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

核苷类似物前体药的活性差和非靶点细胞毒性往往限制了其临床疗效。我们的目标是开发一种专门针对肿瘤细胞的治疗策略，并提高核苷类似物前体药物在治疗某些癌症方面的疗效。我们将对人脱氧胞苷激酶(DCK)进行修饰，使其能够专一性地磷酸化并激活非生理性的L核苷。修饰后的DCK将被靶向并通过使用单链抗体(ScFv)或亲和抗体传递给肿瘤细胞。我们认为，在核苷类似物化疗中，将我们的修饰的DCK有限地输送到肿瘤细胞和使用L-核苷类似物将同时提供更高的细胞毒性和更高的特异性。

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.