1. ¹Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, 15 Cotswold Road, Sutton SM2 5NG, UK
2. ²Northern Institute of Cancer Research, School of Natural Sciences – Chemistry, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
3. ³KuDOS Pharmaceuticals Ltd, 327 Cambridge Science Park, Milton Road, Cambridge CB4 0WG, UK

Correspondence: Dr F Raynaud, E-mail: florence.raynaud@icr.ac.uk

⁴Currently at the National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA

⁵Currently at Antisoma plc, West Africa House, Hanger Lane, Ealing, London W5 3QR, UK.

Received 7 June 2005; Revised 19 September 2005; Accepted 22 September 2005.

Abstract

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 M, 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.