Pizzorno G, Wiegand R A, Lentz S K, Handschumacher R E
Department of Pharmacology and Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Cancer Res. 1992 Apr 1;52(7):1660-5.
Modulation of pyrimidine metabolism or the metabolic fate of 5-fluorouracil by a number of different agents has permitted a significant increase in the response rate to this agent, particularly for colorectal cancers. Brequinar, a noncompetitive inhibitor of mitochondrial dihydroorotate dehydrogenase has been shown to achieve a tumor-specific modulation of the therapeutic effect of 5-fluorouracil. A selective decrease of uridine nucleotide pools in Colon tumor 38 compared to normal tissues of C57/BL6 mice was observed after Brequinar administration. This effect was achieved with very low nontherapeutic doses of Brequinar (8 to 27% of the maximum tolerated dose in this model). Pretreatment with Brequinar 4 and 24 h prior to administration of [3H]fluorouracil significantly increased incorporation of the fluoropyrimidine into Colon 38 tumor RNA, while minimal effects were seen in normal tissues of C57/BL6 mice. Brequinar (15, 30, and 50 mg/kg) was administered 4 h prior to fluorouracil (85 mg/kg) on a weekly basis in Colon 38-bearing mice. All combinations potentiated 5-fluorouracil antitumor activity and the lowest dose of Brequinar (15 mg/kg) showed a reduced toxicity (weight loss) compared to the same dose of 5-fluorouracil as a single agent. When Brequinar preceded fluorouracil by 24 h, greater toxicity and less antitumor activity were observed. A comparison of the optimal Brequinar-fluorouracil regimen with a previously optimized N-(phosphonoacetyl)-L-aspartic acid-fluorouracil combination in Colon 38 tumor indicated that Brequinar-fluorouracil was more effective and less toxic.
多种不同药物对嘧啶代谢或5-氟尿嘧啶代谢命运的调节作用，使得对该药物的反应率显著提高，尤其是对结直肠癌。布喹那是线粒体二氢乳清酸脱氢酶的非竞争性抑制剂，已被证明可实现对5-氟尿嘧啶治疗效果的肿瘤特异性调节。在给C57/BL6小鼠注射布喹那后，观察到与正常组织相比，结肠肿瘤38中的尿苷核苷酸池选择性减少。这种效果是通过非常低的非治疗剂量的布喹那（该模型中最大耐受剂量的8%至27%）实现的。在给予[3H]氟尿嘧啶之前4小时和24小时用布喹那预处理，可显著增加氟嘧啶掺入结肠38肿瘤RNA中，而在C57/BL6小鼠的正常组织中观察到的影响最小。在携带结肠38肿瘤的小鼠中，每周在给予氟尿嘧啶（85mg/kg）前4小时给予布喹那（15、30和50mg/kg）。所有组合均增强了5-氟尿嘧啶的抗肿瘤活性，与相同剂量的单药5-氟尿嘧啶相比，最低剂量的布喹那（15mg/kg）显示出较低的毒性（体重减轻）。当布喹那在氟尿嘧啶之前24小时给药时，观察到更大的毒性和更小的抗肿瘤活性。在结肠38肿瘤中，将最佳的布喹那-氟尿嘧啶方案与先前优化的N-（膦酰基乙酰基）-L-天冬氨酸-氟尿嘧啶组合进行比较，结果表明布喹那-氟尿嘧啶更有效且毒性更低。
