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DNA cross-links FIGURE 11.18 Bioactivation of the prodrug CB-1954.

Target cell membrane

Target cell membrane

FIGURE 11.19 Basis of ADEPT therapy.

uptaken into the tumor cells (Fig. 11.19). One advantage of this approach is the possibility of using nonhuman enzymes, which may be more active for prodrug activation. Its main drawbacks are the scarcity of tumor-selective antigens, the possibility of immune reactions if nonhuman proteins are employed and the need for the active species to cross the cell membrane, since activation occurs extracellularly.

ADEPT strategies appear to be promising to target glucuronidated prodrugs to tumor cells because glucuronidated prodrugs are very poorly taken up by cells and hence are suitable for extracellular activation. p-Glucuronidase is widely used as an activating enzyme in ADEPT. One technique that has proved to have general value for this purpose is the use of p-glucuronyl self-immolative carbamate prodrugs, which is exemplified in Fig. 11.20 for the case of the anthracycline prodrug DOX-GA3 which showed improved antitumor activity in mice compared with DOX-GA3 administration alone.22 Prodrug activation can be assumed to take place by glucuronide hydrolysis to phenol 11.20, followed by spontaneous loss of the p-hydroxybenzyl group through a 1,6-elimination reaction 3 and final decarboxylation of the carbamic acid 11.21 thus generated.

In a related approach, an Escherichia coli nitroreductase can be used to activate prodrugs containing a p-nitrobenzylcarbamate substituent. One example is the mitomycin C prodrug 11.22, whose mechanism of bioactivation involves again a 1,6-elimination process (Fig. 11.21).24

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