PTERIDINE METABOLISM AND TRANSPORT IN MALIGNANT CELLS

临床观察表明，蝶呤代谢改变和增强 向包括恶性肿瘤、病毒性疾病在内的疾病排泄蝶类药物 感染，细胞免疫系统的普遍激活，以及 艾滋病。为了帮助理解这些观察结果，本提案寻求 在人类细胞中研究蝶啶类生物化学的某些领域 系统。具体地说，它旨在测定蝶啶的含量 细胞提取液和培养液；研究细胞提取物和培养基属性 控制这些衍生品的流入和流出的运输系统； 并确定二氢蝶呤和二氢蝶呤的相对作用 二氢叶酸还原酶在控制蝶啶代谢中的作用这个 研究将使用人类淋巴细胞和各种 人源性恶性细胞系包括CEM、WIL2、HL60和K562。 酶研究将使用从大鼠肝脏和 人力资源。特别重要的是确定 可调节排泄的蝶呤类药物。放射性标记 将使用蝶呤和叶酸来确定 由于蝶啶生物合成的中间体或 叶酸的降解可能与此有关。蝶啶类化合物的性质 交通系统将说明这些是否提供了更清晰的情况 某些细胞系统的蝶啶排泄产物是否可能是 通过摄取或表面结合到其他细胞而具有调节意义的 类型。通过这些手段，意在扩大对 蝶呤在人体细胞系统中的作用，从而确定 以前记录的临床观察也可以被利用 诊断上或治疗上。(A)

Clinical observations have linked altered pteridine metabolism and enhanced excretion of pteridines to diseases, which include malignancies, viral infections, generalized activation of the cellular immune system, and AIDS. In order to help understand these observations, this proposal seeks to investigate certain areas of pteridine biochemistry in human cell systems. In particular, it is intended to determine the pteridine content of cell extracts and culture media; to investigate the properties of the transport system which controls the influx and efflux of these derivatives; and to determine the relative roles played by dihydropteridine and dihydrofolate reductases in controlling pteridine metabolism. The investigations will be carried out using human lymphocytes and a variety of malignant cell lines of human origin including CEM, WIL2, HL60, and K562. The enzyme studies will employ the isolated proteins from rat liver and human sources. Of particular importance will be the identification of pteridines subject to modulated excretion. Radioactively labelled pteridines and folates will be employed to establish the origin of the secreted compounds since intermediates of both pteridine biosynthesis or folate degradation could be involved. The properties of the pteridine transport system will illustrate whether these provide a clearer picture of whether the pteridine excretion products of certain cell systems might be of regulatory significance by uptake or surface binding to other cell types. By these means, it is intended to expand the understanding of pteridine function in human cell systems and, thereby, determine whether previously documented clinical observations can be exploited either diagnostically or therapeutically. (A)