Strategies for the Biological Evaluation of Gold Anticancer Agents
Simon P. Fricker.
Since the introduction of the monomeric orally bioavailable anti-arthritic gold compound auranofin in 1985, and the success of the platinum-based anti-cancer drugs, there has been a great deal of interest in the use of gold compounds for cancer therapy. However this early promise has not materialized into an approved drug in spite of extensive and innovative efforts in gold chemistry. Therefore, in the light of this lack of success, the strategies for the biological evaluation of potential gold-based anti-cancer drugs are discussed. It is proposed that the biological testing strategy should be multi-faceted incorporating an understanding of the molecular properties of the compounds under investigation related to their behaviour in a biological environment, an evaluation of their comparative in vitro potency against tumor cells, ascertaining the biochemical mechanism of action and target identification to aid in medicinal chemistry design, evaluation of in vivo activity in relevant tumor models, and an understanding of their toxicological and pharmacokinetic properties. This strategy will be exemplified with work on Au(III) cyclometallated complexes in which an integrated approach to the search for new metal-based anticancer drugs was adopted, incorporating in vitro screening, in vivo human tumor xenograft models, and mechanistic studies. The importance of mechanistic studies which have led to the identification of new molecular targets for gold drugs, and in vivo evaluation are emphasized.
Keywords: Gold, cancer, screening, mechanism, thioredoxin reductase, cathepsin B, bacteriostatic, methylsarcosinedithiocarbamate, flavoenzyme, human tumor xenografts
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