title: Influence of O6-benzylguanine on the anti-tumour activity and normal tissue toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea and molecular combinations of 5-fluorouracil and 2-chloroethyl-1-nitrosourea in mice.
abstract: 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 O6-alkylguanine-DNA-alkyltransferase (ATase) depletion by the pseudosubstrate O6-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.
authors: Clinical Oncology Unit, University of Bradford, UK.
authors: M C
authors: MC
authors: Bibby
authors: M J
authors: MJ
authors: Thompson
authors: J A
authors: JA
authors: Rafferty
authors: G P
authors: GP
authors: Margison
authors: R S
authors: RS
authors: McElhinney
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D002330:Carmustine / Q000009:adverse effects / Q000494:pharmacology*; D003114:Colony-Forming Units Assay; D004338:Drug Combinations; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005472:Fluorouracil / Q000737:chemistry / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D014410:Tumor Stem Cell Assay
chemical_list: D018906:Antineoplastic Agents, Alkylating; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C064976:O(6)-benzylguanine; C017139:1-(2-chloroethyl)-1-nitrosourea; D006147:Guanine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D005038:Ethylnitrosourea; D005472:Fluorouracil; D002330:Carmustine