SPERMINE ANTAGONISTS FOR CANCER THERAPY

精胺是一种普遍存在的、过度表达的内源性多胺。 在众多的人类肿瘤中。精胺对巨噬细胞的抑制作用 在生理浓度下激活，并增强合成和 肿瘤细胞分泌精胺可能在肿瘤发病机制中起关键作用 肿瘤逃避免疫介导的细胞毒作用的能力。我们的预赛 研究表明，与糖皮质激素一样，精胺也能起到反调节作用 前炎性细胞因子的产生和可能被认为是内源性的 能够阻止局部免疫反应的免疫调节剂。精胺 抑制细胞因子合成所需的水平很容易在 据报道，在肿瘤和感染中存在体内和高浓度的 个人。我们正在开发一类重要的抑制剂， 拮抗精胺和ARE的反调节作用 免疫刺激在免疫反应是 被精胺抑制。此外，我们的初步结果表明， 这些药物对肿瘤细胞无毒，但具有抗肿瘤作用 精胺处理的巨噬细胞体外作用及对B-16黑色素瘤的影响 体内的肿瘤。这些结果表明，这些药物可能通过 向宿主免疫系统揭示肿瘤细胞，并可能有利于癌症 通过促进患者的内源性自我修复能力。我们建议 定义这些药物作用于细胞内靶点的机制， 精炼这一类的化学结构以生成铅化合物 具有优化的药理特性，并开发这种化合物 供临床使用。 建议的商业应用： 该提案涉及开发一种新型的无毒抗菌剂。 治疗人类癌症的抗癌药物。

Spermine is a ubiquitous and endogenous polyamine that is overexpressed in numerous human tumors. Spermine potently inhibits macrophage activation at physiologic concentrations, and enhanced synthesis and secretion of spermine by tumor cells may play a critical role in the ability of tumors to evade immune-mediated cytotoxicity. Our preliminary studies indicate that, like glucocorticoids, spermine counterregulates proinflammatory cytokine production and may be considered an endogenous immunomodulator capable of stemming local immune responses. Spermine levels required to suppress cytokine synthesis are readily achieved in vivo and high concentrations have been reported in tumors and in infected individuals. We are developing an important class of inhibitors that antagonize the counterregulatory effects of spermine and are immunostimulatory under conditions where the immune response is suppressed by spermine. Furthermore, our preliminary results indicate that these drugs are nontoxic to tumor cells but elicit anti-tumor effects from spermine-treated macrophages in vitro and on B-16 melanoma tumors in vivo. These results suggest that these drugs may act by revealing tumor cells to the host immune system and may benefit cancer patients by promoting endogenous self-healing capacities. We propose to define the mechanisms by which these drugs act on intracellular targets, refine the chemical structure of this class to generate a lead compound having an optimized pharmacological profile, and develop this compound for clinical use. PROPOSED COMMERCIAL APPLICATIONS: The proposal involves development of a novel class of non-toxic anti- cancer agents for treatment of human cancer.