THE MICROPHARMACOLOGY OF BIOLOGICAL LIGANDS

多年来，我们一直在探索整合 生物药理学的宏观和微观方面 有趣的配体，特别是免疫球蛋白和细胞因子。这个 主要目的是了解是什么限制了有效的访问 这些配体作用于肿瘤的不同区域。该项目涉及到 理论研究和实验研究相结合。理论上：我们 开发了一个程序包(PERC)，它集成了普通的 舱室动力学模型的微分方程组 用偏微分方程式描述药物动力学 组织和组织中配体的对流、扩散、结合和反应 肿瘤。随后的分析使我们制定出了“结合部位” 障碍“假说--即成功绑定到 靶抗原或受体可以限制对物质的渗透。 肿瘤的症状。计算表明：(1)势垒效应可能 防止血管穿透100-200微米；(2) 矛盾的是，高亲和力和高结合部位密度可以产生 更低的配基浓度，从一个容器中只有100微米。 实验：我们验证了结合部位屏障假说 L10肿瘤大体及微转移的实验研究 豚鼠。要做到这一点，有必要结合双标记 放射自显影双生色团免疫组织化学检测 同时检测抗体、对照免疫球蛋白、抗原和 血管。我们已经提出，“结合部位障碍”已经被 自分泌-旁分泌分子和其他分子进化的一个因素 生物配体。作为推论，这种微小的药理屏障 在设计用于外源性给药的配体时必须考虑 或者是转基因细胞体内分泌的。艾滋病标题：艾滋病人 生物配体的微药理学：艾滋病发病机制中的细胞因子。

For a number of years, we have been exploring ways to integrate macroscopic and microscopic aspects of the pharmacology of biologically interesting ligands, in particular immunoglobulins and cytokines. The principal aim has been to understand what limits effective access of these ligands to various regions of a tumor. The project has involved a combination of theoretical and experimental studies. Theoretical: we developed a program package (PERC) that integrates the ordinary differential equations for kinetic modeling of compartmental pharmacokinetics with the partial differential equations that govern convection, diffusion, binding, and reaction of ligands in tissues and tumors. The ensuing analyses led us to formulate the "binding site barrier" hypothesis - i.e., that the very fact of successful binding to a target antigen or receptor can limit penetration into the substance of a tumor. Calculations suggested that (1) the barrier effect could prevent penetration even 100-200 microns from a blood vessel; (2) paradoxically, high affinity and high binding site density could produce lower concentrations of ligand as little as 100 microns from a vessel. Experimental: We validated the binding site barrier hypothesis experimentally in bulk tumors and micrometastases of L10 carcinoma in guinea pigs. To do this it was necessary to combine double-label autoradiography with double-chromophore immunohistochemistry to detect simultaneously the distributions of antibody, control IgG, antigen, and blood vessels. We have proposed that the "binding site barrier" has been a factor in the evolution of autocrine-paracrine molecules and other biological ligands. As a corollary, this micropharmacological barrier must be considered when designing ligands for exogenous administration or for secretion in vivo by genetically modified cells. AIDS Title: The Micropharmacology of Biological Ligands: Cytokines in AIDS Pathogenesis.