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81.
Conversion of 2,6-diamino-9-(2-hydroxyethoxymethyl)purine to acyclovir as catalyzed by adenosine deaminase 总被引:2,自引:0,他引:2
Adenosine deaminase (ADA) was partially purified from several sources using affinity chromatography. These enzymes have the capacity to catalyze the deamination of 2,6-diamino-9-(2-hydroxyethoxymethyl)purine (A134U) to form the antiviral agent acyclovir [9-(2-hydroxyethoxymethyl)guanine]. Their relative substrate efficiencies (Vmax/Km) with A134U (standardized to adenosine = 100) were: dog ADA, 0.092; human ADA, 0.015-0.029; rat ADA, 0.025; calf ADA, 0.016; and Escherichia coli ADA, 0.0003. In addition to having the lowest efficiency with A134U, the bacterial ADA was also distinguished by its lack of binding of the mammalian ADA inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine and by its weak binding to the 9-(p-aminobenzyl)adenine-agarose affinity column. Four minor metabolites of A134U and acyclovir have been reported to be produced in the rat. These compounds are oxidized on either the C-8 position of the ring or the terminal carbon of the side chain. Neither acyclovir nor any of these metabolites produced significant inhibition of calf intestine ADA. The oxidized metabolites containing an N-6 amino group were extremely slow substrates of this enzyme. 相似文献
82.
Radiation recall phenomenon secondary to capecitabine: possible role of thymidine phosphorylase 总被引:1,自引:0,他引:1
Background: The first reported case of radiation (XRT) recall related to capecitabine described dermatitis in a previously radiated field in a breast cancer patient (Ortman; JCO). We previously reported the first case of recall syndrome manifesting as diffuse gastritis and duodenitis related to capecitabine with prior XRT with 5-FU in a pancreatic cancer patient (Saif; JARCET). We report here another pancreatic cancer patient with a radiation recall receiving capecitabine following capecitabine-XRT. Patients and methods: From April 2004 to June 2005, 20 patients with locally advanced pancreatic adenocarcinoma were treated with capecitabine 1,600 mg/m2 daily with concomitant radiation (5040cGy) Monday–Friday (weekends off) for a total of 6 weeks, followed by capecitabine 2,000 mg/m2 daily for 14 days every 3 weeks. One male patient with tumor in the neck and body of pancreas and not infiltrating the duodenum dropped hemoglobin to 7.3 g/dl at the end of the ninth week, and melena on rectal examination. Specimen of primary pancreatic ductal adenocarcinoma was obtained via EUS-guided biopsy before starting XRT on day 1 and utilized for RNA extraction. TP mRNA level was determined by real-time quantitative PCR (RT-Q-PCR). Results: Upper endoscopy revealed gastritis consistent with radiation toxicity. Colonoscopy was negative. Transfusion of three units of packed red blood cells (PRBCs) was given. The dose of capecitabine was reduced by 25%. His anemia continued to progress, a CT scan revealed 39% decrease in the tumor size (PR). Analysis of tumor specimen prior to the start of capecitabine-XRT showed TP expression of 183.16 (high). In addition to TP, DPD was 7.40, and TNF-alpha 4,114.56. Conclusion: We believe this case to be the second case of radiation recall presenting as diffuse gastritis in a patient receiving capecitabine after previous treatment with XRT. Further studies, including the role of TP are warranted into the pathogenesis of this unique phenomenon. 相似文献
83.
Sensitivity of glycogen phosphorylase isoforms to indole site inhibitors is markedly dependent on the activation state of the enzyme 下载免费PDF全文
Freeman S Bartlett JB Convey G Hardern I Teague JL Loxham SJ Allen JM Poucher SM Charles AD 《British journal of pharmacology》2006,149(6):775-785
BACKGROUND AND PURPOSE: Inhibition of hepatic glycogen phosphorylase is a potential treatment for glycaemic control in type 2 diabetes. Selective inhibition of the liver phosphorylase isoform could minimize adverse effects in other tissues. We investigated the potential selectivity of two indole site phosphorylase inhibitors, GPi688 and GPi819. EXPERIMENTAL APPROACH: The activity of glycogen phosphorylase was modulated using the allosteric effectors glucose or caffeine to promote the less active T state, and AMP to promote the more active R state. In vitro potency of indole site inhibitors against liver and muscle glycogen phosphorylase a was examined at different effector concentrations using purified recombinant enzymes. The potency of GPi819 was compared with its in vivo efficacy at raising glycogen concentrations in liver and muscle of Zucker (fa/fa) rats. KEY RESULTS: In vitro potency of indole site inhibitors depended upon the activity state of phosphorylase a. Both inhibitors showed selectivity for liver phosphorylase a when the isoform specific activities were equal. After 5 days dosing of GPi819 (37.5 micromol kg(-1)), where free compound levels in plasma and tissue were at steady state, glycogen elevation was 1.5-fold greater in soleus muscle than in liver (P < 0.05). CONCLUSIONS AND IMPLICATIONS: The in vivo selectivity of GPi819 did not match that seen in vitro when the specific activities of phosphorylase a isoforms are equal. This suggests T state promoters may be important physiological regulators in skeletal muscle. The greater efficacy of indole site inhibitors in skeletal muscle has implications for the overall safety profile of such drugs. 相似文献
84.
