Clinical implications of dihydropyrimidine dehydrogenase inhibition.
نویسنده
چکیده
Dihydropyrimidine dehydrogenase (DPD) is the initial, rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). DPD has an important role in regulating the availability of 5-FU for anabolism. It is now clear that DPD also accounts for much of the variability observed with the therapeutic use of 5-FU, including variable drug levels during 24-hour infusion, erratic pharmacokinetics, variable bioavaialability, inconsistent toxicity, and variability in drug response (resistance). The use of DPD inhibitors has been explored as a means to improve 5-FU pharmacology. This article describes how drugs that modulate DPD activity have been used to develop a new class of orally administered fluoropyrimidines, now referred to as DPD-inhibiting fluoropyrimidine (DIF) drugs. The biochemical basis for using four DIF drugs--uracil and tegafur (UFT), ethynyluracil, S-1, and BOF-A2--currently in clinical evaluation in the United States, is hereby reviewed. Early clinical data suggest that these drugs may achieve antitumor efficacy equivalent to that of conventional intravenously administered 5-FU therapy, with the additional advantages of reduced toxicity, less expense, and improved quality of life.
منابع مشابه
Effects of uridine and thymidine on the degradation of 5-fluorouracil, uracil, and thymine by rat liver dihydropyrimidine dehydrogenase.
The kinetic properties and control mechanisms of 5-fluorouracil (5-FU), uracil, and thymine degradation by rat liver dihydropyrimidine dehydrogenase were studied in vitro. The calculated Michaelis constant (Km) for 5-FU was 3.49 +/- 0.41 (SE) microM, similar to those for uracil (2.26 +/- 0.28 microM) and for thymine (2.23 +/- 0.34 microM). However, the reduction of 5-FU appears to be most sensi...
متن کامل5-Fluorouracil toxicity and dihydropyrimidine dehydrogenase enzyme: implications for practice.
5-fluorouracil (5-FU) is a fluorinated pyrimidine analog, which is commonly used in combination chemotherapy for treating solid tumors. Dihydropyrimidine dehydrogenase plays an important role in catabolism and clearance of 5-FU. Any alteration in that sequence of enzymatic activity can lead to toxicity and even death in some patients. The most common loss of a functional allele of the dihydropy...
متن کامل5-FU multifocal inflammatory leukoencephalopathy and dihydropyrimidine dehydrogenase deficiency
inflammatory leukoencephalopathy and dihydropyrimidine dehydrogenase deficiency Article abstract—Multifocal inflammatory leukoencephalopathy (MIL) is a cerebral demyelinating syndrome that develops after chemotherapy with 5-fluorouracil (5-FU) and levamisole. The authors report a patient who developed MIL after 5-FU administration not in association with levamisole. She was subsequently diagnos...
متن کاملThe Effects of Pyruvate Dehydrogenase Kinase 4 (PDK4) Inhibition on Metabolic Flexibility during Endurance Training in Skeletal Muscles of Streptozotocin-induced Diabetic Rats
Background:Metabolic flexibility is the capacity of a system to adjust fuel (primarily glucose and fatty acids) oxidation based on nutrient availability. Pyruvate Dehydrogenase Kinase 4 (PDK4) is one of the main enzymes that play a critical role in metabolic flexibility. In current study, we examined PDK4 inhibition along with exercise training (ET) on the gene expression of Es...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Oncology
دوره 13 7 Suppl 3 شماره
صفحات -
تاریخ انتشار 1999