Clinical applications of quinone-containing alkylating agents

Abstract

Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety that can be reduced and an alkylating group that can form covalent bonds with a variety of cellular components. The oxidation state of the quinone element can modulate the activity of the alkylating element, and reduction of the quinone is required for activation of the alkylating activity of many of these agents. The quinone element may also contribute to the cytotoxic activity of quinone-containing alkylating agents through the formation of reactive oxygen species during redox cycling.The natural product, mitomycin C, has been the most widely used quinonecontaining alkylating agent in the clinic, but other quinonecontaining alkylating agents like porfiromycin, diaziquone, carbazilquinone, triaziquone and EO9 havealso been used in the clinic for the treatment of cancer. In addition, many other quinone-containing alkylating agents have been tested

Dietary induction of NQO1 increases the antitumour activity of mitomycin C in human colon tumours in vivo

“…MMC is an anticancer agent that has proved to be most effective in the front line treatment of a small number of solid tumours, such as superficial bladder, gastric, pancreatic, anal, oesophageal and non-small-cell cancer (Remers, 1979, pp 27 -32;Doll et al, 1985;Begleiter, 2000). It is also used in palliative treatment of advanced or resistant cancers, generally in combination regimens (Begleiter, 2000).…”

“…It is also used in palliative treatment of advanced or resistant cancers, generally in combination regimens (Begleiter, 2000). There has been continued interest in increasing the effectiveness of this agent because of its activity in solid tumours and its enhanced effectiveness against hypoxic cells that are resistant to radiation (Workman and Stratford, 1993).…”

“…Use of MMC in the clinic has been severely restricted by its toxicity (Hortobagyi, 1993;Begleiter, 2000). The usual doselimiting toxicity is myelosuppression, which occurs 3 -4 weeks after drug administration, with recovery within 8 weeks (Begleiter, 2000).…”

“…The usual doselimiting toxicity is myelosuppression, which occurs 3 -4 weeks after drug administration, with recovery within 8 weeks (Begleiter, 2000). Generally, thrombocytopenia or leukopenia is most severe, but anemia is also common.…”

“…These agents are preferentially active in solid tumours, which represent the majority of cancers and the highest mortality. The clinical potential (Workman and Stratford, 1993) and mode of action (Rauth et al, 1993;Rockwell et al, 1993) of these agents have been actively studied, and the use of the prototype drug mitomycin C (MMC) in the clinic was recently reviewed (Begleiter, 2000). Bioreductive agents are generally activated by one-electron reducing enzymes like NADPH:cytochrome P450 reductase (RED) (Pan et al, 1984;Rockwell et al, 1993) or two-electron reducing enzymes like NAD(P)H:quinone oxidoreductase 1 (NQO1; DT-diaphorase) (Riley and Workman, 1992;Ross et al, 1993).…”