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Reactive oxygen species (ROS) are involved in the pathophysiology of fulminant hepatic failure. Therefore, we developed polyethylene glycol-conjugated bovine serum albumin with multiple reduced thiols (PEG-BSA-SH) for the treatment of fulminant hepatic failure. As a long-circulating ROS scavenger, PEG-BSA-SH effectively scavenged highly reactive oxygen species and hydrogen peroxide in buffer solution. PEG-BSA-SH showed a long circulation time in the plasma after intravenous injection into mice. Fulminant hepatic failure was induced by intraperitoneal injection of lipopolysaccharide and d-galactosamine (LPS/d-GalN) into mice. The LPS/d-GalN-induced elevation of plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels was significantly inhibited by a bolus intravenous injection of PEG-BSA-SH. Furthermore, the changes in hepatic lipid peroxide and hepatic blood flow were effectively suppressed by PEG-BSA-SH. In contrast, l-cysteine, glutathione, and dithiothreitol, three traditional reduced thiols, had no statistically significant effects on the serum levels of ALT or AST. These findings indicate that PEG-BSA-SH is a promising ROS scavenger and useful in the treatment of fulminant hepatic failure. 相似文献
4.
M. G. Rosenblum Lawrence Cheung S. K. Kim Kalpana Mujoo Nicholas J. Donato James L. Murray 《Cancer immunology, immunotherapy : CII》1996,42(2):115-121
The development of cellular resistance to immunotoxins has been demonstrated in a variety of models and can involve a number
of mechanisms. For the present study, an immunotoxin was utilized composed of an antimelanoma antibody ZME-018 recognizing
a 240-kDa surface glycoprotein (gp 240) and the plant toxin gelonin. Human melanoma cells (A375-M) were grown in the presence
of increasing amounts of ZME-gelonin and a clonal variant (A-375-ZR) was developed that was 100-fold resistant to ZME-gelonin
compared to parental cells. Scatchard analysis showed that the A375-M parental cells had 260×103 ZME-gelonin-binding sites/cell with relatively low affinity (5 nM). In contrast, resistant A375-ZR cells demonstrated a reduced
number of low-affinity sites (160×103/cell), but showed a small number (47×103) of higher-affinity sites (0.8 nM). Internalization rates and degradation rates of 125I-labeled ZME-gelonin were identical in both the parental and resistant cells. A375-ZR cells were found to be more resistant
to vincristine and doxorubicin than were parental cells. Both cell lines were almost equally sensitive to native gelonin,
5-fluorouracil (5-FU), cisplatin, melphalan, carmustine, interferon γ (IFNγ) and IFNα. In addition, both cell lines were equally
sensitive to another gelonin-antibody conjugate that binds to cell-surface, GD2 (antibody 14G2A). However, resistant cells were twice as sensitive to the cytotoxic effects of etoposide than were parental cells. Finally,
a variety of agents were tested in combination with ZME-gelonin against A375-ZR cells in an attempt to identify agents to
augment immunotoxin cytotoxic effects against resistant cells. The agents 5-FU, cisplatin, IFNγ, IFNα, and etoposide were
the most effective in augmenting the cytotoxicity of ZME-gelonin against resistant cells. These studies suggest that development
of resistance to one immunotoxin does not cause development of cross-resistance to other gelonin immunotoxins. Further, specific
biological response modifiers and chemotherapeutic agents may be effective in augmenting the effectiveness of immunotoxins
and specifically targeting or reducing the emergence of immunotoxin-resistant cells.
