PREFACE

A great number of currently used clinical antitumor agents contain the quinone moiety in their chemical structure. This places these drugs in a family of compounds whose metabolism is, in general, dictated by the reduction of their quinone by reductases in the organism with the production of the drug’s semiquinone. This unstable semiquinone can donate an electron to molecular oxygen (dioxygen) with the generation of reactive oxygen species (ROS) superoxide radical anion, hydrogen peroxide and hydroxyl radicals (Gutierrez). An example of quinone anticancer agents is the anthracycline and anthracenedione-based family of drugs. There is a large body of literature that studies these compounds (e.g. Anthracycline and Anthracenedione-Based Anticancer Agents. Ed. Lown J W, Elsevier, NY, 1988). One anthracycline compound, doxorubicin, also know as Adriamycin, is perhaps the most often used anti-neoplastic drug in the clinic today. These compound produce ROS, and in the case of Adriamycin, ROS results on its limiting dose due to cardiotoxicity. The anthracycline and anthracenedione-based compounds, in general, do not bind to DNA but intercalate into it resulting in changes in DNA replication. There is another series of quinone anti-cancer agents that are DNA alkylators. This special issue deals with this family of compounds which, because of their quinone structures, undergo metabolism. This has been attributed to one and/or two electrons reductions catalyzed by flavoenzymes in the presence of suitable electron donors.

In the first review paper, Begleiter describes results of clinical trials and the success and failures of some quinone alkylators. A dependence of drug activity on the type of tumor as well as finding the optimal doses for a particular drug are very important parameters in evaluating the activity of compounds in the clinic.

The mechanism of action of these quinone alkylators begins with Gutierrez’s description of their reduction by flavoenzymes leading to redox cycling and the generation of ROS. There is a concerted effort to understand the enzymology of bioreduction/ bioactivation (Hodnick) because it can lead to drug development directed at a particular enzyme (Beall). There has been some work showing that some tumors contain larger amounts of the two electron reduction enzyme DT-Diaphorase (NADPH quinone-acceptor oxidoreductase). Thus, it is reasonable to design anticancer drugs whose activity is mediated by this enzyme (Beall).

The diverse mechanisms of cytotoxicity of these compounds are discussed by Rauth stemming from the redox-cycling and alkylation of the compounds and how they affect the cell’s antioxidant defense. Hargreaves et al then focus on DNA alkylation in detail, another important mechanism in the cytotoxicity of these compounds. These compounds have the ability to preferentially alkylate a certain region of DNA.

The results of the metabolism of quinone alkylators are both DNA alkylation and generation of ROS. Both of these events can activate a variety of genes responsible for pathways that lead, among other things, to apoptosis, cell cycle changes and inhibition of cell proliferation (Cadenas). The generation of ROS during the metabolism of quinone alkylators can also lead to schemes for the development of drugs that induce a great deal of oxidative stress.