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Tad H. KOCH
Office Phone: 303 492 6193
E-mail: Tad.Koch@colorado.edu
FAX: 303 492 5894
Lab: Cristol Chemistry 165
Lab Phone: 303 492 7643
Group Website: http://stripe.colorado.edu/~kocht/Home.html
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
Organic and Bioorganic 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), catalyzes the synthesis of formaldehyde that it uses to covalently link itself to DNA. A combination of this covalent linkage with hydrophobic and hydrogen bonding interactions serves to virtually crosslink the DNA strands. The crosslink, which has a half-life in tumor cells of 29 hrs, serves to trigger programmed as well as non-programmed cell death.
Molecular structure of Doxorubicin
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 and over-expression of redox enzymes that interfere with doxorubicin catalyzed formaldehyde synthesis.
Our mechanistic discoveries prompted the synthesis of drug-formaldehyde conjugates as candidates for treatment of resistant cancer. Conjugates to three clinically important anthracyclines showed significant activity against a wide variety of sensitive and resistant tumor cells and in a mouse mammary model. This success has now prompted the design, synthesis and evaluation of doxorubicin-formaldehyde conjugates specifically targeted to tumor cells. The design incorporates a targeting group and a chemical trigger. The targeting group is selective for proteins overexpressed incancer cells or overexpressed by immature vascular endothelial cells that are forming a blood supply for a new tumor. The trigger releases the doxorubicin-formaldehyde conjugate with a specific time constant. The constructs will be evaluated with target proteins, with tumor cells, with immature endothelial cells, and with mice in collaboration with the University of Colorado Health Sciences Center.
Selected Publications
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.
Burke, P.J.; Kalet, B.T.; Koch, T.H. “Antiestrogen Binding Site and Estrogen Receptor Mediate Uptake and Distribution of 4-Hydroxytamoxifen-Targeted Doxorubicin-Formaldehyde Conjugate in Breast Cancer Cells” J. Med. Chem. 2004, 47, 6509-6518.
Cogan, P.S.; Koch, T.H. “Studies of Targeting and Intracellular Trafficking of an Anti-Androgen Doxorubicin-formaldehyde Conjugate in PC-3 Prostate Cancer Cells Bearing Androgen Receptor-GFP Chimera” J. Med. Chem. 2004, 47, 5690-5699.
Burkhart, D.J.; Kalet, B.T.; Coleman, M.P.; Post, G.C.; Koch, T.H. “Doxorubicin-formaldehyde Conjugates Targeting alpha-v beta-3 Integrin”, Mol. Cancer. Ther. 2004, 3, 1593-1604.
Burke, P.J.; Koch, T.H. "Design, Synthesis, and Biological Evaluation of Doxorubicin-Formaldehyde Conjugates Targeted to Breast Cancer Cells" J. Med. Chem. 2003, 47, , 1193-1206.
Cogan, P.S.; Koch, T.H. "Rational Design and Synthesis of Androgen Receptor Targeted Non-Steroidal Anti-Androgen Ligands for the Tumor Specific Delivery of a Doxorubicin-Formaldehyde Conjugate", J. Med. Chem. 2003, 46, 5258-5270.
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