Darnowski J W, Handschumacher R E
Cancer Res. 1985 Nov;45(11 Pt 1):5364-8.
Benzylacyclouridine (BAU), a potent inhibitor of uridine phosphorylase, delays the disappearance of uridine from plasma, affects the utilization of uridine by selected tissues, and enhances the therapeutic effects of 5-fluorouracil (FUra) in female C57BL/6 mice. A single 30-mg/kg i.v. injection of BAU lengthens the plasma half-life of both a tracer dose of [3H]uridine (3 micrograms/kg) and a pharmacological dose of uridine (250 mg/kg) by 250 and 83%, respectively. This dose of BAU also increases the normal plasma concentration of uridine about 4-fold to 9 microM and sustains these levels for 4 h. Four injections of BAU at 30 mg/kg over 6 h or a single injection at 240 mg/kg increases the plasma concentration of uridine over 10-fold to approximately 50 microM. In addition to affecting the pharmacokinetics of uridine, a 30-mg/kg dose of BAU selectively increases up to 4-fold the ability of normal host tissues to salvage a tracer dose of [3H]uridine for nucleic acid biosynthesis, the uracil nucleotide pool size, and the incorporation of uridine into nucleic acids. However, uridine salvage from plasma by colon tumor 38 is increased only slightly by BAU, while the uracil nucleotide pool size and uridine incorporation into tumor nucleic acids are actually decreased by 15 and 37%. The selective effect of BAU on uridine utilization is reflected in the ability of BAU to modify FUra-induced host toxicity. The dose of FUra required to kill 50% of the treated normal mice (350 mg/kg) is modestly increased by "rescue" regimens consisting of the subsequent administration of repeated injections of either BAU alone (30 mg/kg/injection) or uridine alone (250 mg/kg/injection). However, an increase of 54% is achieved when repeated injections of the combination of BAU and uridine are administered. In C57BL/6 mice bearing advanced transplants of colon tumor 38, the period of tumor growth inhibition resulting from multiple courses of FUra-containing drug regimens can be increased by the delayed administration of BAU alone or BAU combined with uridine.
苄基阿糖胞苷（BAU）是一种有效的尿苷磷酸化酶抑制剂，它能延缓尿苷从血浆中的消失，影响特定组织对尿苷的利用，并增强5-氟尿嘧啶（FUra）对雌性C57BL/6小鼠的治疗效果。静脉注射一次30mg/kg的BAU可使示踪剂量的[3H]尿苷（3μg/kg）和药理剂量的尿苷（250mg/kg）的血浆半衰期分别延长250%和83%。该剂量的BAU还可使尿苷的正常血浆浓度增加约4倍，达到9μM，并维持4小时。在6小时内分4次注射30mg/kg的BAU或单次注射240mg/kg可使尿苷的血浆浓度增加10倍以上，达到约50μM。除了影响尿苷的药代动力学外，30mg/kg剂量的BAU可使正常宿主组织挽救示踪剂量的[3H]尿苷用于核酸生物合成的能力、尿嘧啶核苷酸池大小以及尿苷掺入核酸的量选择性增加高达4倍。然而，BAU仅略微增加了结肠肿瘤38从血浆中挽救尿苷的能力，而尿嘧啶核苷酸池大小和尿苷掺入肿瘤核酸的量实际上分别减少了15%和37%。BAU对尿苷利用的选择性作用体现在其改变FUra诱导的宿主毒性的能力上。通过随后单独重复注射BAU（30mg/kg/次）或单独注射尿苷（250mg/kg/次）组成的“挽救”方案，使50%的经治疗正常小鼠致死所需的FUra剂量适度增加。然而，当重复注射BAU和尿苷的组合时，增加幅度达到54%。在携带晚期结肠肿瘤38移植瘤的C57BL/6小鼠中，单独延迟给予BAU或BAU与尿苷联合使用可延长含FUra药物方案多疗程导致的肿瘤生长抑制期。
