Design of a novel approach for a selective treatment of cancer using the antibody directed enzyme prodrug therapy (ADEPT) and the produg monotherapy (PMT) as well as antibody drug conjugates (ACDs).

The chemotherapy of cancer is hampered by severe side effects of the so far available cytostatic compounds, which can not differentiate between malignant and healthy cells in a sufficient manner. For an improvement of selectivity the exploitation of genetic and phenotypic differences can be used, especially employing monoclonal antibodies for targeting is high adventageous. Thus, one of our approaches for a more selective cancer therapy is based on the antibody directed enzyme prodrug therapy (ADEPT). Here a little toxic prodrug of a highly toxic compound and a conjugate of a monoclonal antibody and an enzyme is emloyed which liberates the cytostatic compound from the prodrug on the surface of cancer cells. In the produg monotherapy (PMT) cancer-selective enzymes effect the cleavage of the prodrug. We have developed glycosidic prodrugs of duocarmycine derivatives, which are about one million times less toxic than the drug with an IC50-value of 150 fM.

Prodrug for ADEPT and PMT

Overview: L.F. Tietze, K. Schmuck Prodrugs for Targeted Tumor Therapies: Recent Developments in ADEPT, GDEPT and PMT. Curr. Pharm. Des. 2011, 17, 3527-3547. Online
K.-C. Chen, K. Schmuck, L.F. Tietze, S.R. Roffler Selective Cancer Therapy by Extracellular Activation of a Highly Potent Glycosidic Duocarmycin Analogue. Mol. Pharmaceutics 2013, 10, 1773-1782. Online
L.F. Tietze, S.A. Sieber Duocarmycin Analogues without a DNA-Binding Indole Unit Associate with Aldehyde Dehydrogenase 1A1 and not DNA: A Reply. Angew. Chem. 2013, 125, 5557-5559; Angew. Chem., Int. Ed. 2013, 52, 5447-5449. Online
L.F. Tietze, M. Müller, S.-C. Duefert, K. Schmuck, I. Schuberth Photoactivatable Prodrugs of Highly Potent Duocarmycin Analogues for a Selective Cancer Therapy. Chem. Eur. J. 2013, 19, 1726-1731. Online
T. Wirth, K. Schmuck, L.F. Tietze, S.A. Sieber Novel mode of action: Duocarmycin analogs target aldehyde dehydrogenase1 in lung cancer cells. Angew. Chem. 2012, 124, 2928-2931; Angew. Chem., Int. Ed. 2012, 51, 2874-2877. Online
L.F. Tietze, J.M. von Hof, M. Müller, B. Krewer, I. Schuberth Glycosidic Prodrugs of Highly Potent Bifunctional Duocarmycin Derivatives for Selective Treatment of Cancer. Angew. Chem. 2010, 122, 7494-7497. Angew. Chem., Int. Ed. 2010, 49, 7336-7339. Online