Stolfi R L, Martin D S, Sawyer R C, Spiegelman S
Cancer Res. 1983 Feb;43(2):561-6.
Partially purified preparations of mouse interferon, administered during the 2-day period following the administration of a toxic dose of 5-fluorouracil (FUra), yielded significant protection from mortality in BALB/c X DBA/2 F1 mice. Protection against FUra-induced toxicity was also observed when the interferon inducer polyinosinic-polycytidylic acid (poly I X poly C) was administered with FUra. The temporal relationship between the administration of poly I X poly C and FUra was found to be a critical determinant of the intensity of toxic manifestations. In relation to FUra alone, poly I X poly C could enhance (when administered 48 hr before FUra), diminish (when administered together with FUra), or not affect (when administered 48 hr after FUra) the degree of resultant toxicity. Cytofluorometric analysis of the DNA content of bone marrow cells indicated a transient period (about 42 hr) of inhibition of cell cycling following the administration of poly I X poly C, followed by reentry into cycle (between 42 and 66 hr) and a return to normal cycle phase distribution by 90 hr. This disturbance of the kinetic pattern of cell cycling in bone marrow would explain the administration time-dependent variability of the effect of poly I X poly C on FUra toxicity, since FUra is known to be a cell cycle-specific cytotoxic drug. Potential practical application of this observation to the clinical use of FUra in cancer therapy is discussed.
在给予毒性剂量的5-氟尿嘧啶（FUra）后的2天内，给予部分纯化的小鼠干扰素制剂，可使BALB/c×DBA/2 F1小鼠的死亡率显著降低。当干扰素诱导剂聚肌苷酸-聚胞苷酸（poly I×poly C）与FUra一起给药时，也观察到对FUra诱导毒性的保护作用。发现poly I×poly C与FUra给药之间的时间关系是毒性表现强度的关键决定因素。与单独使用FUra相比，poly I×poly C可增强（在FUra给药前48小时给药时）、减弱（与FUra同时给药时）或不影响（在FUra给药后48小时给药时）最终毒性程度。对骨髓细胞DNA含量的细胞荧光分析表明，给予poly I×poly C后有一个短暂的细胞周期抑制期（约42小时），随后重新进入细胞周期（在42至66小时之间），并在90小时时恢复到正常的细胞周期阶段分布。骨髓细胞周期动力学模式的这种紊乱可以解释poly I×poly C对FUra毒性作用的给药时间依赖性变异性，因为已知FUra是一种细胞周期特异性细胞毒性药物。本文讨论了这一观察结果在FUra临床癌症治疗中的潜在实际应用。
