New Drugs Targeted to Metastatic Cancer and Angiogenesis

针对转移性癌症和血管生成的新药

基本信息

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
项目类别：
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

项目摘要

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.

拟议研究的长期目标是开发一种同时将原细胞毒素靶向血管生成和转移性肿瘤细胞的策略。血管生成是癌症治疗的重要目标，因为血管内皮细胞遗传稳定，不会对治疗产生耐药性。抗血管生成疗法应该抑制癌症的进展，但是抗血管生成疗法和细胞毒疗法的组合可能会有效治愈。所提出的设计将用触发基团延迟细胞毒素的释放，直到靶向基团有机会定位其细胞表面受体。细胞毒素是多柔比星的活化形式，其对耐药肿瘤细胞和非融合上皮细胞的毒性比多柔比星高10至100倍。为了证明概念，靶向基团将是小肽，其归巢于血管生成部位的内皮细胞表达的受体，而不是成熟脉管系统的内皮细胞表达的受体。其中一种肽也将归巢于转移性乳腺癌和前列腺癌细胞表达的相同受体。具体目标 1 和 2 是合成和表征预激活的多柔比星，该预激活的阿霉素受到触发基团的保护，该触发基团与肽相连，这些肽靶向血管生成部位的内皮细胞表面上的两种不同受体。具体目标 3 是评估乳腺癌和前列腺癌细胞模型以及内皮细胞模型中的靶向前细胞毒素。具体目标 4 是评估转移性乳腺癌和前列腺癌裸鼠模型中的靶向前细胞毒素。靶向的、活化的原细胞毒素应该能有效对抗转移性疾病，并且副作用比阿霉素所观察到的要少得多。通过靶向和预激活所需的剂量较低，可以减少副作用。此外，一旦在血管生成部位释放，预活化的阿霉素相对于转化为阿霉素的半衰期较短，其毒性降低了10倍。因此，远离转移病灶的组织将仅暴露于低水平的阿霉素。