The mechanism of DNA alkylation by the mitosenes is shown in Fig. 6.10, using the compound known as WV15 (6.13) as an example. After reductive activation to 6.14, elimination of an acetate generates iminium cation 6.15, which is able to alkylate DNA to give 6.16. A second elimination of a benzylic acetate group generates cation 6.17, which can again act as a DNA alkylating species, leading to the bis-adduct 6.18. The order of reactivity of the C-1 and C-10 positions of the mitosenes is apparently reversed with regard to that of mitomycin C, and the mitosene C-10 position is covalently bonded to the guanosine 2-amino34 and adenosine 6-amino positions.35

The aziridinylquinone EO9 has undergone extensive clinical trials owing to its good activity against hypoxic cells and its lack of bone marrow toxicity in preclin-ical models but, in spite of achieving partial responses in Phase I studies, it showed no antitumor activity in Phase II trials for breast, colon, pancreatic, gastric,36 and non-small lung37 cancers. The reasons for this failure can be the very short half-life of the drug because of fast elimination following intravenous administration, and its poor tissue penetration. These shortcomings prevent its systemic use but they may actually prove advantageous for local administration. Thus, EO9 is currently being assayed for treatment of early-stage superficial

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