Summary Previous studies have demonstrated that novel molecular combinations of 5-fluorouracil (5FU) and 2-chloroethyl-1-nitrosourea (CNU) have good preclinical activity and may exert less myelotoxicity than the clinically used nitrosoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study examined the effect of O 6 -alkylguanine-DNA-alkyltransferase (ATase) depletion by the pseudosubstrate O 6 -benzylguanine (BG) on the anti-tumour activity and normal tissue toxicity in mice of three such molecular combinations, in comparison with BCNU. When used as single agents at their maximum tolerated dose, all three novel compounds produced a significant growth retardation of BCNU-resistant murine colon and human breast xenografts. This in vivo anti-tumour effect was potentiated by BG, but was accompanied by severe myelotoxicity as judged by spleen colony forming assays. However, while tumour resistance to BCNU was overcome using BG, this was at the expense of enhanced bone marrow, gut and liver toxicity. Therefore, although this ATase-depletion approach resulted in improved anti-tumour activity for all three 5-FU:CNU molecular combinations, the potentiated toxicities in already dose-limiting tissues indicate that these types of agents offer no therapeutic advantage over BCNU when they are used together with BG.Keywords: O 6 -benzylguanine, nitrosoureas, anti-tumour, tissue toxicity, mouse
1332British Journal of Cancer (1999) 79(9/10), 1332-1339 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 6 March 1998 Revised 16 September 1998 Accepted 22 September 1998 Correspondence to: MC Bibby Anti-tumour effect of BG with BCNU or three novel nitrosoureas 1333British Journal of Cancer (1999) 79(9/10), 1332-1339 © Cancer Research Campaign 1999 linear pseudo-sugar fragment linking the CNU and the 5FU by the normal N 1 has been greatly simplified, the closely-related B.3996 (McElhinney et al, 1989b), containing sulphur in place of the normal sugar oxygen and an N 3 link to the pyrimidine ring and B.4152 (Loadman et al, 1996) which retains all four carbon atoms of the furanose skeleton, although lacking the usual sugar hydroxyl groups. Previous studies have shown B.4152 to be relatively marrow-sparing in a mouse in vivo model (Loadman et al, 1996).Here we report the results of a study designed to determine the capacity of BG to potentiate the anti-tumour activity of B.3995, B.3996 and B.4152, in comparison to BCNU, and to investigate the extent to which these molecular combinations are sparing to normal tissues, particularly the bone marrow.
MATERIALS AND METHODS
AnimalsPure strain NMRI mice from an inbred colony were purchased from B&K Universal Ltd, Hull, UK. NCR/Nu mice were obtained from the National Cancer Institute, Frederick, Maryland, USA. They were fed with a pellet diet (CRM, Special Diets Services, Witham, Essex, UK) and water ad libitum. Nude mice were housed in isolation cabinets. All mice had reached a minimum age of 8 weeks before use. Animal experiments were conducted in compliance wit...
