Lookup NU author(s): Dr Alastair Hayes,
Professor Bernard Golding
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 μM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg-1, NU7026 underwent rapid plasma clearance (0.108 l h-1) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg-1 was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg-1 i.p. in order to obtain the drug exposure required for radiosensitisation. © 2005 Cancer Research UK.
Author(s): Nutley BP, Smith NF, Hayes A, Kelland LR, Brunton L, Golding BT, Smith GCM, Martin NMB, Workman P, Raynaud FI
Publication type: Article
Publication status: Published
Journal: British Journal of Cancer
ISSN (print): 0007-0920
ISSN (electronic): 1532-1827
Publisher: Nature Publishing Group
PubMed id: 16249792
Altmetrics provided by Altmetric