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Comparison of recombinant and synthetically formed monoclonal antibody-β-lactamase conjugates for anticancer prodrug activation

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BIOCONJUGATE CHEMISTRY 1999年第6期10卷 1084-1089页

作者： Kerr, DE Vrudhula, VM Svensson, HP Siemers, NO Senter, PD Bristol Myers Squibb Pharmaceut Res Inst Seattle WA 98121 USA

Conjugates of the L49 monoclonal antibody (binds to the p97 antigen on melanomas and carcinomas) were formed by attaching Enterobacter cloacae beta-lactamase (bL) to the L49-Fab' fragment using a heterobifunctional cross-linking reagent or by linking the enzyme to L49-sFv using DNA recombinant technology. The conjugates thus formed, L4g-Fab'-bL and L49-sFv-bL, were designed to activate cephalosporin containing anticancer prodrugs at the surfaces of antigen positive tumor cells. Results from in vitro experiments using two lung carcinoma cell lines demonstrated that the conjugates were equally active in effecting the release of phenylenediamine mustard from the cephalosporin nitrogen mustard prodrug CCM. While treatment with either of the conjugates combined with the maximum tolerated doses of CCM led to cures of established SN12P renal cell carcinoma tumors in nude mice, only the L49-sFv-bL conjugate maintained its ability to do so at 1/4 the maximum tolerated dose of CCM. L49-sFv-bL was also superior to L49-Fab'-bL in the 1934J renal cell carcinoma tumor model and was shown to be quite active in two in vivo models of human lung carcinoma. These results demonstrate that the recombinant fusion protein leads to more pronounced therapeutic windows than the chemical conjugate and is active in an array of human tumor models.

关键词：抗体单克隆/化学抗体单克隆/遗传学抗体单克隆/代谢抗原肿瘤/分析抗原肿瘤/代谢抗肿瘤药/代谢癌肾细胞/药物疗法癌肾细胞/免疫学头孢菌素类/代谢头孢菌素类/治疗应用肾肿瘤/药物疗法肾肿瘤/免疫学肺肿瘤/药物疗法肺肿瘤/免疫学黑色素瘤/免疫学小鼠裸肿瘤蛋白质类/分析肿瘤蛋白质类/代谢肿瘤移植氮芥化合物/代谢氮芥化合物/治疗应用药物前体/代谢重组蛋白质类肿瘤细胞培养的 β内酰胺酶类/化学 β内酰胺酶类/遗传学动物人类小鼠

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Accelerated clearance of polyethylene glycol-modified proteins by anti-polyethylene glycol IgM

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BIOCONJUGATE CHEMISTRY 1999年第3期10卷 520-528页

作者： Cheng, TL Wu, PY Wu, MF Chern, JW Roffler, SR Acad Sinica Inst Biomed Sci Taipei Taiwan Natl Def Med Ctr Grad Inst Life Sci Taipei Taiwan Natl Taiwan Univ Coll Med Taipei 10018 Taiwan Natl Taiwan Univ Sch Pharm Taipei 10764 Taiwan

Tumor therapy by the preferential activation of a prodrug at tumor cells targeted with an antibody-enzyme conjugate may allow improved treatment efficacy with reduced side effects. We examined antibody-mediated clearance of poly(ethylene glycol)-modified beta-glucuronidase (beta G-sPEG) as a method to reduce serum concentrations of enzyme and minimize systemic prodrug activation. Enzyme-linked immunosorbent assay and immunoblot analysis of two monoclonal antibodies generated by immunization of BALB/c mice with an antibody-beta G-sPEG conjugate showed that mAb 1E8 (IgG1) bound beta G and beta G-sPEG whereas mAb AGP3 (IgM) bound poly(ethylene glycol). Neither antibody affected the beta G activity. mAb 1E8 and AGP3 were modified with 36 and 208 galactose residues (1E8-36G and AGP3-208G) with retention of 72 and 48% antigen-binding activity, respectively, to target immune complexes to the asialoglycoprotein receptor on liver cells. mAb 1E8 and AGP3 cleared beta G-PEG from the circulation of mice as effectively as 1E8-36G and AGP3-208G, respectively. mAb AGP3, however, cleared beta G-sPEG more completely and rapidly than 1E8, reducing the serum concentration of beta G-sPEG by 38-fold in 8 h. AGP3 also reduced the concentration of an antibody-beta G-sPEG conjugate in blood by 280-fold in 2 h and 940-fold in 24 h. AGP3-mediated clearance did not produce obvious damage to liver, spleen, or kidney tissues. In addition, AGP3 clearance of beta G-sPEG before administration of BHAMG, a glucuronide prodrug of p-hydroxyaniline mustard, prevented toxicity associated with systemic activation of the prodrug based on mouse weight and blood cell numbers. AGP3 should be generally useful for accelerating the clearance of PEG-modified proteins as well as for improving the tumor/blood ratios of antibody-beta G-PEG conjugates for glucuronide prodrug therapy of cancer.

