Chemotherapeutic Agents with Enhanced Selectivity for the Tumor Microenvironment

对肿瘤微环境具有增强选择性的化疗药物

• 批准号: 8458885
• 负责人: Kevin G. Pinney
• 金额: $ 26.6万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458885
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adherence; Affect; Aftercare; Antibodies; Antineoplastic Agents; Area; Binding; Biochemical; Biological; Biological Assay; Bioluminescence; Blood Vessels; Blood flow; Breast Adenocarcinoma; Breast Cancer Cell; Cancer cell line; Carboplatin; Cell Culture Techniques; Cell Line; Cells; Cellular Morphology; Cessation of life; Characteristics; Clinic; Clinical; Clinical Trials; Collaborations; Colon Carcinoma; Combined Modality Therapy; Combretastatin A-4; Combretastatin A4 Phosphate; Coupled; DU145; Development; Dose; Drug Kinetics; Endothelial Cells; Evaluation; Event; Exhibits; Feedback; Fibronectins; Fluorescence; GTP Binding; Gadolinium; Goals; Growth; Growth Factor; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Histology; Housing; Human; Hydrochloride Salt; Image; Image Analysis; Immunofluorescence Immunologic; In Vitro; Individual; Indoles; Inhibitory Concentration 50; Investigation; Label; Laboratories; Lead; Left; Luciferases; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Mediating; Medical center; Methods; Microtubule Depolymerization; Microtubule stabilizing agent; Microtubules; Modeling; Molecular; Molecular Mechanisms of Action; Monitor; Morphology; Movement; Mus; National Cancer Institute; Nature; Necrosis; Nutrient; Ovarian Carcinoma; Oxygen; Paclitaxel; Pentetic Acid; Perfusion; Peripheral; Pharmaceutical Chemistry; Pharmacodynamics; Play; Positioning Attribute; Procedures; Prodrugs; Prostate carcinoma; Protocols documentation; Public Health; Relative (related person); Research; Residual Tumors; Reverse Transcriptase Polymerase Chain Reaction; Rho-associated kinase; Role; Route; Saline; Salts; Serum; Signal Transduction; Small Interfering RNA; Structure; Techniques; Texas; Time; Translating; Treatment Efficacy; Tube; Tubular formation; Tubulin; Tubulin Binding Agent; Umbilical vein; United States Food and Drug Administration; Universities; Validation; Variant; Vascular Endothelial Growth Factors; Vascular blood supply; Water; Western Blotting; Work; Xenograft Model; Xenograft procedure; analog; angiogenesis; base; bioluminescence imaging; cancer therapy; cancer type; cell growth; chemical synthesis; chemotherapeutic agent; chemotherapy; clinically relevant; clinically significant; cytotoxicity; density; design; feeding; fluorescence microscope; functional group; gadolinium oxide; improved; in vivo; innovation; inorganic phosphate; interdisciplinary approach; kinase inhibitor; knock-down; light emission; lung Carcinoma; matrigel; neoplastic cell; new growth; novel; polymerization; preclinical study; prevent; programs; public health relevance; research study; rho; rho GTP-Binding Proteins; rhotekin; screening; success; tissue oxygenation; tool; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): The discovery and development of new treatment agents for cancer that demonstrate enhanced selectivity for the tumor microenvironment continues to be an important and challenging goal in today's world. Vascular disrupting agents (VDAs) are compounds that are effective at selectively damaging the tumor vasculature while leaving the blood supply to healthy cells intact. These compounds effectively disrupt blood flow to tumors thus starving them of necessary nutrients and oxygen. This has the potential to ultimately lead to tumor death. While a number of VDAs are in human clinical trials, none have reached approval by the Food and Drug Administration (FDA), to date. Certain of these compounds function by inhibiting the assembly of tubulin into microtubules, thus causing morphology changes to the endothelial cells lining the tumor vasculature. This triggers a cascade of cell signaling events that results in catastrophic damage to the vessels feeding the tumor. The research presented in this proposal focuses on a highly collaborative, multidisciplinary approach to the synthesis and rapid biological evaluation of promising new VDAs. A combination of synthetic/medicinal chemistry to prepare newly designed compounds coupled with rapid biochemical and biological evaluation, including tumor imaging (BLI and MRI), will provide a strong platform for the discovery of new and improved VDAs. Importantly, this type of research may ultimately translate to the clinic providing additional chemotherapeutic agents that have enhanced selectivity towards the tumor microenvironment.

描述（由申请人提供）：发现和开发新的癌症治疗剂，证明对肿瘤微环境的选择性增强，仍然是当今世界的一个重要且具有挑战性的目标。血管破坏剂 (VDA) 是一种化合物，可有效选择性地破坏肿瘤血管系统，同时保持健康细胞的血液供应完好无损。这些化合物有效地扰乱了肿瘤的血流，从而使它们缺乏必要的营养和氧气。这有可能最终导致肿瘤死亡。虽然许多 VDA 正在进行人体临床试验，但迄今为止尚未获得美国食品和药物管理局 (FDA) 的批准。这些化合物中的某些通过抑制微管蛋白组装成微管来发挥作用，从而引起肿瘤脉管系统内皮细胞的形态变化。这会引发一系列细胞信号传导事件，从而对肿瘤的血管造成灾难性的损害。该提案中提出的研究重点是采用高度协作、多学科的方法来合成和快速生物学评估有前景的新型 VDA。将合成/药物化学结合起来制备新设计的化合物，再加上快速生化和生物学评估，包括肿瘤成像（BLI 和 MRI），将为发现新的和改进的 VDA 提供强大的平台。重要的是，此类研究最终可能会转化为临床，提供额外的化疗药物，增强对肿瘤微环境的选择性。