2-Deoxy-L-ribose inhibits the invasion of thymidine phosphorylase-overexpressing tumors by suppressing matrix metalloproteinase-9 总被引:1,自引:0,他引:1
Nakajima Y Haraguchi M Furukawa T Yamamoto M Nakanishi H Tatematsu M Akiyama S 《International journal of cancer. Journal international du cancer》2006,119(7):1710-1716
Thymidine phosphorylase (TP), an enzyme involved in pyrimidine metabolism, is identical with an angiogenic factor, platelet-derived endothelial cell growth factor. 2-Deoxy-D-ribose (D-dRib), the degradation product of thymidine generated by TP activity, has been suggested to be a downstream mediator of TP function. 2-Deoxy-L-ribose (L-dRib), a stereoisomer of D-dRib, inhibited the promotion of angiogenesis, tumor growth and metastasis by TP. In our study, we have shown that nude mice inoculated with TP-overexpressing KB/TP cells had shorter survival times than those injected with control KB/CV cells. KB/TP tumors were also more highly invasive than KB/CV tumors in mice. The expression levels of matrix metalloproteinase (MMP)-9 in KB/TP tumors were significantly higher than those in KB/CV tumors. L-dRib and a TP inhibitior, TPI, extended the survival period of KB/TP tumor-bearing mice. L-dRib also reduced MMP-9 mRNA levels in KB/TP tumors. Furthermore, L-dRib suppressed the mRNA level of MMP-9 in cultured KB/TP cells, and the invasive activity of the cells. L-dRib may be useful for the suppression of invasion of TP-expressing tumor cells. 相似文献
85.
Histocytochemical and immunohistochemical studies related to the role of glycogen in human developing digestive organs 总被引:2,自引:0,他引:2
Koji Hashimoto Katsuhiro Tamura Hiroki Otani Osamu Tanaka 《Anatomy and embryology》1995,192(6):497-505
To elucidate the role of glycogen in the epithelium of developing digestive organs, we investigated the appearance of glycogen and glycogen phosphorylase (GP) in these organs. We studied 64 externally normal human embryos at Carnegie stages 13–23 (5.1–28.0 mm in crown-ramp length, 4–8 weeks of gestation) by histocytochemical staining for glycogen and immunohistochemical staining with antibodies against two isoenzymes of GP: brain-type (BGP) and mucle-brain-type (MBGP) GP. At stage 13, glycogen appeared in the epithelium of the digestive tract and the parenchyma of the pancreas. As development advanced, glycogen granules increased in number and size in these tissues, and they became evenly distributed in the epithelium of the digestive tract as either single particles or aggregates, as deduced by electron microscopy at late embryonic stages. Immunoreactivity specific both for BGP and for MBGP was detected in the digestive tract and the pancreas from stage 13. As development advanced, both BGP- and MBGP-immunoreactive cells increased in number and in immunoreactivity, and the number of MBGP-immunoreactive cells became larger than that of BGP-immunoreactive cells. By contrast, in hepatic cells, which serve as a major storage site for glycogen in adults, glycogen was detected only from stage 20, in smaller amounts, without formation of aggregates, and no immunoreactivity specific for BGP or MBGP was apparent throughout the embryonic stages examined. Thus, in the epithelium of the digestive tract and the parenchyma of the pancreas, but not in hepatic cells, the appearance and localization of GP coincided almost exactly with that of glycogen. These observations suggest that glycogen in the epithelium of the digestive tract and the parenchyma of the pancreas has not only been synthesized but also degraded from an early embryonic period and may, thus, be related to active cellular metabolism that is specific for embryonic development, including proliferation of the epithelium and interactions between epithelium and mesenchyme. 相似文献
86.
