Matsushita T, Ryu E K, Hong C I, MacCoss M
Cancer Res. 1981 Jul;41(7):2707-13.
The nucleoside 5'-diphosphate-L-1,2-dipalmitin derivatives of 1-beta-D-arabinofuranosylcytosine (ara-C), 9-beta-D-arabinofuranosyladenine (ara-A), and tubercidin have been synthesized, and their cytotoxicity has been evaluated against a mouse myeloma cell line (MPC-11) in vitro and against L1210 lymphoid leukemia both in vitro and in vivo. Sonication methods were utilized to solubilize these lipophilic derivatives in aqueous solution in order to facilitate such biological evaluation; the ara-A derivative resisted solubilization by several techniques. The nucleoside:phospholipid conjugates of ara-C and tubercidin both were cytotoxic towards the two cell lines, and detailed experiments were cytotoxic towards the two cell lines, and detailed experiments were carried out to show that the new derivatives (a) were not degraded in the medium prior to cellular uptake and (b) acted as prodrugs or molecular depots of the parent nucleoside analog. In addition, 1-beta-D-arabinofuranosylcytosine 5'-diphosphate'5'-L-1,2-dipalmitin was not a substrate for cytidine deaminase (cytidine aminohydrolase, EC 3.5.4.5), the primary enzyme responsible for the rapid catabolism of ara-C. In in vivo studies against L1210 lymphoid leukemia in mice, the 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin showed an increased efficacy (increased life span, 260%) relative to the parent ara-C (increased life span, 89%) regardless of treatment schedule used, whereas the tubercidin 5'-diphosphate-5'-L-1,2-dipalmitin appeared extremely toxic even at low dosages. That 1-beta-D-arabinofuranosylcytosine 5'-diphosphate-5'-L-1,2-dipalmitin was acting as a sustained release drug in vivo was demonstrated by utilizing a single dose administered on Days -1, 0, +1, and +2 relative to inoculation of the L1210 lymphoid leukemia cells on Day 0. Again, a much increased efficacy relative to the best treatment using ara-C was apparent. The potential advantages and the biochemical rationale for the development of these novel prodrugs are discussed.
已合成了1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，ara-C）、9-β-D-阿拉伯呋喃糖基腺嘌呤（阿糖腺苷，ara-A）和杀结核菌素的核苷5'-二磷酸-L-1,2-二棕榈酸酯衍生物，并在体外针对小鼠骨髓瘤细胞系（MPC-11）以及在体外和体内针对L1210淋巴细胞白血病评估了它们的细胞毒性。采用超声处理方法将这些亲脂性衍生物溶解于水溶液中，以便于进行此类生物学评估；阿糖腺苷衍生物难以通过多种技术溶解。阿糖胞苷和杀结核菌素的核苷：磷脂缀合物对这两种细胞系均具有细胞毒性，并进行了详细实验以表明新衍生物（a）在细胞摄取之前不会在培养基中降解，且（b）作为母体核苷类似物的前药或分子储存库发挥作用。此外，1-β-D-阿拉伯呋喃糖基胞嘧啶5'-二磷酸'5'-L-1,2-二棕榈酸酯不是胞苷脱氨酶（胞苷氨基水解酶，EC 3.5.4.5）的底物，该酶是负责阿糖胞苷快速分解代谢的主要酶。在针对小鼠L1210淋巴细胞白血病的体内研究中，无论采用何种治疗方案，1-β-D-阿拉伯呋喃糖基胞嘧啶5'-二磷酸-5'-L-1,2-二棕榈酸酯相对于母体阿糖胞苷均显示出更高的疗效（寿命延长，260%，而母体阿糖胞苷寿命延长89%），而杀结核菌素5'-二磷酸-5'-L-1,2-二棕榈酸酯即使在低剂量下也显得极具毒性。通过在相对于第0天接种L1210淋巴细胞白血病细胞的第-1、0、+1和+2天给予单剂量药物，证明了1-β-D-阿拉伯呋喃糖基胞嘧啶5'-二磷酸-5'-L-1,2-二棕榈酸酯在体内作为缓释药物发挥作用。同样，相对于使用阿糖胞苷的最佳治疗方法，疗效明显提高。讨论了开发这些新型前药的潜在优势和生化原理。
