Influence of O-6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-l-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice

Previous studies have demonstrated that novel molecular combinations of 5-f luorouracil (5-FU) and 2-chloroethyl-1-nitrosourea (CNU) have good preclini cal activity and may exert less myelotoxicity than the clinically used nitr osoureas such as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). This study ex amined the effect of O-6-alkylguanine-DNA-alkyltransferase (ATase) depletio n by the pseudosubstrate O-6-benzylguanine (BG) on the anti-tumour activity and normal tissue toxicity in mice of three such molecular combinations, i n comparison with BCNU. When used as single agents at their maximum tolerat ed dose, all three novel compounds produced a significant growth retardatio n of BCNU-resistant murine colon and human breast xenografts. This in vivo anti-tumour effect was potentiated by BG, but was accompanied by severe mye lotoxicity as judged by spleen colony forming assays. However. while tumour resistance to BCNU was overcome using BG, this was at the expense of enhan ced bone marrow, gut and liver toxicity. Therefore, although this ATase-dep letion approach resulted in improved anti-tumour activity for all three 5-F U:CNU molecular combinations, the potentiated toxicities in already dose-li miting tissues indicate that these types of agents offer no therapeutic adv antage over BCNU when they are used together with BG.