LEVODOPA AND DOPAMINE ANALOGS AS DNA-POLYMERASE INHIBITORS AND ANTI-TUMOR AGENTS IN HUMAN-MELANOMA

  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (5) , 1414-1418
Abstract
L-Dopa and dopamine are naturally occurring catecholamines with antitumor activity in several experimental tumor systems. Previous studies suggested that their cytotoxic effect was related in part to their inhibitory effect upon DNA polymerase. The effects of L-dopa, dopamine, L-dopa methyl ester, norepinephrine and the analog 3,4-dihydroxybenzylamine upon human and murine melanoma cells were studied. When exponentially growing cells were exposed to these drugs, a characteristic inhibition of thymidine incorporation was observed with much less inhibition of uridine or leucine incorporation. To ascertain that inhibition was occurring at the level of DNA synthesis, the effects of the drugs upon the incorporation of thymidine triphosphate by permeabilized melanoma cells were studied. When melanoma cells were permeabilized by lysolecithin, permitting the direct incorporation of labeled thymidine triphosphate, a similar inhibition of incorporation was observed. Dopamine at a concentration of 4.8 .mu.M caused a 50% reduction in incorporation of label. Inhibition probably did occur at the level of DNA synthesis. In the presence of the melanocyte-specific oxidase, tyrosinase, these derivatives are potent inhibitors of isolated [calf thymus] DNA polymerase .alpha. with 50% inhibitory concentrations between 1 and 10 .mu.M. The inhibition could be completely prevented by the presence of reducing agents such as dithiothreitol (1.0 mM). The quinols themselves were not inhibitors of DNA polymerase. Dopamine analogs represent an interesting class of antitumor agents with inhibitory activity for DNA polymerase.