for this disease. Unfortunately, treatment of TAM increases the incidence of endometrial cancer; this may be due to the genotoxic damage induced by TAM metabolites. Formation of TAM-DNA adducts in rat liver correlates with the development of hepatocarcinoma. TAM-DNA adducts are proposed to be formed through O-sulfonation and/or O-acetylation of alpha-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not been extensively investigated. Rat or human hydroxysteroid sulfotransferases (HST), acetyltransferases, and liver cytosol were incubated with calf thymus DNA, alpha-OHTAM, and either 3'-phosphoadenosine 5'-phosphosulfate (PAPS) or acetyl coenzyme A (acetyl-CoA) as a cofactor and analyzed for TAM-DNA adduct formation, using 32P postlableling/polyacrylamide gel electrophoresis analysis. TAM-DNA adduct was formed when PAPS, not acetyl-CoA, was used. No TAM-DNA adducts were produced using human N-acetyltransferase I and II. HST antibody inhibited approximately 90% of TAM-DNA adduct formation generated by the cytosol or HST, suggesting that HST is primarily involved in the formation of TAM-DNA adducts. The formation of TAM-DNA adducts with rat liver cytosol and HST was much higher than that of human liver cytosol and HST. Our results indicate that TAM-DNA adducts are formed via O-sulfonation, not O-acetylation, of alpha-hydroxylated TAM and its metabolites. 相似文献
62.
Naomi Morita Hiroyuki Kusuhara Yoshitane Nozaki Hitoshi Endou Yuichi Sugiyama 《Drug metabolism and disposition》2005,33(8):1151-1157
Rat organic anion transporter 2 (rOat2, Slc22a7) is a sinusoidal multispecific organic anion transporter in the liver. The role of rOat2 in the hepatic uptake of drugs has not been thoroughly investigated yet. rOat2 substrates include nonsteroidal anti-inflammatory drugs, such as ketoprofen, indomethacin, and salicylate. In the present study, the uptake of ketoprofen, indomethacin, and salicylate by freshly isolated rat hepatocytes was characterized. The uptake of ketoprofen, indomethacin, and salicylate by hepatocytes was sodium-independent, and the rank order of their uptake activities was indomethacin > ketoprofen > salicylate. Kinetic analysis based on Akaike's Information Criterion suggested that the uptake of ketoprofen and indomethacin by hepatocytes consists of two saturable components and one nonsaturable one. The K(m) and V(max) values for the high- and low-affinity components for ketoprofen uptake were 0.84 and 97 microM and 35 and 1800 pmol/min/mg protein, respectively, whereas those for indomethacin were 1.1 and 140 microM and 130 and 16,000 pmol/min/mg protein, respectively. The K(m) values of the high-affinity component were similar to those for rOat2 (3.3 and 0.37 microM for ketoprofen and indomethacin, respectively). The uptake of ketoprofen by hepatocytes was significantly inhibited by probenecid and rOat2 inhibitors (indocyanine green, indomethacin, glibenclamide, and salicylate). Other inhibitors of rOatps (taurocholate and pravastatin) and rOat3 (pravastatin and p-aminohippurate) had a slight effect, but digoxin had no effect. These results suggest that rOat2 accounts partly for the hepatic uptake of ketoprofen and, presumably, indomethacin as a high-affinity site and that other transporters, such as rOatps, but not rOatp2, and rOat3, are also involved. 相似文献
63.
64.
Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. 总被引:4,自引:0,他引:4
Toshiya Chiba Koichi Tokuuye Yasushi Matsuzaki Shinji Sugahara Yoshimichi Chuganji Kenji Kagei Junichi Shoda Masaharu Hata Masato Abei Hiroshi Igaki Naomi Tanaka Yasuyuki Akine 《Clinical cancer research》2005,11(10):3799-3805
PURPOSE: We present results of patients with hepatocellular carcinoma (HCC) treated with proton beam therapy. EXPERIMENTAL DESIGN: We reviewed 162 patients having 192 HCCs treated from November 1985 to July 1998 by proton beam therapy with or without transarterial embolization and percutaneous ethanol injection. The patients in the present series were considered unsuitable for surgery for various reasons, including hepatic dysfunction, multiple tumors, recurrence after surgical resection, and concomitant illnesses. The median total dose of proton irradiation was 72 Gy in 16 fractions over 29 days. RESULTS: The overall survival rate for all of the 162 patients was 23.5% at 5 years. The local control rate at 5 years was 86.9% for all 192 tumors among the 162 patients. The degree of impairment of hepatic functions attributable to coexisting liver cirrhosis and the number of tumors in the liver significantly affected patient survival. For 50 patients having least impaired hepatic functions and a solitary tumor, the survival rate at 5 years was 53.5%. The patients had very few acute reactions to treatments and a few late sequelae during and after the treatments. CONCLUSIONS: Proton beam therapy for patients with HCC is effective, safe, well tolerable, and repeatable. It is the useful treatment mode for either cure or palliation for patients with HCC irrespective of tumor size, tumor location in the liver, insufficient feeding of the tumor with arteries, presence of vascular invasion, impaired hepatic functions, and coexisting intercurrent diseases. 相似文献
65.
Continuous exposure to dibromoacetic acid delays pubertal development and compromises sperm quality in the rat. 总被引:1,自引:0,他引:1
Gary R Klinefelter Lillian F Strader Juan D Suarez Naomi L Roberts Jerome M Goldman Ashley S Murr 《Toxicological sciences》2004,81(2):419-429
Previously our work on the haloacid by-products of drinking water disinfection focused on adult exposures. Herein we evaluate the consequence of continuous exposure to dibromoacetic acid (DBA) via drinking water through reproductive development into adulthood. An initial study in which offspring were exposed from gestation day (GD) 15 through adulthood revealed significant delays in preputial separation and vaginal opening, dose-related decreases in the fertility of cauda epididymal sperm, and dose-related diminutions in the sperm membrane protein SP22. Subsequent studies consisted of groups in which exposure ceased on postnatal day 21 (PND 21) versus adulthood. For each exposure, animals were evaluated after puberty (PND 56) as well as at adulthood (PND 120). Exposure to 4, 40, or 400 ppm DBA from GD 15 through PND 21 failed to result in any significant reproductive alterations. By contrast, continuous exposure until adulthood resulted in dose-related alterations consistent with those observed in the dose-finding study. Preputial separation and vaginal opening were delayed 4 and 3 days in males and females exposed to 400 ppm (76.3 mg/kg) DBA. This was associated with increased responsiveness of both the testis and ovary to hCG ex vivo; hCG-stimulated testosterone production by testicular parenchyma on PND 56 was increased at 4 ppm (0.6 mg/kg) DBA and higher. Finally, the quality of proximal cauda epididymal sperm was compromised by continuous exposure to DBA. The sperm membrane proteome was altered in a dose-related manner with SP22, and one of its charged variants, diminished at 40 ppm (3.6 mg/kg) DBA and higher. As more sensitive endpoints are evaluated, lower effect levels can be attributed to haloacid exposure. We are now extending our evaluations to epidemiology studies designed to evaluate sperm quality in men exposed to varying levels of disinfection by-products. 相似文献
66.
Nakagata N 《Nihon yakurigaku zasshi. Folia pharmacologica Japonica》2007,129(5):343-348
67.
Meijie Tian Adam T. Cheuk Jun S. Wei Abdalla Abdelmaksoud Hsien-Chao Chou David Milewski Michael C. Kelly Young K. Song Christopher M. Dower Nan Li Haiying Qin Yong Yean Kim Jerry T. Wu Xinyu Wen Mehdi Benzaoui Katherine E. Masih Xiaolin Wu Zhongmei Zhang Sherif Badr Naomi Taylor Brad St. Croix Mitchell Ho Javed Khan 《The Journal of clinical investigation》2022,132(16)
68.
