SPERMINE ANTAGONISTS FOR CANCER THERAPY

精胺是一种普遍存在的内源性多胺， 在许多人类肿瘤中。精胺有效抑制巨噬细胞 在生理浓度下活化，并增强合成， 肿瘤细胞分泌精胺可能在 肿瘤逃避免疫介导的细胞毒性的能力。我们的初步 研究表明，像糖皮质激素一样，精胺 促炎细胞因子的产生，并可被认为是内源性的 免疫调节剂能够阻止局部免疫应答。精胺 抑制细胞因子合成所需的水平容易达到， 据报道，在肿瘤和受感染的 个体我们正在开发一类重要的抑制剂， 拮抗精胺的反调节作用， 在免疫应答被抑制的条件下， 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， 精胺处理的巨噬细胞在体外和对B-16黑色素瘤的作用 体内肿瘤这些结果表明，这些药物可能通过 向宿主免疫系统揭示肿瘤细胞， 患者通过促进内源性自我修复能力。我们建议 确定这些药物作用于细胞内靶点的机制， 改进该类化合物的化学结构以生成先导化合物 具有优化的药理学特征，并开发这种化合物 临床使用。 拟议的商业应用： 该提案涉及开发一类新型无毒抗- 用于治疗人类癌症的抗癌剂。

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.