Prodrugs antibody-directed enzyme prodrug therapy

A review describes how penicillins and cephalosporins having S-aminosulfenamine side-chains at the 6- and 7-positions, respectively, may act as P-lactamase-dependent prodrugs either as antibiotics or in antibody-directed enzyme prodmg therapy (ADEPT) in the treatment of cancer <00T5699>. 

Houba PHJ, Leenders RGG. Boven E, Scheeren JW, Pinedo HM, Haisma HJ. Characterization of novel anthracyciine prodrugs activated by human p-glticuronidase for use in antibody-directed enzyme prodiug therapy. Biochem Pharmacol 1996 52 455-463. 

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. 

K. D. Bagshawe, Antibody Directed Enzymes Revive Anti-Cancer Prodrugs Concept , Br. J. Cancer 1987, 56, 531-532 K. D. Bagshawe, Antibody-Directed Enzyme/Pro-drug Therapy (ADEPT) , Biochem. Soc. Trans. 1990, 18, 750-752. 

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. 

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