Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue. Correlation of antitumor activity with dosage and FUra incorporation into RNA.
Biochemical modulation of 5-fluorouracil with leucovorin or delayed uridine rescue. Correlation of antitumor activity with dosage and FUra incorporation into RNA.
复制标题
用亚叶酸或延迟尿苷救援对 5-氟尿嘧啶进行生化调节。
DOI：
10.1016/0006-2952(92)90142-6
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发表时间：
1992
影响因子：
5.8
通讯作者：
Martin,DS
中科院分区：
文献类型：
--
作者：
Nord,LD;Stolfi,RL;Martin,DS
从化疗活性、抑制胸腺苷酸合成酶（TSase）活性和将FUra掺入RNA (FU)RNA这三个参数，比较了两种调节5-氟尿嘧啶（FUra）活性的策略在晚期小鼠cd8f1乳腺肿瘤中的作用。FUra对TSase的抑制作用可通过亚叶酸蛋白（LV）调节，并且在给药致死剂量FUra后再用尿苷“拯救”FUra可增加FUra与RNA的结合。低剂量FUra （25 mg/kg）显著抑制胸苷酸合成酶活性（49%），但每日重复相同剂量（FUra25 × 4）不能进一步增强（48%）。在FUra25 × 4中添加LV对TSase的抑制作用有所增强（55%），并且FUra25 × 4+ LV比单独使用FUra25 × 4获得更大的治疗效果。FUra单药在最大耐受周剂量为100 g/kg时，对TSase活性的抑制率为66% ~ 73%。添加LV后，这种抑制作用进一步略有增强（71-82%），其治疗效果优于添加或不添加LV的FUra25 × 4。然而，与低剂量FUra25 × 4相比，LV并未增强fura100的抗肿瘤作用。（FU）RNA随FUra剂量增加，从0.4 （FUra25）增加到2.2 nmol/mg DNA （FUra100）。在高剂量FUra （200-225 mg/kg）和尿苷“拯救”后，TSase抑制作用没有进一步增强，但（FU）RNA （4.8 nmol/mg DNA）和治疗效果均有所提高。由于在FUra100以上的剂量下，TSase不能被进一步抑制，因此增加的化疗疗效与增加的（FU）RNA相关。
Two strategies for modulation of 5-fluorouracil (FUra) activity were comparedin vivoin advanced murine CD8F1breast tumors with regard to three parameters: chemotherapeutic activity, inhibition of thymidylate synthase (TSase) activity, and incorporation of FUra into RNA, (FU)RNA. Inhibition of TSase by FUra was modulated by leucovorin (LV), and the incorporation of FUra into RNA was increased by the administration of otherwise lethal doses of FUra followed by uridine “rescue”. Thymidylate synthase activity was inhibited substantially (49%) by low-dose FUra at 25 mg/kg, but was not further enhanced (48%) by repeated daily treatments at the same dose (FUra25 × 4). Inhibition of TSase was somewhat enhanced (55%) by the addition of LV to FUra25 × 4,and a greater therapeutic effect was obtained with FUra25 × 4+ LV over FUra25 × 4alone. FUra as a single agent at the maximum tolerated weekiy dose of 100 g/kg inhibited TSase activity 66–73%. This inhibition was further enhanced slightly by the addition of LV (71–82%), and its therapeutic efficacy was greater than with FUra25 × 4with or without LV. However, in contrast to low dose FUra25 × 4,the antitumor effect of FUra100was not enhanced by LV. (FU)RNA increased with FUra dose from 0.4 (FUra25) to 2.2 nmol/mg DNA (FUra100). At a very-high-dose of FUra (200–225 mg/kg) followed by uridine “rescue”, TSase inhibition was not further enhanced, but both (FU)RNA (4.8 nmol/mg DNA) and the therapeutic efficacy were increased. Since TSase could not be further inhibited at doses above FUra100, the increased chemotherapeutic efficacy correlated with increased (FU)RNA.