INTRACELLULAR FREE CA2+ AND ANTICANCER DRUG ACTION

正常细胞和癌细胞之间的一个根本区别是 癌基因在癌细胞中的表达与肿瘤的独立性 细胞由多种生长因子促进增殖。最近的研究表明 癌基因的功能是编码细胞内的成分 生长因子的信号转导途径，从而缓解癌症 细胞对生长因子的正常要求。真核细胞 维持非常低的细胞内游离钙([钙]i)水平，这是 比细胞外钙低一万多倍。低水平和 细胞对[Ca~(2+)]i施加的精细控制允许在 [CA2]作为高响应性的细胞内信使 携带来自作用于细胞受体的生长因子的信号 表面到原子核。生长因子与植物生长因子的密切关系 癌基因作用表明[Ca~(2+)]_i的变化在 调节致癌基因的影响。我们的研究所依据的假设 其基础是通过开发影响[钙]i和 相关的第二信使调节生长因子和 致癌基因应该可以利用基本的生物学差异 正常细胞和癌细胞之间的相互作用 癌症。为了有效地做到这一点，我们需要更好地理解这一角色 [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 选择性阻断肿瘤内[Ca~(2+)]i信号通路的化合物 细胞。因此，我们的研究集中在了解这些机制。 生长因子、癌基因和信号转导涉及[钙]i和 相关的第二信使，以及与细胞增殖的关系。我们 将采用多种方法来测量[Ca~(2+)]_i、Ca~(2+)通量，如 以及其他细胞内定义的生长因子第二信使- 依赖细胞系统。我们已经确定了五类新的代理人 那个阻断[Ca~(2+)]i的信号可能是新类别的原型 细胞生长抑制药。我们研究的最终目标是找到 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.