Received: 15 March 1995 / Accepted: 28 November 1995 相似文献
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《Bioorganic & medicinal chemistry》2014,22(19):5234-5240
Through synthetic lethality screening of isogenic cell lines with and without the oncogenic KRAS gene and through lead compound optimization, we recently developed a novel anticancer agent designated NSC-743380 (oncrasin-72) that has promising in vitro and in vivo anticancer activity in a subset of cancer cell lines, including KRAS-mutant cancer cells. However, NSC-743380 tends to form dimers, which dramatically reduces its anticancer activity. To improve the physicochemical properties of NSC-743380, we synthesized a prodrug of NSC-743380, designated oncrasin-266, by modifying NSC-743380 with cyclohexylacetic acid and evaluated its in vitro and in vivo properties. Oncrasin-266 spontaneously hydrolyzed in phosphate-buffered saline in a time-dependent manner and was more stable than NSC-743380 in powder or stock solutions. In vivo administration of oncrasin-266 in mice led to the release of NSC-743380 which improved the pharmacokinetics of NSC-743380. Tissue distribution analysis revealed that oncrasin-266 was deposited in liver, whereas released NSC-743380 was detected in liver, lung, kidney, and subcutaneous tumor. Oncrasin-266 was better tolerated in mice at a higher dose level treatment (150–300 mg/kg, ip) than the parent agent was, suggesting that the prodrug reduced the acute toxicity of the parent agent. Our results demonstrated that the prodrug strategy could improve the stability, pharmacokinetic properties, and safety of NSC-743380. 相似文献
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Electrical pulses have been widely used in biomedical fields, whose applications depend on the parameters such as durations and electric intensity. Conventional electroporation (0.1-1 kV/cm, 100 μs) has been used in cell fusion, transfection and electrochemotherapy. Recent studies with high-intensity (MV/cm) electric field applications with durations of several tens of nanoseconds can affect intracellular signal transduction and intracellular structures with plasma intact, resulting in an application of intracellular manipulation. The most recent development is the finding that parameters between those two ranges could be used to induce apoptosis of cancer cells. Proposal of apoptosis induction and tumor inhibition has advantages to pursue the treatment of cancer free of cytotoxic drugs. 相似文献
7.
《Bioorganic & medicinal chemistry》2016,24(15):3291-3303
The characterization of the target proteins of drug molecules has become an important goal in understanding its mode of action and origin of side effects due to off-target binding. This is especially important for covalently binding drugs usually containing electrophilic moieties, which potentially can react with nucleophilic residues found in many proteins. This review gives a comprehensive overview of the use of activity-based protein profiling (ABPP) as an efficient tool for the target identification of covalently binding drugs. 相似文献
8.
《Bioorganic & medicinal chemistry》2016,24(2):294-303
New cyclic RGD peptide-anticancer agent conjugates, with different chemical functionalities attached to the parent peptide were synthesized in order to evaluate their biological activities and to provide a comparative study of their drug release profiles. The Integrin binding c(RGDfK) penta-peptide was used for the synthesis of Camptothecin (CPT) carbamate and Chlorambucil (CLB) amide conjugates. Substitution of the amino acid Lys with Ser resulted in a modified c(RGDfS) with a new attachment site, which enabled the synthesis of an ester CLB conjugate. Functional versatility of the conjugates was reflected in the variability of their drug release profiles, while the conserved RGD sequence of a selective binding to the αv integrin family, likely preserved their recognition by the Integrin and consequently their favorable toxicity towards targeted cancer cells. This hypothesis was supported by a computational analysis suggesting that all conjugates occupy conformational spaces similar to that of the Integrin bound bio-active parent peptide. 相似文献
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摘要 目的:探讨肺癌合并肺部感染患者病原菌分布、耐药性分析及血清炎性因子检测的临床意义。方法:选取我院于2018年6月~2020年3月期间收治的肺癌合并肺部感染患者90例为感染组,选取同期我院收治的肺癌未合并肺部感染患者100例为肺癌组,选取同期于我院进行体检的健康志愿者60例为对照组,对肺癌合并肺部感染患者的感染病原菌类型进行总结分析,分析常见病原菌药敏试验结果,统计病原菌耐药率。对比三组受试者的炎性因子水平。结果:90例肺癌合并肺部感染患者的送检痰液标本共检出100株病原菌,100株病原菌中以革兰阴性菌为主,其次为革兰阳性菌、真菌,分别占比63.00%、22.00%、15.00%。肺炎克雷伯菌、鲍氏不动杆菌、铜绿假单胞菌对亚胺培南的耐药率较低,对氨苄西林、甲氨苄啶的耐药率均较高。凝固酶阴性葡萄球菌、金黄色葡萄球菌对万古霉素的耐药率较高,对左氧氟沙星的耐药率较低。白色念珠菌、热带念珠菌对两性霉素B、氟康唑、酮康唑、伊曲康唑的耐药率均较低。感染组、肺癌组的血清白介素-6(IL-6)、降钙素原(PCT)、肿瘤坏死因子-α(TNF-α)水平均高于对照组,且感染组以上指标水平高于肺癌组(P<0.05)。结论:肺癌合并肺部感染患者体内病原菌种类繁多,对常见抗菌药物的耐药性存在差异,且患者体内存在较强的炎性反应,临床应根据药敏结果合理应用抗菌药物 。 相似文献