Targeted Cancer Chemotherapy: The Potential of L-Nucleoside Prodrugs

该项目的目的是开发新型抗癌药物。我们计划使用一种不寻常的糖(L核苷)，这种糖在人体内通常是不存在的。这种不寻常的糖具有被肿瘤细胞而不是正常细胞所摄取的特性。我们将使用这种不同寻常的糖在肿瘤细胞内运输一种有毒化合物，从而杀死肿瘤细胞。通过这种方式，我们将优先杀死肿瘤细胞，而不影响正常细胞。因此，我们将生产一种抗癌剂，这种抗癌剂在杀死肿瘤细胞方面非常有效，但由于它不进入正常细胞，因此几乎没有副作用。在实验上，我们将合成L-核苷与毒剂、氟尿嘧啶或顺铂类似物结合的化合物。然后，我们将评估这些新化合物杀死实验室中生长的肿瘤细胞以及老鼠中生长的肿瘤的能力。此外，我们将试图通过调查以下内容来确定这些药物的作用机制：药物的运输特性；这些药物如何以及在哪里破坏DNA；基因P53的作用，它可以阻止肿瘤的生长。本项目的最终目的是开发一种基于L的新型抗肿瘤药物-核苷。这些L核苷类似物有望在杀死肿瘤细胞方面更有效，但副作用更少。

The aim of this project to develop novel anti-cancer agents. We plan to use an unusual sugar (an L-nucleoside) that is not normally found in the body. This unusual sugar has the property of being taken up by tumour cells but not normal cells. We will use this unusual sugar to transport a toxic compound inside tumour cells so that the tumour cells are killed. In this way, we will preferentially kill tumour cells but leave normal cells unaffected. Hence we will produce an anti-cancer agent that is highly effective at killing tumour cells but has few side-effects because it does not enter normal cells. Experimentally we will synthesise compounds where the L-nucleoside is attached to a toxic agent, fluorouridine or cisplatin analogues. We will then assess the ability of these novel compounds to kill tumour cells grown in the laboratory as well as tumours growing in mice. Additionally we will attempt to determine the mechanism of action of these drugs by investigating the following: the transport properties of the drugs; how and where these drugs damage DNA; the effect of the gene, p53, which can act to stop tumour growth. The ultimate aim of this project is to develop a novel class of anti-tumour agent based on L-nucleosides. These L-nucleoside analogues are expected to be more efficient at killing tumour cells but have fewer side effects.