INTRACELLULAR FREE CA2+ AND ANTICANCER DRUG ACTION

正常细胞和癌细胞之间的根本区别是 癌基因在癌细胞中的表达和癌症的独立性 细胞从许多生长因子增殖。 最近的研究表明 癌基因的功能是编码细胞内 生长因子的信号传导途径，从而缓解癌症 细胞对生长因子的正常需求。 真核细胞 维持非常低的细胞内游离Ca 2+（[Ca 2 +]i）水平， 比细胞外Ca 2+低10，000倍以上。 低水平和 细胞对[Ca 2 +]i的精细控制允许细胞中的微小变化。 [Ca2+]i用作高响应性细胞内信使， 携带生长因子作用于细胞受体的信号 表面到细胞核。 生长因子与 癌基因的作用表明，[Ca 2 +]i的变化也是重要的， 介导致癌基因的作用。 我们的研究所依据的假设 基于的是，通过开发影响[Ca 2 +]i和 相关的第二信使介导生长因子的作用， 癌基因应该有可能利用基本的生物学差异 正常细胞和癌细胞之间的选择性治疗， 癌 为了有效地做到这一点，我们需要更好地了解 [Ca 2 +]i和相关的第二信使在正常和 癌细胞生长因子和癌基因。 我们还需要确定 选择性阻断肿瘤中[Ca 2 +]i信号通路的化合物 细胞 因此，我们的研究重点是了解 与细胞内[Ca ~（2+）]i和[Ca ~（2+）]i有关的信号转导 相关的第二信使，以及与细胞增殖的关系。 我们 将采用多种方法测量[Ca 2 +]i、Ca 2+通量， 以及其他细胞内的第二信使在定义，生长因子- 依赖细胞系统。 我们已经确定了五种新型的代理人 阻断[Ca 2 +]i信号传导，这可能是新类型的 细胞生长抑制剂 我们研究的最终目的是 通过靶向药物发现治疗癌症的新方法。

A fundamental difference between normal cells and cancer cells is the expression of oncogenes in cancer cells and the independence of cancer cells from many growth factors for proliferation. Recent work suggests that the function of oncogenes is to code for components of intracellular signal transduction pathways for growth factors, thus, relieving the cancer cell of the normal requirements for growth factors. Eukaryotic cells maintain very low levels of intracellular free Ca2+ ([Ca2+]i) which are over 10,000-fold lower than extracellular Ca2+. The low levels and the exquisite control exerted by the cell over [Ca2+]i allow small changes in [Ca2+]i to be used as a highly responsive intracellular messenger for carrying signals from growth factors acting on receptors at the cell surface to the nucleus. The close relationship between growth factor and oncogene action indicates that changes in [Ca2+]i are also important in mediating the effects of oncogenes. The hypothesis upon which our studies are based is that by developing agents that effect the way [Ca2+]i and related second messengers mediate the effects of growth factors and oncogenes it should be possible to exploit basic biological differences between normal cells and cancer cells for the selective treatment of cancer. To do this effectively we need a better understanding of the role of [Ca2+]i and related second messengers in the control of normal and cancer cell growth factors and oncogenes. We also need to identify compounds that selectively block [Ca2+]i signalling pathways in tumor cells. Our studies are, therefore, focused on understanding the mechanisms of growth factor and oncogene and signal transduction involving [Ca2+]i and related second messengers, and the relationship to cell proliferation. We will employ a number of approaches for measuring [Ca2+]i, Ca2+ fluxes, as well as other intracellular second messengers in defined, growth factor- dependent cell systems. We have identified five novel classes of agents that block [Ca2+]i signalling that may be prototypes for new classes of cell growth inhibitors. The ultimate objective of our studies is to find new ways of treating cancer through target directed drug discovery.