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首页> 外文学位 >Strategies in anti-angiogenic cancer therapy: Exploiting the role of vascular endothelial growth factor (VEGF) in tumor growth and endothelial cell survival.
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Strategies in anti-angiogenic cancer therapy: Exploiting the role of vascular endothelial growth factor (VEGF) in tumor growth and endothelial cell survival.

机译：抗血管生成癌治疗的策略：利用血管内皮生长因子（VEGF）在肿瘤生长和内皮细胞存活中的作用。

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摘要

The research presented in this dissertation focuses on the critical evaluation of anti-angiogenic cancer therapies. First, this project investigated the general applicability of targeting VEGF receptors as a means of experimental cancer treatment. Preliminary results showed that chemical conjugates of VEGF with Diphtheria Toxin (DT) effectively inhibited endothelial cell proliferation, angiogenesis and solid tumor growth. However, further studies were necessary to critically evaluate the potential application of these constructs in a clinical setting. Therefore, I determined the activity of this vascular targeting agent in various in vivo tumor models. VEGF-Toxin conjugate significantly inhibited tumor growth of established cancers, which correlated with decreased tumor microvessel density. In addition, VEGF-Toxin constructs proved to be effective tumor preventive agents in a spontaneous tumorigenesis model. Here, I also identified important initial pharmacological and pharmacokinetic parameters. I established a dose-dependent toxicity profile, which will have a significant impact on the further development of this construct. Finally, I evaluated the use of a smaller molecular weight VEGF isoform as an alternative targeting moiety with potentially decreased toxicity.; In the second part of this dissertation, I investigated the therapeutic potential of combining chemotherapeutic agents with anti-angiogenic approaches. I discovered that Carboplatin directly influences endothelial cells and tumor vessels by inducing the expression of the endothelial cell specific survival factor VEGF. Up-regulation of VEGF might protect tumor vessels from undergoing apoptosis and as a consequence counteracts the cytotoxic effects of the drug. Therefore, concomitant neutralization of the survival factor by specific antibodies results in the synergistic inhibition of tumor growth. Results obtained from these studies should have significant implications on how future therapies for cancer might be designed to maximize the therapeutic effect.
机译：本文的研究集中在抗血管生成癌治疗的关键评价上。首先，该项目研究了靶向VEGF受体作为实验性癌症治疗手段的一般适用性。初步结果显示，VEGF与白喉毒素（DT）的化学缀合物可有效抑制内皮细胞增殖，血管生成和实体瘤生长。但是，需要进一步的研究来严格评估这些构建体在临床中的潜在应用。因此，我确定了这种血管靶向剂在各种 in vivo 肿瘤模型中的活性。 VEGF-毒素偶联物显着抑制已确立的癌症的肿瘤生长，这与降低的肿瘤微血管密度相关。另外，在自发肿瘤发生模型中，VEGF-毒素构建体被证明是有效的肿瘤预防剂。在这里，我还确定了重要的初始药理和药代动力学参数。我建立了剂量依赖性毒性谱，这将对该构建体的进一步发展产生重大影响。最后，我评估了使用分子量较小的VEGF亚型作为潜在的毒性降低的替代靶向部分的方法。在本文的第二部分，我研究了将化学治疗药物与抗血管生成方法相结合的治疗潜力。我发现卡铂通过诱导内皮细胞特异性存活因子VEGF的表达直接影响内皮细胞和肿瘤血管。 VEGF的上调可能保护肿瘤血管免于凋亡，并因此抵消了药物的细胞毒性作用。因此，特异性抗体对生存因子的中和作用导致肿瘤生长的协同抑制。从这些研究中获得的结果应该对如何设计未来的癌症治疗方法以最大程度地发挥治疗效果产生重大影响。

著录项

  • 作者

    Wild, Robert Christian.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Health Sciences Pharmacology.; Biology Cell.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2000
  • 页码 123 p.
  • 总页数 123
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;细胞生物学;肿瘤学;
  • 关键词

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