Tumor-selective Anticancer Prodrugs
肿瘤选择性抗癌前药
基本信息
- 批准号:6552125
- 负责人:
- 金额:$ 12.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-09-16 至 2003-11-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): The proteolytic activity of matrix metalloproteases (MMPs)-2 and -9 is highly localized to the outer surfaces of invasive tumors. The goal of this project is to synthesize and evaluate prodrugs that are selectively cleaved by MMP-2 and -9 at the tumor site. Using both direct attachment and cleavable linkers, we will synthesize derivatives of two classes of antitumor compounds, the amino secocyclopropylbenzindolines (CBls) and doxorubicin, to which short MMP-cleavable peptides are appended. The CBIs are an extraordinarily potent class of minor groove binding/alkylating agents that show in vitro cytotoxicity at picomolar concentrations. Doxorubicin, white 1000-fold less potent in vitro, is a clinically approved drug having a well-described therapeutic profile against many hematologic and solid tumors. Our strategy takes advantage of the highly regulated, tumor-restricted proteotytic activity of MMPs-2 and -9, and the high turnover rates of these enzymes. We plan to demonstrate through our in vitro enzymatic assays, in vitro cytotoxicity assays, and in vivo therapy experiments, that MMP-substrate peptidyl prodrugs will have attenuated toxicities compared to their corresponding parent drugs, tumor selectivity, and therapeutic efficacy for the treatment of cancer.
PROPOSED COMMERCIAL APPLICATION: Cancer therapy still represents one of the largest unmet medical needs. The goal of many prodrug strategies is to increase the amount of active drug delivered to a tumor through selective activation pathways. The prodrugs we propose are designed to be significantly less toxic until reactivated at the tumor site by tumor-selective enzymatic activity. this strategy could represent a significant advancement toward the goal of distinguishing between normal and malignant cells, and, as such, a significant advancement in the treatment of cancer.
描述(申请人提供):基质金属蛋白水解酶(MMPs)-2和-9高度定位于侵袭性肿瘤的外表面。该项目的目标是合成和评估在肿瘤部位选择性地被基质金属蛋白酶-2和-9切割的前药物。利用直接连接物和可裂解连接物,我们将合成两类抗肿瘤化合物的衍生物,即氨基二环丙基苯并吲哚(CBLS)和阿霉素,并在其上附加可裂解的短肽。CBIS是一类非常有效的微小沟槽结合/烷基化试剂,在皮摩尔浓度下显示出体外细胞毒性。阿霉素在体外的效力是白色的1000倍,是一种临床批准的药物,对许多血液和实体肿瘤具有良好的治疗效果。我们的策略利用了MMPs-2和MMPs-9高度调控、肿瘤受限的蛋白分解活性,以及这些酶的高周转率。我们计划通过我们的体外酶分析、体外细胞毒性分析和体内治疗实验来证明,与相应的母体药物相比,基质金属蛋白酶底物多肽前药具有减轻毒性、肿瘤选择性和治疗癌症的疗效。
拟议的商业应用:癌症治疗仍然是最大的未得到满足的医疗需求之一。许多前药策略的目标是通过选择性激活途径增加给肿瘤的活性药物的量。我们建议的前药设计为毒性显著降低,直到肿瘤部位通过肿瘤选择性酶活性重新激活。这一策略可能代表着朝着区分正常细胞和恶性细胞的目标迈进了一大步,也因此在癌症治疗方面取得了重大进步。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Toni KLINE其他文献
Toni KLINE的其他文献
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{{ truncateString('Toni KLINE', 18)}}的其他基金
SYNTHETIC ANTAGONISTS OF THE PSEUDOMONAS AUTOINDUCER
假单胞菌自诱导剂的合成拮抗剂
- 批准号:
2712395 - 财政年份:1998
- 资助金额:
$ 12.88万 - 项目类别:
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