Benson A B
Division of Hematology/Oncology, Department of Medicine, Clinical Investigations Program, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
Oncology (Williston Park). 2001 Jan;15(1 Suppl 2):57-63; discussion 64.
5-fluorouracil (5-FU) is irreversibly catabolized to dihydrofluorouracil, an inactive metabolite, by the enzyme dihydropyrimidine dehydrogenase (DPD). This catabolic pathway is a critical step in determining 5-FU availability for conversion to nucleotides and eventual incorporation into either RNA or DNA. Inactivation of DPD, therefore, is an approach to enhance the availability of 5-FU for potential improved therapeutic effect. Preclinical animal and human studies have demonstrated that eniluracil is an effective inactivator of DPD. Phase I studies have been completed showing the tolerability of two dosing schedules, including (1) a chronic schedule with twice-daily administration of eniluracil plus oral fluorouracil (5-FU) (10:1 ratio) for 28 days, and (2) a schedule of eniluracil administered daily on days 1-7 with oral 5-FU once daily on days 2-6. The phase I trials have demonstrated limited toxicities including diarrhea, mucositis, and neutropenia. Follow-up clinical trials have targeted colon and breast cancers in particular.
5-氟尿嘧啶（5-FU）通过二氢嘧啶脱氢酶（DPD）不可逆地分解代谢为无活性的代谢产物二氢氟尿嘧啶。这条分解代谢途径是决定5-FU转化为核苷酸并最终掺入RNA或DNA的可用性的关键步骤。因此，使DPD失活是一种提高5-FU可用性以潜在改善治疗效果的方法。临床前动物和人体研究表明，乙磺酰尿是一种有效的DPD失活剂。I期研究已经完成，显示了两种给药方案的耐受性，包括：（1）一种慢性方案，每天两次给予乙磺酰尿加口服氟尿嘧啶（5-FU）（比例为10:1），持续28天；（2）一种方案，在第1 - 7天每天给予乙磺酰尿，在第2 - 6天每天给予一次口服5-FU。I期试验显示出有限的毒性，包括腹泻、粘膜炎和中性粒细胞减少。后续的临床试验尤其针对结肠癌和乳腺癌。
