NO, GUANYLATE CYCLASE AND IMMUNOTHERAPY OF CANCER

一氧化氮(NO)通过诱导蛋白质对癌细胞产生细胞毒作用 酪氨酸亚硝化，蛋白质硫醇亚硝化，蛋白质ADP核糖基化， 抑制线粒体呼吸，抑制核糖核苷酸还原酶。 白血病和实体瘤细胞暴露于NO可诱导细胞凋亡。论 此外，NO是参与生理调节的重要介质 全身血管舒缩的音调。NO作为一种有效的血管扩张剂激活 血管平滑肌可溶性鸟苷环化酶(SGC)和cGMP的产生 细胞。NO的细胞毒作用不依赖于sGC/cGMP。 白介素2(IL-2)对小鼠和人的强烈诱导(NO) 综合。在小鼠中，NO在抗肿瘤作用中起重要作用。 IL-2。IL-2治疗的剂量限制性毒性表现为心血管 由低血压和血管渗漏综合征(VLS)引起。一氧化氮的抑制作用 经IL-2处理的小鼠产生的VLS可阻止VLS，但可减少其 抗肿瘤作用。调查员的假设是 SGC/cGMP信号转导介导IL-2的心血管毒性 轴心，因为没有生产的结果。这个概念的重要性在于 抑制sGC信号通路可以选择性地抑制 IL-2无干预诱导NO合成的心血管毒性 没有依赖的细胞毒性机制。这一假设将在 建议使用选择性sGC抑制剂的实验 H-[1，2，4]恶二唑[4，3，-a]喹恶啉-龙(ODQ)。目标如下 L-测定药代动力学、最佳给药途径、给药程序 SGC抑制剂ODQ的给药、剂型及毒性研究 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联合ODQ对体内肿瘤生长的影响 使用小鼠模型。 通过将NO(从而IL-2)的肿瘤细胞毒性与其 血管效应，他们将证明不使用诱导剂是可行的 或体内没有供体用于治疗恶性肿瘤而没有 心血管毒性令人望而却步。此外，这种方法将允许剂量 IL-2的升级研究，也可能适用于其他免疫学 癌症的治疗策略。

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.