Prophage induction and mutagenicity of a series of anti-tumour platinum(II) and platinum(IV) co-ordination complexes.
11 platinum compounds with nitrogen donor ligands, previously tested for anti-tumour activity, were studied for induction of prophage lambda and for mutagenicity in the Ames assay, with various strains of Salmonella. The compounds included cis and trans isomers of Pt(II) and Pt(IV) complexes and were tested with and without metabolic activation. All the cis compounds elicited prophage induction, whereas the trans compounds were inactive. Mutagenicity was found only in strains containing the R factor, indicating that SOS-type repair processes are required for the conversion of initial DNA lesions into mutations. Mutation induction was also influenced by the excision-repair process. The 2 trans compounds were not, or only slightly, mutagenic; all other compounds were mutagenic in at least one strain, exhibiting a 2-20-fold increase over the spontaneous background level. Addition of liver homogenate had no significant effect on the number of mutants. One compound induced exclusively frameshift mutations. The other mutagenic compounds induced frameshift mutations as well as base-pair substitutions. 7 compounds were more mutagenic for the repair-proficient than for the repair-deficient strains; only one showed the opposite effect. This suggests that for mutagenicity testing of platinum compounds, repair-proficient strains are more sensitive indicators. The differences in response of the various strains are more sensitive indicators. The differences in response of the various strains toward the compounds suggest the formation of different DNA lesions and/or a selective action of repair processes on these lesions. In general, a good qualitative correlation was observed between prophage-inducing capacity, mutagenicity in bacterial and mammalian cells and anti-tumour activity.
D000970:Antineoplastic Agents / Q000494:pharmacology*; D010582:Bacteriophage lambda / Q000254:growth & development; D006639:Histidine / Q000235:genetics; D009152:Mutagenicity Tests; D009153:Mutagens; D010984:Platinum / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000235:genetics; D014775:Virus Activation / Q000187:drug effects*
D000970:Antineoplastic Agents; D009153:Mutagens; D010984:Platinum; D006639:Histidine