Antibody directed enzyme prodrug

Structure 139 represents a cephalosporin conjugate of SIN-1 13 that has been synthesized and evaluated as a /3-lactamase-dependent, nitric oxide-releasing conjugate with potential application in antibody-directed enzyme prodrug therapy (ADEPT) <2003BML1687>. 

Figure 13.7 Outline of antibody-directed enzyme prodrug therapy (ADEPT). Subsequent to its enzymatic activation, the active drug is taken up by the cell, upon which it exhibits a cytocidal effect. Refer to text for specific detail...

M. P. Napier, S. K. Sharma, C. J. Springer, K. D. Bagshawe, A. J. Green, J. Martin, S. M. Stribbling, N. Cushen, D. O Malley, R. H. Begent, Antibody-Directed Enzyme Prodrug Therapy Efficacy and Mechanism of Action in Colorectal Carcinoma , Clin. Cancer Res. 2000, 6, 765-772. 

G. K. Smith, S. Banks, T. A. Blumenkopf, M. Cory, J. Humphreys, R. M. Laethem, J. Miller, C. P. Moxham, R. Muhin, P. H. Ray, L. M. Walton, L. A. Wolfe III, Toward Antibody-Directed Enzyme Prodrug Therapy with the T286G Mutant of Human Carboxypeptidase A1 and Novel in vivo Stable Prodrugs of Methotrexate , J. Biol. Chem. 1997, 272, 15804-15816. 

A. B. Mauger, P. J. Burke, H. H. Somani, F. Friedlos, R. J. Knox, Self-Immolative Prodrugs Candidates for Antibody-Directed Enzyme Prodrug Therapy in Conjunction with a Nitroreductase Enzyme , J. Med. Chem. 1994, 37, 3452-3458. 

P. H. J. Houba, R. G. G. Leenders, E. Boven, J. W. Scheeren, H. M. Pinedo, H. J. Hais-ma, Characterization of Novel Anthracycbne Prodrugs Activated by Human /3-Glucuronidase for Use in Antibody-Directed Enzyme Prodrug Therapy , Biochem. Pharmacol. 

Y. L. Leu, S. R. Roffler, J. W. Chern, Design and Synthesis of Water-Soluble Glucuro-nide Derivatives of Campothecin for Cancer Prodrug Monotherapy and Antibody-Directed Enzyme Prodrug Therapy (ADEPT) , J. Med. Chem. 1999, 42, 3623 - 3628. 

Antibody-directed enzyme prodrug therapy (ADEPT) illustrates a further application of... 

ADEPT antibody directed enzyme prodrug therapy... 

Fig. 11. Principle of antibody directed enzyme prodrug therapy. Hatched circles represent cells that have not bound antibody-enzyme conjugate. Internalized drug is abbreviated with the letter d . (From [172] with permission)...

Abbreviations. NMRI, nuclear magnetic resonance imaging Antp, antennapedia RES, reticuloendothelial system ADEPT, antibody-directed enzyme prodrug therapy TAT. 

Smith GK, Banks S, Blumenkopf TA, et al. Toward antibody directed enzyme prodrug therapy with the T268G mutant of human carboxypeptidase Al and novel in vivo stable prodrugs of methotrexate. J Biol Chem 1997 272(25) 15804—15816. 

Bagshawe, K D. (1994) Antibody-directed enzyme prodrug therapy Clin Pharmacokmet 27, 368—376. 

Francis RJ, Sharma SK, Springer C, Green AJ, et al. 2002. A phase I trial of antibody directed enzyme prodrug therapy (ADEPT) in patients with advanced colorectal carcinoma or other CEA producing tumours. Br J Cancer. 87 600-607. 

Schmidt, R Ungureanu, I. Duval, R. Pompon, A. Monneret, C. Cancer therapy a paclitaxel prodrug for ADEPT (antibody-directed enzyme prodrug therapy). Eur. J. Org. Chem., 2001, 2129-2134. 

There have been also attempts to prepare targeted drugs based on anthracyclines employing the recognition of some specific sugars by receptors on the tumor cells. Thus, a /3-glucoside derivative of adriamycin (41) was used in an antibody-directed enzyme-prodrug therapy (O Scheme 16) [53],... 

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