Effects of some sugar alcohol derivatives on mutation and induction of sister chromatid exchanges

The mutagenicity of various alkylating sugar alcohol derivatives in the Salmonella-microsome assay was studied, and the effects of these compounds on the colony-forming ability and the frequency of sister chromatid exchange (SCE) in Chinese hamster cells were determined. Cytostatic drugs under clinical trial [Elobromol (DBD), Myelobromol (DBM), Lycurim (LY), Zitostop (ZI)], others in preclinical analysis [dianhydrogalactitol (DAG), 3,4-diacetyldianhydrogalactitol (DiacDAG), 3,4-disuccinyldianhydrogalactitol (DisuDAG)], and compounds without any known antitumor effect in transplantable tumors [1-bromo-3,6-anhydrodulcitol (BAD), 1,2-epoxi-3,6-anhydrodulcitol (EAD)] were examined. All the tested compounds except DisuDAG were directly mutagenic in Salmonella strains TA 1535 and TA 100. The mutagenic effect of the chemicals was not influenced by S9 mix from rat liver, with the exception of ZI and DiacDAG. DisuDAG appeared nonmutagenic in strains TA 1535 and TA 100 exposed to microsomal enzymes from rat liver, lung, and kidney and mouse and hamster liver, nor was DisuDAG mutagenic in strains TA 1537, TA 1538, and TA 98 in either the presence or the absence of rat liver S9 mix. Mouse urine, after a single administration of DisuDAG to the animal, proved to be mutagenic in strain TA 1535. This effect can be attributed to the presence of DAG and EAD which could be identified by thin-layer chromatography of urine, thus establishing the premutagenic character of DisuDAG. All sugar alcohol derivatives increased the frequency of SCE. Doses required to double the control SCE frequency were in the sublethal range of the survival curve for DBD, DBM, LY, DAG, and DiacDAG. Doses higher than the sublethal ones were required of ZI, DisuDAG, BAD, and EAD to achieve a 2-fold increase in SCE frequency. On the basis of these doses, the relative potencies for SCE induction of the compounds were as follows: EAD less than BAD less than DisuDAG less than ZI less than DiacDAG less than DAG less than DBD less than DBM less than LY. Within this range, there was a 2 million-fold difference in the SCE production of these chemically related compounds.