New Drugs Targeted to Metastatic Cancer and Angiogenesis

该研究的长期目标是开发一种同时靶向血管生成和转移性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遗传上是稳定的，不会随着治疗而产生耐药性。抗血管生成治疗应能抑制肿瘤的进展，但抗血管生成和细胞毒性联合治疗可能会对治疗产生影响。提出的设计将延迟细胞毒素的释放与触发组，直到目标组有机会定位其细胞表面受体。这种细胞毒素将是一种活化形式的阿霉素，它对耐药肿瘤细胞和非融合上皮细胞的毒性比阿霉素高10到100倍。为了证明这一概念，目标群体将是小肽，这些肽是血管生成部位内皮细胞表达的受体的所在地，而不是成熟血管的内皮细胞表达的受体。其中一种肽也会与转移性乳腺癌和前列腺癌细胞表达的相同受体结合。具体目标1和2是合成和表征预激活的阿霉素，由一个触发组保护，该触发组连接到肽上，该肽针对血管生成部位内皮细胞表面的两种不同受体。具体目的3是评估靶向前细胞毒素在乳腺癌和前列腺癌细胞模型和内皮细胞模型中的作用。具体目的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、活化的前细胞毒素应该对转移性疾病有效，副作用比阿霉素少得多。由于靶向和预激活所需的剂量较低，副作用较小。此外，一旦在血管生成部位释放，预激活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只暴露于低水平的阿霉素。

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.