Purine nucleoside phosphorylase (PNP, EC 2.4.2.1) activity was revealed by enzyme histochemistry in Toxoplasma gondii ME49 strain isolated from murine cerebral cysts and from in vitro cultivation. The activity of the enzyme was revealed by
an insoluble electron-opaque precipitate of lead phosphate at the site of the reaction. In bradyzoites and tachyzoites of
T. gondii, the enzyme activity could be observed only in the cytoplasm. In bradyzoites, one or two foci of important PNP activity were
detected near the nucleus. In tachyzoites, an important PNP activity underlined the plasma membrane. For both bradyzoites
and tachyzoites, localization neither in the nucleus nor in cytoplasmic organelles could be detected. 相似文献
87.
目的探讨胃癌中胸苷磷酸化酶(TP)和基质金属蛋白酶2(MMP-2)表达的意义及其与肿瘤浸润转移的关系。方法免疫组化SP法检测69例不同胃黏膜组织(正常胃黏膜组10例、慢性胃炎组10例、胃癌组39例、胃癌转移的淋巴结组10例)中TP和MMP-2的表达情况。结果胃癌组织及淋巴结胃癌转移灶中TP与MMP-2的表达较正常组及慢性胃炎组显著增高(P〈0.05)。TP与MMP-2表达与胃癌患者的性别、年龄及肿瘤的分化程度无关。肿瘤≥5cm组及T3-4组TP阳性率湿著高于〈5cm组及T1-2组,有远处转移的胃癌组TP阳性率高于无远处转移组,差具有显著性(P〈0.05);临床Ⅰ-Ⅱ期和Ⅲ-Ⅳ期之间TP阳性率的差异也具有显著性(P〈0.001)。MMP-2在T1-2组与T3-4组的阳性率分别为60.87%和93.75%,有显著性差异(P〈0.05)。在有淋巴结转移的胃癌组MMP-2阳性率显著高于无淋巴结转移组(P〈0.05);临床Ⅰ-Ⅱ期阳性表达59.09%,Ⅲ-Ⅳ期阳性表达为94.12%,两组有显著性差异(P〈0.05)。而MMP-2表达却与肿瘤大小及远处转移无关。TP表达阳性的胃癌中MMP-2阳性率88.00%高于TP阴性组的50.00%。结论胃癌中TP与MMP-2表达增高与肿瘤进展的病理临床参数有关;TP的表达与MMP-2的表达有关,提示TP在影响肿瘤进展的过程中可能通过MMP-2促进肿瘤浸润转移。 相似文献
88.
Immunocytochemical analysis of rat vagus nerve by antibodies against glycogen phosphorylase isozymes
Pfeiffer-Guglielmi B Coles JA Francke M Reichenbach A Fleckenstein B Jung G Nicaise G Hamprecht B 《Brain research》2006,1110(1):23-29
Glycogen is an endogenous store of glucose equivalents for energy metabolism in many tissues. The brain contains a significant amount of glycogen the role of which as an energy reserve is currently under debate. Apparently little is known concerning a possible role of glycogen in peripheral nerves. We have demonstrated immunocytochemically the presence of glycogen phosphorylase (GP), a key enzyme in glycogen metabolism, in large and small axons of the rat vagus nerve, but not in Schwann cells. Furthermore, the isozyme-specific antibodies applied detected only the presence of the brain isoform BB of GP, but not the muscle isoform MM. This is in agreement with the occurrence of solely the BB isoform in the few brain and spinal cord neurons that contain GP. In contrast, astroglial cells in brain and spinal cord have previously been shown to contain both isoforms. Since GP isozymes are regulated differentially, the expression of isoform BB may provide hints to possible functions of glycogen in the vagus nerve. 相似文献
89.
90.
《Expert opinion on therapeutic patents》2013,23(8):987-994
As parasites cannot synthesise purines de novo and must salvage them from their hosts, purine salvage pathways have long been considered an attractive chemotherapeutic target. Recently, the discovery of specific transition-state inhibitors, the interest in antiviral nucleoside analogues due to AIDS and their potential in lymphoproliferative diseases gave a new impulse to this research field. Among the patents disclosed recently, only iminoribitol derivatives have documented antiparasitic activities, especially against nucleoside N-hydrolases (NH), purine nucleoside phosphorylase (PNP) and also against 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAP), an enzyme at the border of polyamine biosynthesis and purine salvage. Disclosed compounds with modifications of the pentose ring aimed to mimic ATP, are only expected to have an antiparasitic activity. The last group of patents consists of carboxamidines and inhibitors of nucleoside transporters with potential antiparasitic effect. Antiparasite chemotherapy should benefit from the ongoing research in this field, if these promising molecules are effectively tested on parasite models. 相似文献