Analytical Method Develop.--Anticancer /Antiviral Agents

分析方法开发--抗癌/抗病毒药物

• 批准号: 6558335
• 负责人: William Douglas Figg
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6558335
• 关键词: analytical chemistry; angiogenesis inhibitors; antineoplastics; antiviral agents; butyrates; chromatography; cofactor; drug screening /evaluation; enzyme linked immunosorbent assay; human tissue; immunoconjugates; melphalan; method development; paclitaxel; patient oriented research; pharmacokinetics; phenylacetates; phenylbutyrates; phenylcarboxylate; radioimmunoassay; spectrometry; staurosporine; suramin; tamoxifen; thalidomide; tissue inhibitor of metalloproteinases; vinblastine; zidovudine

The first priority in characterizing the pharmacokinetics of an agent is to have a reliable and reproducible analytical method for quantitating agents in biological fluids and tissues. Our research efforts have been devoted to the development of agents that specifically target the aberrant biology of neoplasms, e.g., altered signal transduction pathways, inhibition of angiogenesis, or binding of peptide growth factors involved in the genesis of the malignant phenotype. The successful development of such compounds requires extensive use of pharmacokinetic and pharmacodynamic concepts. In addition, determining the concentration of these agents in tissue or plasma is of the utmost importance in correlating efficacy or toxicity. This differs from the development of standard cytotoxic agents in which myelosuppression is the predominate complication noted and concentration analysis is not emphasized. Within the Clinical Pharmacology Research Core (CPRC), HPLC is often utilized to develop analytical methods. We use state of the art equipment to support our translational pharmacokinetic/ pharmacodynamic research. This includes several Liquid Chromatograph systems equipped with photo diode array detectors which are controlled by HP Chemstation software (run on pentium computers), as well as precision fluorescence, LC-MSD (mass spectroscopy detector), and electrochemical detectors. We also utilize GC techniques and collaborate with laboratories that have NMR and AAS instruments. In some cases, ELISA and RIA are the preferred method of quantification. The CPRC has developed analytical methods for monitoring TNP-470, phenylacetate, phenylbutyrate, tamoxifen, UCN-01, CAI, thalidomide, COL-3 and coenzyme Q10. Furthermore, we are also quantitating suramin, paclitaxel, melphalan, docetaxel, vinblastine, perifosine, SU5416, 2ME, MS275, ketoconazole, CC5013, and AZT from biological fluids. The laboratory is also working in collaboration on the development of two RIA assay methods: PSC 833 and ricin immunotoxins (CD19 and CD22). Lastly, the CPRC is active in measuring plasma concentrations of numerous cytokines and growth factors by ELISA (VEGF, bFGF, TGFb, TNF, MMP2, MMP9).

表征一种制剂的药代动力学的首要任务是有一种可靠和可重复性的分析方法来定量生物体液和组织中的制剂。我们一直致力于开发针对肿瘤异常生物学的药物，例如，改变信号转导途径，抑制血管生成，或结合参与恶性表型发生的多肽生长因子。这类化合物的成功开发需要广泛使用药代动力学和药效学概念。此外，确定这些药物在组织或血浆中的浓度对于关联疗效或毒性是至关重要的。这与标准细胞毒药物的发展不同，在标准细胞毒药物中，骨髓抑制是主要的并发症，不强调浓度分析。在临床药理学研究核心(CPRC)中，高效液相色谱法经常被用来开发分析方法。我们使用最先进的设备来支持我们的翻译药代动力学/药效学研究。这包括几个配备光电二极管阵列检测器的液态色谱仪系统，这些检测器由惠普化学站软件(在奔腾计算机上运行)控制，以及精密荧光、LC-MSD(质谱仪检测器)和电化学检测器。我们还利用GC技术，并与拥有核磁共振和原子吸收光谱仪器的实验室合作。在某些情况下，酶联免疫吸附试验和放射免疫分析是首选的定量方法。CPRC开发了监测TNP-470、苯乙酸酯、苯丁酸酯、他莫昔芬、UCN-01、CAI、沙利度胺、Col-3和辅酶Q10的分析方法。此外，我们还从生物体液中定量苏拉明、紫杉醇、马法兰、多西紫杉醇、长春花碱、周福辛、SU5416、2Me、MS275、酮康唑、CC5013和AZT。该实验室还在合作开发两种放射免疫分析方法：PSC 833和蓖麻免疫毒素(CD19和CD22)。最后，CPRC通过酶联免疫吸附试验检测血浆中多种细胞因子和生长因子(血管内皮生长因子、碱性成纤维细胞生长因子、肿瘤生长因子b、肿瘤坏死因子、基质金属蛋白酶2、基质金属蛋白酶9)的浓度。