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Evaluation of the in Vivo Antitumor Activity and in Vitro Cytotoxic Properties of Auranofin, a Coordinated Gold Compound, in Murine Tumor Models

Departments of Molecular Pharmacology, Immunology, and Natural Products Pharmacology, Smith Kline and French Laboratories, 19101 [C.K.M., R.K.J., C.M.S., L.F., K.M., S.T.C.] and Department of Pharmacology, University of Pennsylvania [C.K.M., S.T.C.], Philadelphia, Pennsylvania 19104; and Department of Pharmacology, Baylor College of Medicine [S.T.C.], Houston, Texas 77030

The coordinated gold compound, 2,3,4,6-tetra-O-acetyl-1-thio-ß-D-glucopyranosato-S-triethylphosphine gold (auranofin; Ridaura), was evaluated for antitumor activity in a variety of mouse tumor models. Of the 15 tumor models evaluated, auranofin was found to be active only against i.p. P388 leukemia. A number of dose schedules was used to measure activity against P388 with optimal activity observed at 12 mg/kg given daily, i.p., on Days 1 to 5. Auranofin was active against i.p. P388 leukemia only when administered i.p.; the drug was completely inactive when administered i.v., s.c., or p.o. on Days 1 to 5.

Evaluation of the effects of auranofin in vitro demonstrated that (a) survival curves for B16 melanoma cells as measured by the clongenic and dye exclusion assays were exponential and monophasic; (b) cell cycle distribution was not altered, and auranofin displayed no preferential cytotoxicity to logarithmic or plateau growth phase cell populations; (c) auranofin inhibited DNA, RNA, and protein synthesis at cytotoxic concentrations but showed no selective effect; (d) the cytotoxic activity and cellular association of gold from auranofin were dose, time, and temperature dependent; and (e) binding of auranofin gold to serum proteins markedly decreased cellular uptake of gold and cytotoxicity of auranofin in vitro.

¹ To whom requests for reprints should be addressed.

Received 7/26/84. Accepted 10/ 9/84.