Ph.D.: Iowa State University, 1968
Member of the University of Colorado Cancer Center and the Graduate Faculty of the School of Pharmacy, University of Colorado Health Sciences Center
Chemical Biology and Medicinal Chemistry
Our research group is currently focused on the design, synthesis and evaluation of drugs targeted to breast, prostate, lung, liver and pancreatic cancer, especially metastatic resistant cancer.
The strategy is based upon our discovery that the natural product, anthracycline, anti-tumor drug, doxorubicin (Adriamycin), reacts with formaldehyde at the amino group to form an oxazolidine. The resulting derivative, doxazolidine, is orders of magnitude more toxic to cancer cells than doxorubicin and induces cell death by a new mechanism. Doxorubicin induces apoptosis primarily through complexation with the DNA topoisomerase 2 complex to yield double strand breaks; whereas, doxazolidine induces apoptosis through cross-linking DNA.
Molecular structures of Doxorubicin, Doxazolidine, and Prodrug
Treatment of cancer is often unsuccessful because of tumor cell drug resistance coupled with tumor metastasis and side effects of chemotherapy. Resistance mechanisms relevant to doxorubicin include over-expression of a cell membrane protein which pumps drug out of the cell. Doxazolidine is not a substrate for this efflux pump. The treatment limiting chronic side effect of doxorubicin is cardiotoxicity. In fact, doxorubicin is more toxic to cardiomyocytes than to cancer cells; whereas, doxazolidine is more toxic to cancer cells than to cardiomyocytes.
These discoveries have now prompted the design, synthesis and evaluation of doxazolidine prodrugs specifically targeted to tumor cells and/or the microenvironment of tumors. The prodrugs are inactive until they are cleaved by an enzyme expressed at the site of the tumor. PPD, shown above, is a doxazolidine prodrug activated by carboxylesterase 2.
Barthel, B.L.; Rudnicki, D.L.; Kirby, T.P.; Colvin, S.M.; Burkhart, D.J.; Koch, T.H.; Synthesis and Biological Characterization of Protease-Activated Prodrugs of Doxazolidine, J. Med. Chem., 55, 6595-6607 (2012).
Barthel, B.L.; Zhang, Z.; Rudnicki, D.L.; Coldren, C.D.; Polinkovsky, M.; Sun, H.; Koch, G.G.; Chan, D.C.F.; Koch, T.H. "Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine" J. Med. Chem. 52, 7678-7688 (2009).
Spencer, D.M.; Bilardi, R.A.; Koch, T.H.; Post, G.C.; Nafie, J.W.; Kimura, K.I.; Cutts, S.M.; Phillips, D.R. “DNA repair in response to anthracycline-DNA adducts: A role for both homologuous recombination and nucleotide excision repair” Mutat. Res., 638, 110-121 (2008).
Koch, T.H.; Barthel, B.L.; Kalet, B.T.; Rudnicki, D.L.; Post, G.C.; Burkhart, D.J. “Anthracycline-formaldehyde conjugates and their targeted prodrugs” In Anthracylines: Chemistry and Biology, Topics in Current Chemistry (Krohn, K., ed.), Springer, Heidelberg, 283, 141-170 (2008).
Barthel, B.L.; Torres, R.C.; Hyatt, J.L.; Edwards, C.C.; Hatfield, M.J.; Potter, P.M.; Koch, T.H. “Identification of human intestinal carboxylesterase as the primary enzyme for activation of a doxazolidine carbamate prodrug” J. Med. Chem. 51, 298-304 (2008).
Kalet, B.T.; McBryde, M.B.; Espinosa, J.M.; Koch, T,H. “Doxazolidine induction of apoptosis by a topoisomerase II independent mechanism” J. Med. Chem. 50, 4493-4500 (2007).
Burkhart, D. J.; Barthel, B.L.; Post, G.C.; Kalet, B.T.; Nafie, J.W.; Shoemaker, R.K.; Koch, T.H. "Design, synthesis, and preliminary evaluation of doxazolidine carbamates as prodrugs activated by carboxylesterases" J. Med. Chem. 49, 7002-7012 (2006).
Post, G.C.; Barthel, B.L.; Burkhart, D.J.; Hagadorn, J.R.; Koch, T.H. “Doxazolidine, a Proposed Active Metabolite of Doxorubicin that Cross-links DNA” J. Med. Chem. 2005, 48, 7648-7657.