Prodrugs therapy

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...

Fig. 6.13. Schematic representation of a selective delivery obtained by antibody-directed en-zyme-prodrug therapy (ADEPT). An exogenous enzyme is coupled to a monoclonal antibody (mAb) targeted for tumor cells. In a second step, a prodrug is administered, which, as a selective substrate of the exogenous enzyme, will be selectively activated at the tumor site.

Fig. 6.14. Schematic representation of selective delivery obtained by gene-directed enzyme-prodrug therapy (GDEPT). The gene encoding an exogenous enzyme is transferred to tumor cells, where it is to be expressed. In a second step, a prodrug is administered that is selectively activated at the tumor site by the exogenous enzyme expressed by the tumor cells.

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I. Niculescu-Duvaz, F. Friedlos, D. Niculescu-Duvaz, L. Davies, C. J. Springer, Prodrugs for Antibody- and Gene-Directed Enzyme Prodrug Therapies (ADEPT and GDEPT) , Anti-Cancer Desing 1999,14, 517-538. 

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. 

J. Cassidy, Polymer-Directed Enzyme Prodrug Therapy , Drug News Perspect. 2000, 13, 477 - 480. 

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. 

Various protocols have been used to treat cancer by gene therapy using adenoviruses, which include gene-based immunotherapy, prodrug therapy and gene replacement approaches. These procedures are often employed in combination with... 

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