© 1982 Oxford University Press
research-article |
Mutagenicity of dibromodulcitol (DBD), an alkylating anticancer drug) and its mono- and bifunctional conversion products studied by the Salmonella/microsome assay
1National Oncological Institute: Research Institute of Oncopathology Ráth György-u. 7-9, H-1122 Budapest
2Chinoin Chemical and Pharmaceutical Works Tó-u. 1-5, H-1045 Budapest, Hungary
Dibromodulcitol (DBD) and one of its most important bifunctional transformation products, dianhydrogalactitol (DAG) with similar cytostatic effect, were tested by the Salmonella/microsome assay on strains TA 1535, TA 1538, TA 98 and TA 100 using the plate incorporation technique. Both drugs were direct mutagens in strains TA 1535 and TA 100 and non-mutagenic in other strains. Their mutagenic effect was not influenced by S-9 mix from rat liver. Mutagenicity of DAG was very limited because of its marked toxicity. The other monofunctional alkylating derivatives, i.e., 1-bromo-3, 6-anhydrodulcitol and 1,2-epoxy-3,6-anhydrodulcitol were highly mutagenic in strains TA 1535 and TA 100 with and without S-9 mix despite having no anticancer effect. Anticancer activity was exerted only by the bifunctional alkylating hexitols (DBD, DAG) which showed moderate mutagenic activity compared to the monofunctional derivatives. No correlation could be established between the mutagenic and anticancer effect of the four structurally related hexitols. Mutagenicity of urine and bile from rats after a single administration of the maximum tolerated (450 mg/kg) dose of DBD was also examined, and the hexitol components of the same urine sample were identified by t.l.c. DBD and its mutagenic transformation products were excreted in urine and not through the bile. The mutagenic effect of DBD observed cannot be attributed exclusively to DBD itself, because the parent molecule, like other alkylating agents, easily undergoes spontaneous decomposition under in vitro and in vivo conditions to release both bi- and monofunctional alkylating solvolysis products and these highly reactive derivatives may play a role in this effect. No significant difference in the relative mutagenicity was detected between DBD and cyclophosphamide, used as a reference substance.