Klubes P, Cerna I
Cancer Res. 1983 Jul;43(7):3182-6.
We examined the ability of uridine to increase the therapeutic index of 5-fluorouracil (FUra) against C57BL/6 X DBA/2 F1 mice bearing a Day 1 B16 melanoma or L1210 leukemia. FUra (400, 600, or 800 mg/kg, i.p.) followed in 24 hr by a 5-day s.c. infusion with uridine (5 g/kg/day, s.c.) was compared with the maximum tolerated dose of FUra (200 mg/kg, i.p.) plus a 5-day infusion with 0.9% NaCl solution. High-dose FUra plus delayed infusion with uridine was more effective than FUra (200 mg/kg) in inhibiting the growth of the B16 melanoma. High-dose FUra plus uridine rescue was, however, no more effective than FUra (200 mg/kg) in increasing the survival times of mice bearing the L1210 leukemia. To see if uridine rescue from FUra toxicity correlated with effects against a sensitive normal tissue, bone marrow nucleated cellularity of normal, non-tumor-bearing mice was monitored after drug treatment. In mice treated with FUra (200 mg/kg) followed in 24 hr by a 5-day infusion with either uridine (5 g/kg/day) or 0.9% NaCl solution, there was not as great a decrease in cellularity at the nadir with uridine, and, in addition, uridine accelerated recovery as compared to 0.9% NaCl solution. Furthermore, uridine (5 g/kg/day), but not thymidine (dThd) (5 g/kg/day) or 2'-deoxyuridine (dUrd) (5 g/kg/day), had a sparing effect on the depression in bone marrow nucleated cellularity seen at the nadir on Day 4 after Fura (200 mg/kg). The specificity of uridine to rescue mice from the lethal toxicity of the related fluorinated pyrimidines, 5-fluorouridine and 5-fluoro-2'-deoxyuridine, was also examined. Mice were treated with 5-fluorouridine (250 mg/kg, i.p.) followed in 24 hr by a 5-day infusion with uridine (1, 5, or 10 g/kg/day), dThd (1, 5, or 10 g/kg/day), or dUrd (1 or 5 g/kg/day). Uridine (1, 5, or 10 g/kg/day) rescued mice from the lethal toxicity of 5-fluorouridine, whereas dThd or dUrd was ineffective. Similarly, a 5-day infusion with uridine, but not dThd or dUrd, rescued mice from the lethal toxicity of 5-fluoro-2'-deoxyuridine (1800 mg/kg, i.p.).
我们研究了尿苷提高5-氟尿嘧啶（FUra）对携带第1天B16黑色素瘤或L1210白血病的C57BL/6×DBA/2 F1小鼠治疗指数的能力。将FUra（400、600或800mg/kg，腹腔注射）在24小时后皮下注射5天尿苷（5g/kg/天）与FUra的最大耐受剂量（200mg/kg，腹腔注射）加5天输注0.9%氯化钠溶液进行比较。高剂量FUra加延迟输注尿苷在抑制B16黑色素瘤生长方面比FUra（200mg/kg）更有效。然而，高剂量FUra加尿苷挽救在延长携带L1210白血病小鼠的存活时间方面并不比FUra（200mg/kg）更有效。为了观察尿苷对FUra毒性的挽救是否与对敏感正常组织的作用相关，在药物治疗后监测正常、无肿瘤小鼠的骨髓有核细胞数。在用FUra（200mg/kg）治疗24小时后，再皮下注射5天尿苷（5g/kg/天）或0.9%氯化钠溶液的小鼠中，尿苷组最低点时细胞数的减少没有那么大，此外，与0.9%氯化钠溶液相比，尿苷加速了恢复。此外，尿苷（5g/kg/天），但胸苷（dThd）（5g/kg/天）或2'-脱氧尿苷（dUrd）（5g/kg/天）对FUra（200mg/kg）后第4天最低点时骨髓有核细胞数的减少没有保护作用。还研究了尿苷从相关氟嘧啶5-氟尿苷和5-氟-2'-脱氧尿苷的致死毒性中挽救小鼠的特异性。小鼠用5-氟尿苷（250mg/kg，腹腔注射）治疗，24小时后皮下注射5天尿苷（1、5或10g/kg/天）、dThd（1、5或10g/kg/天）或dUrd（1或5g/kg/天）。尿苷（1、5或10g/kg/天）可使小鼠从5-氟尿苷的致死毒性中获救，而dThd或dUrd无效。同样，皮下注射5天尿苷可使小鼠从5-氟-2'-脱氧尿苷（1800mg/kg，腹腔注射）的致死毒性中获救，而dThd或dUrd则无效。