Preclinical and first‐in‐human phase I studies of KW‐2450, an oral tyrosine kinase inhibitor with insulin‐like growth factor receptor‐1/insulin receptor selectivity 下载免费PDF全文
Gary K. Schwartz Mark A. Dickson Patricia M. LoRusso Edward A. Sausville Yoshimi Maekawa Yasuo Watanabe Naomi Kashima Daisuke Nakashima Shiro Akinaga 《Cancer science》2016,107(4):499-506
Numerous solid tumors overexpress or have excessively activated insulin‐like growth factor receptor‐1 (IGF‐1R). We summarize preclinical studies and the first‐in‐human study of KW‐2450, an oral tyrosine kinase inhibitor with IGF‐1R and insulin receptor (IR) inhibitory activity. Preclinical activity of KW‐2450 was evaluated in various in vitro and in vivo models. It was then evaluated in a phase I clinical trial in 13 patients with advanced solid tumors (NCT00921336). In vitro, KW‐2450 inhibited human IGF‐1R and IR kinases (IC50 7.39 and 5.64 nmol/L, respectively) and the growth of various human malignant cell lines. KW‐2450 40 mg/kg showed modest growth inhibitory activity and inhibited IGF‐1‐induced signal transduction in the murine HT‐29/GFP colon carcinoma xenograft model. The maximum tolerated dose of KW‐2450 was 37.5 mg once daily continuously; dose‐limiting toxicity occurred in two of six patients at 50 mg/day (both grade 3 hyperglycemia) and in one of seven patients at 37.5 mg/day (grade 3 rash). Four of 10 evaluable patients showed stable disease. Single‐agent KW‐2450 was associated with modest antitumor activity in heavily pretreated patients with solid tumors and is being further investigated in combination therapy with lapatinib/letrozole in patients with human epidermal growth factor receptor 2‐postive metastatic breast cancer. 相似文献
69.
70.
Yuichiro Ono Yasuhiro Takeuchi MD Naomi Hisanaga Masamitsu Iwata Junzoh Kitoh Yasuo Sugiura 《International archives of occupational and environmental health》1982,50(3):219-229
Summary Petroleum benzine is one of the mixtures of organic solvents containing n-hexane. The occurrence of polyneuropathy in the workers using petroleum benzines is attributed mainly to n-hexane, though other hydrocarbons present are also suspected of having some neurotoxicity or some potential which could modify the neurotoxicity of n-hexane. The present experiment was performed in order to clarify the toxicity of petroleum benzine to the peripheral nerve and compare it with that of n-hexane.Forty rats were randomly divided into five groups. The groups were exposed to 200 ppm n-hexane, 500 ppm n-hexane, and petroleum benzine vapor containing 200 ppm n-hexane or 500 ppm n-hexane, together with aliphatic and aromatic hydrocarbons for 12 h a day for 24 weeks. The body weight, motor nerve conduction velocity, motor distal latency, and mixed nerve conduction velocities were measured before exposure and every 4 weeks of exposure. A rat from each exposed group was histopathologically examined after 24 weeks' exposure.The function of the peripheral nerve was conspicuously impaired by 500 ppm n-hexane, slightly impaired by 200 ppm n-hexane and petroleum benzine containing 500 ppm n-hexane, and even less impaired by petroleum benzine containing 200 ppm n-hexane. Degenerations of the myelin sheaths and axons were demonstrated in all exposed groups upon examination of the raveled tail nerves. Thus, the experiment revealed that petroleum benzine could impair the peripheral nerves, while some components of petroleum benzine were considered to inhibit the neurotoxicity of n-hexane.This investigation was partly supported by a grant for scientific research from the Chiyoda Mutual Life Foundation in 1980–1981 相似文献