PRODRUGS TARGETING HYPOXIC TUMOR CELLS

靶向缺氧肿瘤细胞的前药

基本信息

批准号：
6173105
负责人：
ALAN CLAYTON SARTORELLI
金额：
$ 23.41万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-04-15 至 2001-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6173105
关键词：
NADPH cytochrome c2 reductase acidity /alkalinity apoptosis athymic mouse chemical stability crosslink cytochrome b5 reductase cytotoxicity dihydrolipoamide dehydrogenase drug design /synthesis /production drug screening /evaluation enzyme activity hydrazines hydropathy hypoxia neoplastic cell oxidation reduction reaction prodrugs

项目摘要

DESCRIPTION: Solid tumors contain deficient vascular beds and areas of severe vascular insufficiency and, as a consequence, develop regions containing hypoxic cells. These oxygen deficient malignant cells, which frequently constitute 5 to 30 percent of the total viable tumor cell population, represent a therapeutically resistant group of cells that limits the curability of many solid tumors by radiation and most chemotherapeutic agents. Thus, hypoxic neoplastic cells may be capable of proliferating and causing tumor regrowth after treatments that produce tumor regression. However, hypoxia creates an environment conducive to reductive events that results in a major exploitable difference between normal and neoplastic cells. The primary objective of this grant application is to employ the exceedingly efficacious and broad spectrum activity of the 1-(2-chloroethyl)sulfonylhydrazine family of agents to develop prodrugs of this class with preferential toxicity to hypoxic cells of solid tumors relative to their aerobic counterparts. To accomplish this the following specific aims are planned: 1. The synthesis of a prodrug with a large pH-dependent shift in redox potential such that the bioreductive activation of the drug occurs more readily under the acidic conditions found in areas of solid tumors that at the physiological pH value present in well oxygenated normal tissue and that this property is important to the preferential kill of hypoxic tumor cells. The agent will also be designed to have an appropriate balance between hydrophobicity and hydrophilicity to permit penetration of the solid tumor to reach unperfused hypoxic tumor areas in adequate cytotoxic concentrations; 2. A determination of the role of NADPH:cytochrome C (P450) reductase, NADH:cytochrome b5 reductase and DT-diaphorase in the reductive action of the prodrug, employing purified enzymes and cells overexpressing each of these catalysts to ascertain their involvement in situ under conditions of aeration and hypoxia; and 3. A determination of the importance of DNA cross-links to cell death.

描述：实体瘤包含不足的血管床和区域严重的血管功能不全，因此发展了区域含有低氧细胞。这些缺氧缺氧的恶性细胞，通常占总可行肿瘤细胞的5％至30％人口代表限制治疗性的细胞抗性群通过辐射和大多数化学治疗的许多实体瘤的可耐加工性代理商。因此，低氧肿瘤细胞可能能够增殖和在产生肿瘤消退的治疗后引起肿瘤再生。但是，缺氧创造了有利于还原事件的环境导致正常和肿瘤之间的主要可利用差异细胞。本赠款申请的主要目的是采用极其有效和广泛的活动 1-（2-氯乙基）磺酰氢嗪家族，以发展为前药该类对实体瘤缺氧细胞的优先毒性相对于他们的有氧对应物。实现以下内容计划了具体目的：1。前药的合成氧化还原电势的pH依赖性转移，使生物补充激活该药物的发生在区域中发现的酸性条件下更容易发生井中存在的pH值的实体瘤氧化正常组织，该特性对优先杀死低氧肿瘤细胞。代理商也将被设计在疏水性和亲水性之间保持适当的平衡允许实体瘤渗透到未灌注的低氧肿瘤足够的细胞毒性浓度的区域； 2。确定角色 NADPH：细胞色素C（P450）还原酶，NADH：细胞色素B5还原酶和使用纯化酶和细胞过表达这些催化剂，以确定其在充气和缺氧条件下参与原位；和3 确定DNA交联对细胞死亡的重要性。