Inhibitory effects of gold sodium thiomalate on DNA polymerase alpha.

The usefulness of gold compounds in the therapy of rheumatoid arthritis is well established, however, the pharmacological mechanisms of the compounds are still unclear. In this report, effects of gold compounds on DNA synthesis were examined. Gold sodium thiomalate inhibited DNA synthesis in the HeLa "nuclei system" as well as in the enzyme reaction using DNA polymerase alpha. More precisely, gold sodium thiomalate inhibited the activity of DNA polymerase alpha using activated DNA, poly[d(A-T)] or poly[d(G-C)] for the template, but did not inhibit the activity of DNA polymerase I with each template. The compound had also no inhibitory effect on DNA polymerase beta or gamma. On the other hand, auranofin inhibited the incorporation of [3H]thymidine into HeLa DNA but did not inhibit DNA synthesis in the HeLa "nuclei system". The inhibition of DNA polymerase alpha activity by gold sodium thiomalate was competitive with poly(dA).oligo(dT) for template but noncompetitive with dTTP. Thus, gold sodium thiomalate is a potent and specific inhibitor of DNA polymerase alpha and this inhibitory effect could play an important role in the therapeutic and pharmacological effects of gold sodium thiomalate.