New Drugs Targeted to Metastatic Cancer and Angiogenesis

针对转移性癌症和血管生成的新药

• 批准号: 6361790
• 负责人: TAD H KOCH
• 金额: $ 22.15万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-20 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6361790
• 关键词: 3,4 methylenedioxyamphetamine; CD antigens; Carnivora; angiogenesis; aspartate; athymic mouse; blood vessels; breast neoplasms; cell membrane; cell migration; chromophore; doxorubicin; drug adverse effect; fats; formaldehyde; gender difference; glutamates; integrins; intracellular transport; mammary gland; mass spectrometry; metastasis; neoplasm /cancer chemotherapy; neoplastic cell; neoplastic process; nonhuman therapy evaluation; nuclear magnetic resonance spectroscopy; prostate; prostate neoplasms; protein transport; toxin

The long term goal of the proposed research is the development of a strategy for simultaneously targeting a pro- cytotoxin to angiogenesis and metastatic tumor cells. Angiogenesis is an important target for cancer therapy because vascular endothelial cells are genetically stable and do not become resistant with treatment. Anti-angiogenic therapy should inhibit the progression of cancer, but the combination of anti- angiogenic and cytotoxic therapy may effect cures. The proposed design will delay release of the cytotoxin with a triggering group until the targeting group has had an opportunity to locate its cell surface receptor. The cytotoxin will be an activated form of doxorubicin which is 10- to 100-fold more toxic to resistant tumor cells and to non-confluent epithelial cells than doxorubicin. For proof of concept, the targeting groups will be small peptides which home to receptors expressed by endothelial cells at the site of angiogenesis but not by endothelial cells of mature vasculature. One of the peptides will also home to the same receptor expressed by metastatic breast and prostate cancer cells. Specific aims 1 and 2 are to synthesize and characterize preactivated doxorubicin, protected by a triggering group which is tethered to peptides which target two different receptors on the surface of endothelial cells at the site of angiogenesis. Specific aim 3 is to evaluate targeted pro-cytotoxins in breast and prostate cancer cell models and in an endothelial cell model. Specific aim 4 is to evaluate the targeted pro-cytotoxins in nude mouse models for metastatic breast and prostate cancer. The targeted, activated pro-cytotoxin should be effective against metastatic disease with substantially less side effects than observed with Doxorubicin. Less side effects will result from the lower dose required through targeting and preactivation. Further, once released at the site of angiogenesis, preactivated doxorubicin has a short half-life with respect to conversion to doxorubicin which is 10-fold less toxic. Hence, tissues remote from the metastatic lesion will only be exposed to low levels of doxorubicin.

拟议的研究的长期目标是开发同时针对血管生成和转移性肿瘤细胞的促毒素的策略。血管生成是癌症治疗的重要靶标，因为血管内皮细胞在遗传上是稳定的，并且不会因治疗而变得抗药性。 抗血管生成疗法应抑制癌症的进展，但抗血管生成和细胞毒性疗法的结合可能会影响治疗。 提出的设计将延迟使用触发组的细胞毒素释放，直到靶向组有机会定位其细胞表面受体。 细胞毒素将是阿霉素的活化形式，比阿霉素比抗性肿瘤细胞的毒性高10至100倍。 为了获得概念证明，靶向组将是小肽，在血管生成部位，由内皮细胞表达的受体的家园，而不是成熟血管的内皮细胞。 其中一种肽还将在转移性乳腺癌和前列腺癌细胞表达的同一受体中。 具体目的1和2是合成和表征前毒性霉素的特征，该阿霉素受到触发基团的保护，该诱发基团束缚在血管生成部位的内皮细胞表面上的两个不同受体的肽。具体目的3是评估乳腺癌和前列腺癌细胞模型中的靶向促胞毒素以及内皮细胞模型中。特定目的4是评估裸鼠模型中靶向的促胞毒素的转移性乳腺癌和前列腺癌。 靶向活化的促胞毒素应对转移性疾病有效，其副作用要比阿霉素观察到的副作用要少得多。 较小的副作用将是由于靶向和预灭剂所需的较低剂量所致。此外，一旦在血管生成部位释放，预毒性阿霉素的半衰期就短暂的半衰期延伸到阿霉素的毒性较小10倍。 因此，远离转移性病变的组织只会暴露于少量的阿霉素。