NO, GUANYLATE CYCLASE AND IMMUNOTHERAPY OF CANCER

不，鸟苷酸环化酶与癌症免疫治疗

• 批准号: 6129929
• 负责人: Paul J Shami
• 金额: $ 4.49万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6129929
• 关键词: cardiovascular pharmacology; drug administration rate /duration; drug administration routes; enzyme inhibitors; fibrosarcoma; guanylate cyclase; interleukin 2; laboratory mouse; laboratory rat; myelogenous leukemia; neoplasm /cancer immunotherapy; nitric oxide; pharmacokinetics; quinoxalines

Nitric oxide (NO) is cytotoxic to cancer cells by inducing protein tyrosine nitrosation protein thiol nitrosylation, protein ADP ribosylation, inhibiting mitochondrial respiration, and inhibiting ribonucleotide reductase. Exposure of leukemia and solid tumor cells to NO induces apoptosis. On the other and, NO is an important mediator involved in the physiologic regulation of systemic vasomotor tone. NO acts as a potent vasodilator by activating the soluble guanylate cyclase (sGC) and cGMP production in vascular smooth muscle cells. The cytotoxic effects of NO are sGC/cGMP independent. Interleukin 2 (IL-2) treatment of mice or humans strongly induces (NO) synthesis. In mice, NO contributes significantly to the anti-tumor effects of IL-2. The dose limiting toxicity of IL-2 treatment is cardiovascular manifested by hypotension and the vascular leak syndrome (VLS). Inhibition of NO production in mice treated with IL-2 prevents the VLS but diminishes its anti-neoplastic effects. The investigator's hypothesis is that the cardiovascular toxicity of IL-2 is mediated by the sGC/cGMP signal transduction axis as a consequence of NO production. The importance of this concept is that inhibition of the sGC signaling pathway could allow the selective inhibition of the cardiovascular toxicities of IL-2-induced NO synthesis without interfering with NO dependent cytotoxic mechanisms. This hypothesis will be tested in the proposed experiments using the selective sGC inhibitor H-[1,2,4]oxadiazole[4,3,-a]quinoxaline-lone (ODQ). The aims are as follow l -Determine the pharmacokinetics, optimal dosage route, schedule of administration, formulation and the toxicity profile of the sGC inhibitor ODQ in a murine model. 2 - Study the effect of ODQ on the IL-2 induced cardiovascular toxicity and VLS. 3 - Study the effect of the combination of IL-2 and ODQ on tumor growth in vivo using murine models. By dissociating the tumor cytotoxicity of NO (and therefore IL-2) from its vascular effects, they will demonstrate that it is feasible to use NO inducers or NO donors in vivo for the treatment of malignant neoplasms without prohibitive cardiovascular toxicity. Furthermore, this approach will allow dose escalations studies of IL-2 and could also be applicable to other immunologic therapeutic strategies for cancer.

一氧化氮（NO）是通过诱导蛋白质合成而对癌细胞产生细胞毒性的 酪氨酸亚硝化蛋白巯基亚硝化，蛋白ADP核糖基化， 抑制线粒体呼吸和抑制核糖核苷酸还原酶。 白血病和实体瘤细胞暴露于NO诱导凋亡。上 NO是参与生理调节的重要介质 全身血管紧张素NO通过激活血管内皮细胞， 血管平滑肌中可溶性鸟苷酸环化酶（sGC）和cGMP产生 细胞NO的细胞毒作用不依赖于sGC/cGMP。 小鼠或人的白细胞介素2（IL-2）处理强烈诱导（NO） 合成.在小鼠中，NO显著促进了 IL-2。IL-2治疗的剂量限制性毒性表现为心血管毒性 低血压和血管渗漏综合征（VLS）。抑制NO 用IL-2处理的小鼠中的VLS的产生防止了VLS，但减少了其 抗肿瘤作用。研究人员的假设是， IL-2的心血管毒性是由sGC/cGMP信号转导介导的 轴作为NO生产的结果。这个概念的重要性在于， 抑制sGC信号通路可以选择性抑制 IL-2诱导的NO合成的心血管毒性，而不干扰 具有NO依赖性细胞毒性机制。这一假设将在 使用选择性sGC抑制剂的拟议实验 H-[1，2，4]恶二唑[4，3，-a]喹喔啉酮（ODQ）。其目的如下 l -确定药代动力学、最佳给药途径、给药时间表 sGC抑制剂ODQ的给药、制剂和毒性特征 在小鼠模型中。 2.研究ODQ对IL-2诱导的心血管毒性的影响， VLS。 3 -研究IL-2和ODQ的组合对体内肿瘤生长的影响 使用鼠模型。 通过将NO（以及因此IL-2）的肿瘤细胞毒性与其自身的肿瘤细胞毒性分离， 血管效应，他们将证明使用NO诱导剂是可行的 或没有体内供体用于治疗恶性肿瘤， 禁止心血管毒性。此外，这种方法将允许剂量 IL-2的升级研究，也可以适用于其他免疫学 癌症的治疗策略。