关键词：苯胺氮芥/类似物和衍生物苯胺氮芥/代谢抗肿瘤药/代谢半乳糖/化学半乳糖/免疫学葡糖醛酸糖苷酶/化学葡糖醛酸糖苷酶/药代动力学免疫球蛋白M/免疫学免疫球蛋白M/代谢代谢清除率小鼠近交BALBC 聚乙烯二醇类/化学聚乙烯二醇类/药代动力学药物前体/代谢动物女(雌)性小鼠

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Molecular analysis of yeast and human type II topoisomerases - Enzyme-DNA and drug interactions

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JOURNAL OF BIOLOGICAL CHEMISTRY 1999年第40期274卷 28246-28255页

作者： Strumberg, D Nitiss, JL Dong, JW Kohn, KW Pommier, Y NCI Mol Pharmacol Lab Div Basic Sci NIH Bethesda MD 20892 USA St Jude Childrens Res Hosp Dept Mol Pharmacol Memphis TN 38105 USA

The DNA sequence selectivity of topoisomerase LI (top2)-DNA cleavage complexes was examined for the human (top2 alpha), yeast, and Escherichia coli (i.e, gyrase) enzymes in the absence or presence of anticancer or antibacterial drugs. Species-specific differences were observed for calcium-promoted DNA cleavage. Similarities and differences in DNA cleavage patterns and nucleic acid sequence preferences were also observed between the human, yeast, and E. coli top2 enzymes in the presence of the non-intercalators fluoroquinolone CP-115,953, etoposide, and azatoxin and the intercalators amsacrine and mitoxantrone. Additional base preferences were generally observed for the yeast when compared with the human top2 alpha enzyme. Preferences in the immediate flanks of the top2-mediated DNA cleavage sites are, however, consistent with the drug stacking model for both enzymes. We also analyzed and compared homologous mutations in yeast and human top2, i.e. Ser(740) --> Trp and Ser(763) --> Trp, respectively. Both mutations decreased the reversibility of the etoposide-stabilized cleavage sites and produced consistent base sequence preference changes. These data demonstrate similarities and differences between human and yeast top2 enzymes. They also indicate that the structure of the enzyme/DNA interface plays a key role in determining the specificity of top2 poisons and cleavage sites for both the intercalating and non-intercalating drugs.

关键词：抗菌药抗感染药/代谢抗肿瘤药/代谢碱基序列钙/代谢 DNA/代谢 DNA引物 DNA拓扑异构酶类 Ⅱ型/遗传学 DNA结合蛋白质类/遗传学大肠杆菌/酶学诱变定点酿酒酵母菌/酶学人类

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MYCN enhances P-gp/MDR1 gene expression in the human metastatic neuroblastoma IGR-N-91 model

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 321-331页

作者： Blanc, E Goldschneider, D Ferrandis, E Barrois, M Le Roux, G Leonce, S Douc-Rasy, S Bénard, J Raguénez, G Inst Gustave Roussy UMR 8126 Serv Genet Dept Biol F-94805 Villejuif France Univ Paris Sud 11 CNRS UMR 8126 Paris France Inst Gustave Roussy Inst Federat Rech F-94805 Villejuif France Inst Rech Int Servier Dept Biol Croissy sur Seine France

