Design and cellular delivery of a modified human deoxycytidine kinase with L-nucleoside analogue activity for use in cancer therapy

活性差和脱靶细胞毒性常常限制核苷类似物前药在临床上的功效。我们的目标是开发一种治疗策略，专门针对肿瘤细胞，并增加核苷类似物前药在治疗某些癌症中的疗效。我们将修改酶人脱氧胞苷激酶（dCK），使其能够专门磷酸化和激活非生理L-核苷。修饰的dCK将通过使用单链抗体（scFv）或抗体靶向并递送至肿瘤细胞。我们建议，我们的修饰dCK的局限性交付到肿瘤细胞和L-核苷类似物的使用将提供增加的细胞毒性和增加的特异性核苷类似物化疗。

Poor activation and off-target cytotoxicity often limit the efficacy of nucleoside analogue pro-drugs in the clinic. Our aim is to develop a therapeutic strategy which specifically targets tumour cells and increases the efficacy of nucleoside analogue pro-drugs in the treatment of certain cancers. We will modify the enzyme human deoxycytidine kinase (dCK) to enable it to exclusively phosphorylate and activate non-physiological L-nucleosides. The modified dCK will be targeted and delivered to tumour cells by the use of single chain antibodies (scFv) or affibodies. We propose that the confined delivery of our modified dCK to tumour cells and the use of L-nucleoside analogues will provide both increased cytotoxicity and increased specificity in nucleoside analogue chemotherapy.