UW Home

McArdle Home

Home

Faculty

Research

Teaching/Training

Resources

Events

Alumni

Research Interests: Genome protection against natural, environmental, chemotherapy or radiation-induced toxins

Research Description: The research in our laboratory is designed to enable cells to protect their genomes against toxic molecules, whether the toxins are formed during normal oxidative life, cancer therapy, metabolism of environmental toxicants or exposure to ionizing radiation. We approach this goal using two strategies: (1) the design, synthesis and pharmaceutical application of protective drug molecules to at-risk epithelial cells in hair follicles, oral mucosa, etc., first tested in animal models then in clinical studies of target cells in cancer patients to prevent alopecia, oral mucositis, etc. induced by cancer therapy; and (2) the design and synthesis of a new generation of bifunctional aminothiol radioprotector molecules, which are administered systemically; these molecules scavenge oxygen free radicals and reversibly bind to DNA to create a reversible, G1/S phase cell cycle block. The prototype of this family of low molecular weight aminothiols confers complete protection against an otherwise 100% lethal dose of gamma radiation to mice or rats. This combination of efficient oxygen free radical scavenging and reversible cell cycle block provides an effective, next generation, systemic radioprotector suitable for military, civil defense and related applications.

In both strategies (1) and (2) above, significant research is also done to optimize pharmaceutical formulation and delivery of the active agent drugs to at-risk cell populations. This involves optimization of often conflicting elements of drug solubility, mammalian pharmacokinetics and metabolism/activation of prodrug forms to achieve pharmacologic efficacy in target cell populations.

Selected patents

US 7,314,959: Fahl, W.E., Peebles, D.D., Copp, R.C. Amino Thiol Compounds and Compositions for Use in Conjunction with Cancer Therapy.

US 20070077219A1 (pending): Fahl, W.E., Ruoho, A.E., and Mehta, M. Topical vasoconstrictor preparations and methods for protecting cells during cancer chemotherapy and radiotherapy.

US 7,414,154: Fahl, W.E., Copp, R.C., Ochsner, C.E., Peebles, D. D. and Fahl, K.L. Polyamine Compounds and Compositions for Use in Conjunction with Cancer Therapy.

US 6,136,605: Fahl, W.E., Gulick, A.M., Manoharan, T.H., Puchalski, R.B., Kramer, K. and Wasserman, W.W. Glutathione S-Transferase Isoforms.

US 6,040,424: Fahl, W.E. and Wasserman, W.W. Protein and Gene for Antioxidant Response.

Selected recent publications

Pi, J., Bai, Y., Reece, J. M., Williams, J., Liu, D., Freeman, M. L., Fahl, W. E., Shugar, D., Liu, J., Qu, W., Collins, S., and Waalkes, M. P.  Molecular Mechanism of Human Nrf2 Activation and Degradation:  Role of Sequential Phosphorylation by Protein Kinase CK2.  Free Radic. Biol. Med., 42:  1797-1806, 2007.

Raghavachari, N., and Fahl, W. E. Targeted Gene Delivery to Skin Cells In Vivo: A Comparative Study of Liposomes and Polymers as Delivery Vehicles. J. Pharm. Sci., 91: 615-622, 2002.

Zhu, M., and Fahl, W. E. Functional Characterization of Transcription Regulators That Interact with the Electrophile Response Element. Biochem. Biophys. Res. Commun., 289: 212-219, 2001.

Zhu, M., Chapman, W. G., Oberley, M. J., Wasserman, W. W., and Fahl, W. E. Polymorphic Electrophile Response Elements in the Mouse Glutathione S-Transferase GSTa1 Gene That Confer Increased Induction. Cancer Lett., 164: 113-118, 2001.

Yu, R., Mandlekar, S., Lei, W., Fahl, W. E., Tan, T.-H., and Kong, A.-N. T. p38 Mitogen-activated Protein Kinase Negatively Regulates the Induction of Phase II Drug-metabolizing Enzymes That Detoxify Carcinogens. J. Biol. Chem., 275: 2322-2327, 2000.

Zhu, M., and Fahl, W. E. Development of a Green Fluorescent Protein Microplate Assay for the Screening of Chemopreventive Agents. Anal. Biochem., 287: 210-217, 2000.

Zhu, M., Chapman, W. G., Oberley, M. J., Wasserman, W. W., and Fahl, W. E.Chemoprotection Conferred by Electrophile Responsive Element-Regulated Expression of Endogenous Glutathione S-Transferase Genes. Clin. Chem. Enzym. Comm., 8: 303-313, 2000.

Chaplen, F. W. R., Fahl, W. E., and Cameron, D. C. Evidence of High Levels of Methylglyoxal in Cultured Chinese Hamster Ovary Cells. Proc. Natl. Acad. Sci. USA, 95: 5533-5538, 1998.

Kujoth, G. C., Robinson, D. F., and Fahl, W. E. Binding of ETS Family Members Is Important for the Function of the c-sis/Platelet-derived Growth Factor-B TATA Neighboring Sequence in 12-O-Tetradecanoylphorbol-13-acetate-treated K562 Cells. Cell Growth & Different., 9: 523-534, 1998.

Mehta, M. P., Sinha, P., Kanwar, K., Inman, A., Albanese, M., and Fahl, W. E. Evaluation of Internet-Based Oncologic Teaching for Medical Students. J. Cancer Educat., 13: 197-202, 1998.

Manoharan, H.T., Gallo, J., Gulick, A.M., and Fahl, W.E. High-Level Production and Purification of Biologically Active Proteins from Bacterial and Mammalian Cells Using the Tandem pGFLEX Expression System. Gene, 193: 229-237, 1997.

Wasserman, W.W., and Fahl, W.E. Functional Antioxidant Responsive Elements. Proc. Natl. Acad. Sci. USA, 94: 5361-5366, 1997.

Gulick, A.M., and Fahl, W.E. Forced Evolution of Glutathione S-Transferase to Create a More Efficient Drug Detoxication Enzyme. Proc. Natl. Acad. Sci. USA, 92: 8140-8144, 1995.