Despite intensive high-dose chemotherapy and autologous hematopoietic stem cell transplantation, disseminated neuroblastoma (NB) frequently proves to be chemosensitive but not chemocurable, and more often so in NB-presenting MYCN amplification. To assess the direct relationship between the MYCN oncogene and chemoresistance acquisition during NB metastatic dissemination, we have studied MYCN and MDR1 genes using the human IGR-N-91 ectopic xenograft metastatic model. This characterized experimental in vitro model includes human neuroblasts derived from a subcutaneous primary tumor xenograft, disseminated blood cells, myocardium, and bone marrow (BM) metastatic cells. All IGR-N-91-derived neuroblasts harbor a consistent MYCN genomic content but, unlike primary tumor xenograft, BM, and myocardium, human neuroblasts elicit a concomitant increase in MYCN and MDR1 transcripts levels, consistent with chemoresistance phenotype and active P-gp. In contrast, no variation of MRP1 transcript level was associated with the metastatic process in this model. Using an MDR1 promoter-CAT construct, we have shown that the MycN protein activates MDR1 transcription both in exogenous transient MYCN-transfected SK-N-SH cells and in endogenous BM metastatic neuroblasts with an increase in the MYCN transcript level. Band-shift experiments indicate that IGR-N-91 cells enriched with the MycN transcription factor do bind to two E-box motifs localized within the MDR1 promoter. Overall, our data indicate that MYCN overexpression increment contributes to the acquired drug resistance that occurs throughout the NB metastatic process.

关键词：抗肿瘤药/代谢抗肿瘤药/治疗应用抗药性多药/生理学基因表达调控肿瘤小鼠裸肿瘤转移肿瘤移植神经母细胞瘤/药物疗法神经母细胞瘤/代谢神经母细胞瘤/病理学核蛋白质类/遗传学核蛋白质类/代谢癌基因蛋白质类/遗传学癌基因蛋白质类/代谢启动区遗传移植异种肿瘤细胞培养的动物儿童人类男(雄)性小鼠

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Direct interaction between a quinoline derivative, MS-209, and multidrug resistance protein (MRP) in human gastric cancer cells

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第3期255卷 618-624页

作者： Nakamura, T Oka, M Aizawa, K Soda, H Fukuda, M Terashi, K Ikeda, K Mizuta, Y Noguchi, Y Kimura, Y Tsuruo, T Kohno, S Nagasaki Univ Sch Med Dept Internal Med 2 Nagasaki 8528501 Japan Niigata Univ Sch Med Dept Surg 1 Niigata 9518122 Japan Mitsui Pharmaceut Inst Biol Sci Chiba 2970017 Japan Univ Tokyo Inst Mol & Cellular Biosci Bunkyo Ku Tokyo 1130032 Japan

MS-209 is a novel quinoline derivative reversing P-glycoprotein-mediated multidrug resistance (MDR). We investigated the interaction between MS-209 and multidrug resistance protein (MRP) in MRP-overexpressing human gastric cancer cells. me measured [H-3]leukotriene C-4 uptake into the membrane vesicles of the cells and intracellular calcein and [H-3]vincristine accumulation with or without MS-209. In muti-drug-resistant MKN45R0.8 cells selected by doxorubicin, MS-209 dose dependently reduced MRP-mediated [H-3]leukotriene C-4 uptake and increased calcein accumulation. In both resistant and unselected cell lines expressing the MRP gene, MS-209 increased [H-3]vincristine accumulation in proportion with the level of MRP mRNA expression and enhanced the cytotoxicity of etoposide, doxorubicin, and vincristine. The reversal effects correlated with the level of MRP mRNA expression in these cells. Our results indicate that MS-209 effectively reverses intrinsic and acquired MRP-mediated MDR of gastric cancer cells by interacting directly with MRP. (C) 1999 Academic Press.

关键词： ATP结合匣式转运子/遗传学 ATP结合匣式转运子/代谢抗肿瘤药/代谢多柔比星/代谢抗药性多药/遗传学依托泊甙/代谢荧光素类/代谢基因表达调控肿瘤/遗传学基因 MDR/遗传学白三烯C4/药代动力学多药耐药相关蛋白质类肿瘤蛋白质类/代谢丙磺舒/药理学喹啉类/代谢喹啉类/药理学 RNA 信使/遗传学胃肿瘤/代谢肿瘤细胞培养的长春新碱/代谢人类

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Induction of the cytochrome P450 gene CYP26 during mucous cell differentiation of normal human tracheobronchial epithelial cells

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MOLECULAR PHARMACOLOGY 2000年第3期58卷 483-490页

作者： Kim, SY Adachi, H Koo, JS Jetten, AM NIEHS Cell Biol Sect Pulm Pathobiol Lab NIH Res Triangle Pk NC 27709 USA

