Induction of trifluorothymidine-resistant mutants by metal ions in L5178Y/TK+/- cells

Abstract

7 inorganic metal salts including magnesium chloride, cadmium chloride, nickel chloride, zinc chloride, cobalt(II) chloride, lead acetate, sodium arsenate, and the platinum coordination complex, trans-platinum(II) diaminedichloride, were tested for the potential to induce trifluorothymidine-resistant (TFTRes) mutants in L5178Y/TK+/- mouse lymphoma cell by directly exposing cells to varied doses of each compound for 3 h. Of these 8 chemicals, cadmium chloride, nickel chloride, and trans-platinum(II) diaminedichloride consistently produced dose-related increases in the absolute number of TFTRes mutants as well as increases in mutation frequencies at compound concentrations permitting greater than 20% survival. Trans-platinum(II) diaminedichloride was a particularly effective mutagen, comparable to the direct-acting mutagen, methyl methanesulfonate. 15 representative TFTRes mutant cell clones derived from cultures originally treated with either the cadmium, or nickel, or platinum compounds were first grown out for 7 days in nonselective medium, then verified as phenotypically stable TK-/- mutants by demonstrated cross-resistance to 5-bromodeoxyuridine and 100% sensitivity to the folate antagonist methotrexate in THMG medium. These results demonstrate that the soluble salts of 2 metals reported to be human carcinogens and 1 noble metal complex known to bind DNA are all mammalian cell mutagens as well.