Prodrugs ADEPT

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...

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>. 

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.

Table 6.3. Substrate Selectivity of Human Carboxypeptidases A1 andA2 (hCPAl and hCPA2) and Artificial Mutants toward Methotrexate Prodrugs for Use in ADEPT [62] ...

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. 

The so-called self-immolative prodrugs are other relevant and intriguing examples as candidates for ADEPT (Fig. 8.17). Here, the primary bioactivation product is not the active agent, but an intermediate that breaks down spontaneously to liberate this active agent. Various cytotoxic drugs that bear an amino group were investigated, i. e., 4-[bis(2-chloroethyl)amino]aniline, actinomycin D, doxorubicin, and mitomycin C [206]. These were trans-... 

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. 

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... 

This field was recently reviewed [172]. Enzymes that have been used for ADEPT are, e.g., alkaline phosphatase, carboxypeptidase A, cytosine deaminase, -lactamase prodrugs and corresponding drugs were, e.g., adriamycin phosphate and adriamycin, methotrexate-alanine and methotrexate, 5-fluorocytosine and 5-fluorouracil, and vinca-cephalosporin and vinca alkaloid [172 and references therein]. 

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

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. 

The first clinically tested ADEPT prodrug, 4-[(2-chloroethyl)(2-mesy-loxyethyl) amino]benzoyl-L-glutamic acid (CMDA), is converted in vivo to the cytotoxic parent drug 4-[(2-chloroethyl)[2-(mesyloxy)ethyl]amino]ben-zoic acid, as shown in Fig. 3.15. 

Several ADEPT systems that are beyond the scope of this chapter have been studied extensively and are the subject of many reviews.15,92-93 One of the most widely cited ADEPT systems employs a glucouronidase (GUS)-monoclonal antibody conjugate that activates a doxorubicin-glu-curonide prodrug. Studies have shown that there is a substantial therapeutic benefit, a higher level of drug in tumor tissue when compared... 

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