O

B-lactamase

Drug

O OH 62b 62c

(Activated drugs)

Scheme 27. Bioactivation of prodrugs by b-lactamase.

and Figure 11.11 shows the structures of the prodrugs of a vinca derivative (63), phenylenediamine mustard (64), doxorubicin (65), melphalan (66), paclitaxel (67), and mitomycin (68) prepared based on this chemistry.11 The first report of in vivo activity in a mAb-lactamase system used the p-lactamase from E. cloacae and a cephalosphorin-vinca alkaloid prodrug LY266070 (63, Figure 11.11).108 Nude mice implanted with human colorectal carcinoma were used for the investigation. The tumor inhibitory effects of the ADEPT with mAb-lactamase conjugate and LY266070 were superior to those produced by prodrug alone. The effects were also superior to those obtained when the vinca alkaloid (Figure 11.11) was attached directly to the mAb. Long-term regression of established tumors was observed in several dosing regimens, even in animals having tumors as large as 700 mm3 at the initiation of therapy.108

In a related study, Kerr et al. reported that ADEPT treatment with a combination of a mAb-lactamase conjugate and a prodrug of cephalosphorin-phenylenediamine mustard (64) in nude mice bearing subcutaneous 3677 human tumor xenografts produced regression in all the treated mice at doses that caused no apparent toxicity.109 At day 120 post tumor implant, four of five mice who had received this treatment remained tumor free. Significant antitumor effects were even seen in mice that had large (800 mm3) tumors before the first prodrug treatment.

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