Prodrugs activation

Fraaije MW, NM Kammerbeek, AJ Heidkamp, R Fortin, DB Janssen (2004) The prodrug activator EtaA from Mycobacterium tuberculosis is a Baeyer-Villiger monooxygenase. J Biol Chem 279 3354-3360. 

Roffler, S.R., and Tseng, T.-L. (1994) Enhanced serum half-life and tumor localization of PEG-modified antibody-enzyme conjugates for targeted prodrug activation. Antibody Engineering Conference. San Diego, California. 

Fig. 2. Ligand substitution as a prodrug strategy for metallochem-otherapeutics (a) general scheme of prodrug activation by ligand substitution hydrolysis of a metal—halide bond is a typical activation pathway of metal-based anticancer drugs, as exemplified by the activation of cisplatin (b) and a ruthenium—arene complex (c).

Fig. 3. Photoactivation of Pt(IV) complexes as a prodrug strategy for metallochemotherapeutics (a) general scheme of prodrug activation by photoreduction (b) photosubstitution and photoisomerization are competing photoreaction pathways, which can result in different reactive species upon reduction (c) an example of a photoactive platinum(IV) diazido complex developed in our lab.

An alternative approach is the use of a tumour-specific antibody to which a prodrug activating enzyme has been attached. Therapeutically inactive prodrugs could be administered by,... 

Much the most developed example of prodrug activation comes from our own laboratory. The cytotoxicity of nitrogen mustards is dependent on substitution on the nitrogen atom electron-withdrawing substituents... 

Prodrug activation occurs enzymatically, nonenzymatically, or, also, sequentially (an enzymatic step followed by a nonenzymatic rearrangement). As much as possible, it is desirable to reduce biological variability, hence the particular interest currently received by nonenzymatic reactions of hydrolysis or intramolecular catalysis [18][20], Reactions of cyclization-elimination appear quite promising and are being explored in a number of studies. 

C. J. Springer, I. Niculescu-Duvaz, Prodrug-Activating Systems in Suicide Gene Therapy , J. Clin. Invest. 2000,105, 1161-1167. 

Prodrugs, which occupy a significant position in the scope of the present volume, were defined and discussed in Chapt. 1. In addition to this chapter, prodrugs activated by reactions of hydrolysis receive further attention in Chapt. 4, 6, 9, and 11. 

T. Ikeda, Two Prodrugs Activated by Serum Esterases Including Albumin , in Serum Albumin and rAcid Glycoprotein From Basic Sciences to Clinical Applications , Eds. M. Otagiri, Y. Sugiyama, B. Testa, J. P. Tillement, University of Kumamoto, 2001, p. 173-180. 

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. 

Kim, I., Song, X., Vig, B.S., Mittal, S., Shin, H.-C., Lorenzi, P.J. and Amidon, G.L., A novel nucleoside prodrug-activating enzyme substrate specificity of biphenyl hydrolase-like protein. Mol. Pharm., 2004,1, 117-127. 

Cefuroxime is also a second-generation cephalosporin resistant to some -lactamases. It is used in veterinary medicine in intramammary treatments. Cefuroxime axetil is also a prodrug active by the oral route. It is absorbed from the gastrointestinal tract and its absorption is enhanced if the compound is given after... 

Fig. 2. Structure of the antibody Fab fusion protein expressed from the vector in Fig. 1 The antigen-binding region is formed by the VH and VL domains, the foreign protein (FP) fused to the truncated hinge region (H1) may be a toxin or prodrug activating enzyme.

Springer, C. J., and Niculescu-Duvaz, I. Prodrug-activating systems in suicide gene therapy. J. Clin. Invest. 105 1161-1167, 2000. 

J. D. Harris, A. A. Gutierrez, H. C. Hurst, K. Sikora, and N. R. Lemoine, Gene therapy for cancer using tumour-specific prodrug activation, Gene Ther. 7 170 (1994). 

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