New Drugs Targeted to Metastatic Cancer and Angiogenesis

这项拟议研究的长期目标是开发一种同时靶向血管生成和转移肿瘤细胞的前细胞毒素的策略。血管生成是癌症治疗的一个重要目标，因为血管内皮细胞在基因上是稳定的，不会对治疗产生抵抗力。抗血管生成治疗应该抑制癌症的进展，但抗血管生成治疗和细胞毒治疗的结合可能会对治愈产生影响。拟议的设计将推迟细胞毒素的释放，直到靶向小组有机会定位其细胞表面受体为止。这种细胞毒素将是阿霉素的一种活化形式，它对耐药肿瘤细胞和非融合上皮细胞的毒性是阿霉素的10到100倍。为了验证概念，靶向基团将是小肽，它们是血管生成部位的内皮细胞表达的受体，而不是成熟血管系统的内皮细胞表达的受体。其中一种多肽还将与转移性乳腺癌细胞和前列腺癌细胞表达的同一受体结合。具体的目标1和2是合成和表征预激活的阿霉素，它受到一个触发基团的保护，该基团被捆绑在针对血管生成部位内皮细胞表面两种不同受体的多肽上。具体目标3是评估乳腺和前列腺癌细胞模型以及内皮细胞模型中的靶向细胞毒素。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原细胞毒素。靶向的、激活的原细胞毒素对转移性疾病应该是有效的，而且副作用比阿霉素少得多。通过靶向和预激活所需的较低剂量将产生较少的副作用。此外，一旦在血管生成部位释放，预活化的阿霉素在转化为阿霉素的过程中具有较短的半衰期，毒性降低10倍。因此，远离转移灶的组织只会接触到低水平的阿霉素。

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.