In this study, the expression of CYP26 is examined in relation to retinoid-induced mucosecretory differentiation in human tracheobronchial epithelial (HTBE) cells and compared with that in human lung carcinoma cell lines. In HTBE cells, retinoic acid (RA) inhibits squamous differentiation and induces mucous cell differentiation as indicated by the suppression of transglutaminase I and increased expression of the mucin gene MUC2. The latter is accompanied by increased expression of CYP26 mRNA. RA is required but not sufficient to induce RAR beta, CYP26, and MUC2 mRNA because induction is only observed in confluent but not in logarithmic cultures, suggesting that additional factors are critical in their regulation. CYP26 mRNA can be induced by the RAR-selective retinoid 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)-benzoic acid (TTAB) but not by the RXR-selective retinoid SR11217 or the anti-activator-protein 1-selective retinoid SR11302. RAR alpha-, beta-, and gamma-selective retinoids are able to induce CYP26;this induction is inhibited by the RAR alpha-selective antagonist Ro41-5253. TTAB is able to induce CYP26 mRNA expression in only a few of the lung carcinoma cell lines tested. The lack of CYP26 induction in many carcinoma cell lines may relate to previously reported defects in the retinoid-signaling pathway. The induction of CYP26 correlated with increased metabolism of RA into 18-hydroxy-, 4-oxo-, and 4-hydroxy-RA. The latter metabolite was shown to be able to induce MUC2 and MUC5AC expression in HTBE cells. Our results demonstrate that in normal HTBE cells, CYP26 expression is closely associated with mucous cell differentiation and that many lung carcinoma cells exhibit increased RA metabolism and a defective regulation of CYP26.

关键词：抗肿瘤药/代谢抗肿瘤药/药理学支气管/细胞学支气管/生理学细胞分化/药物作用细胞分化/遗传学细胞系细胞色素P450酶系统/生物合成细胞色素P450酶系统/遗传学上皮细胞/细胞学上皮细胞/生理学基因表达调控/药物作用肺肿瘤 RNA 信使/生物合成受体维甲酸/代谢维甲酸/类似物和衍生物维甲酸/代谢维甲酸/药理学肿瘤细胞培养的人类

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Preparation, ^99mTc-labeling, and in vitro characterization of HYNIC and N₃S modified RC-160 and [Tyr³]octreotide

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BIOCONJUGATE CHEMISTRY 1999年第3期10卷 431-438页

作者： Decristoforo, C Mather, SJ St Bartholomews Hosp Nucl Med Res Lab London EC1 7BE England

The synthesis of conjugates of two somatostatin analogues, RC-160 and [Tyr(3)]octreotide with different bifunctional chelators for labeling with Tc-99m, is described. Conjugates with hydrazinonicotinamide (HYNIC) and two N3S compounds (benzoyl MAG3 and a N3S adipate derivative) were prepared on a small scale with high purity allowing evaluation of different bifunctional chelators on the same peptide without extensive peptide synthesis. High in vitro stability and retained binding affinity was found for all conjugates except for the N3S adipate. Peptide conjugates could be labeled at high specific activities (>1 Ci/mu mol) with Tc-99m, and different coligands were explored for the HYNIC conjugates. The resulting radiolabeled complexes were highly stable and showed binding affinity to somatostatin receptors in the nanomolar range. Varying labeling yield, stability, lipophilicity, and isomerism were found for different coligands used for labeling HYNIC conjugates, with lower lipophilicity, higher stability, and fewer coordination isomers for EDDA and tricine/nicotinic acid as ternary coligand compared to tricine. In particular, HYNIC complexes showed promising results for further in vivo evaluation.

关键词：抗肿瘤药/化学抗肿瘤药/代谢结合竞争性细胞系螯合剂交联试剂甘氨酸/类似物和衍生物甘氨酸/化学肼类/化学烟酰胺/类似物和衍生物烟酰胺/化学奥曲肽/化学奥曲肽/代谢受体生长抑素/代谢生长抑素/类似物和衍生物生长抑素/化学生长抑素/代谢锝酪氨酸/化学动物人类小鼠大鼠

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Triazene drug metabolites. Part 17: Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes

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BIOORGANIC & MEDICINAL CHEMISTRY 2000年第7期8卷 1719-1725页

作者： Carvalho, E Francisco, AP Iley, J Rosa, E Univ Lisbon Fac Farm CECF P-1600 Lisbon Portugal Open Univ Dept Chem Milton Keynes MK7 6AA Bucks England

A series of 3-acyloxymethyloxycarbonyl-1-aryl-3-methyltriazenes 5 was synthesised by the sequential reaction of 1-aryl-3-methyltriazenes with (i) chloromethyl chloroformate, (ii) NaI in dry acetone, and (iii) either the silver carboxylate or the carboxylic acids in the presence of silver carbonate. The hydrolysis of these compounds was studied in pH 7.7 isotonic phosphate buffer and in human plasma. Triazene acyloxycarbamates demonstrated their ability to act as substrates for plasma enzymes. For compound 5f, a pH-rate profile was obtained which showed the hydrolysis to involve acid-base catalysis. The reaction is also buffer catalysed. Thus, at pH 7.7, pH-independent, base-catalysed and buffer-catalysed processes all contribute to the hydrolysis reaction. The sensitivity of the hydrolysis reaction to various structural parameters in the substrates indicates that hydrolysis occurs at the ester rather than the carbamate functionality. In plasma, the rates of hydrolysis correlate with partition coefficients, the most lipophilic compounds being the most stable. An aspirin derivative suffers two consecutive enzymatic reactions, the scission of the aspirin acetyl group being followed by the scission of the acyloxy ester group. These results indicate that triazene acyloxymethyl carbamates are prodrugs of the antitumour monomethyltriazenes. They combine chemical stability with a rapid enzymatic hydrolysis, and are consequently good candidates for further prodrug development. Moreover, this type of derivative allowed the synthesis of mutual prodrugs, associating the antitumour monomethyltriazenes with anti-inflammatory NSAIDs as well as with the anticancer agent butyric acid. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：抗肿瘤药/化学合成抗肿瘤药/代谢阿司匹林/代谢阿司匹林/药理学氨甲酸酯类/化学合成氨甲酸酯类/化学氨甲酸酯类/代谢氨甲酸酯类/药理学色谱法高压液相药物稳定性氢离子浓度水解作用动力学血浆/酶学药物前体/化学合成药物前体/代谢药物前体/药代动力学构效关系三氮烯/化学合成三氮烯/代谢三氮烯/药代动力学三氮烯/药理学人类

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Cartilage-derived growth factor and antitumor factor: Past, present, and future studies

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 1999年第1期259卷 1-7页

作者： Suzuki, F Osaka Univ Osaka 5650871 Japan

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Thrombospondin-2: A potent endogenous inhibitor of tumor growth and angiogenesis

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第26期96卷 14888-14893页

作者： Streit, M Riccardi, L Velasco, P Brown, LF Hawighorst, T Bornstein, P Detmar, M Massachusetts Gen Hosp Cutaneous Biol Res Ctr Charlestown MA 02129 USA Massachusetts Gen Hosp Dept Dermatol Charlestown MA 02129 USA Harvard Univ Sch Med Charlestown MA 02129 USA Harvard Univ Sch Med Boston MA 02215 USA Beth Israel Deaconess Med Ctr Dept Pathol Boston MA 02215 USA Univ Washington Dept Biochem Seattle WA 98195 USA

Recent evidence suggests a potential role for thrombospondin-2 (TSP-2), a matricellular glycoprotein, in the regulation of primary angiogenesis. To directly examine the biological effect of TSP-2 expression on tumor growth and angiogenesis, human A431 squamous cell carcinoma cells, which do not express TSP-2, were stably transfected with a murine TSP-2 expression vector or with vector alone. A431 cells expressing TSP-2 did not show an altered growth rate, colony-forming ability, or susceptibility to induction of apoptosis in vitro. However, injection of TSP-2-transfected clones into the dermis of nude mice resulted in pronounced inhibition of tumor growth that was significantly stronger than the inhibition observed in A431 clones stably transfected with a thrombospondin-1 (TSP-1) expression vector, and combined overexpression of TSP-1 and TSP-2 completely prevented tumor formation. Extensive areas of necrosis were observed in TSP-2-expressing tumors, and both the density and the size of tumor vessels were significantly reduced, although tumor cell expression of the major tumor angiogenesis factor, vascular endothelial growth factor, was maintained at high levels. These findings establish TSP-2 as a potent endogenous inhibitor of tumor growth and angiogenesis.

关键词：血管生成抑制剂/代谢抗肿瘤药/代谢癌鳞状细胞/预防和控制小鼠近交BALBC 小鼠裸肿瘤实验性/预防和控制新生血管化病理性/预防和控制重组蛋白质类/代谢凝血酶敏感蛋白类/遗传学凝血酶敏感蛋白类/代谢肿瘤细胞培养的动物人类小鼠

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