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|Kandace J. Williams, Ph.D.
Professor of Biochemistry & Cancer Biology
A subset of malignant cells that have been exposed to chemotherapeutic alkylators
invariably survive and become resistant to further treatment. The underlying basis for a cells’
decision to develop chemo-resistance, senescence, or death is not understood. The
current focus of our research is to re-direct pathways of senescence and death of
1) normal human cells, 2) alkylation-sensitive cancer cells, and 3) cancer cells that
have developed resistance to alkylation chemotherapy. Tumor cells exposed to chemotherapeutic
alkylators undergo a prolonged and inefficient caspase cleavage-independent cell death
pathway that eventually culminates either in death, stasis without senescence, or
clonogenic survival with increased alkylation tolerance and mutator phenotype. We
seek to solve two questions: 1) will inhibition of the inefficient apoptosis inducing
factor (AIF) cell death pathway redirect the tumor cell to undergo the more efficient
caspase cleavage death pathway and/or induce senescence? 2) alternatively, will inhibition
of caspase cleavage inhibit death or senescence of normal dividing cells after alkylation
treatment? Our objective is to determine how to encourage pathways within tumor cells that produce rapid cytotoxicity
and/or true senescence, and to avoid inefficient pathways that invariably produces
therapy-resistant tumor cells. Alternatively, inhibition of caspase cleavage apoptosis
in normally dividing cells should improve the therapeutic index of current chemotherapy
regimes by increased survival of nontumorigenic cells. Our central hypothesis is that
treatment with alkylating chemotherapeutics initiates less efficient and more mutation
prone pathways of cellular stasis and/or death in malignant cells, as compared to
normal replicating cells. This hypothesis has been formulated on the basis of data produced in our laboratory.
Our rationale is that a clear understanding of altered biochemical pathways in cancer
cells exposed to alkylation chemotherapeutics will allow a more logical design of
cancer treatment regimens that will enhance tumor cell death and decrease emergence
of therapy-resistant cells.
Member of the mentoring faculty for the Biomedical Sciences Graduate Program (Cancer Biology Track).
1980 B.S. (Cum Laude) Medical Technology, University of Alaska Anchorage
1987 Ph.D. Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH
1988-1991 Postdoctoral Fellow, Joseph Gottstein Memorial Cancer Research Laboratory, Dept. of Pathology, University of Washington College of Medicine, Seattle, WA
2006-present Professor, Dept. of Biochemistry & Cancer Biology, University of Toledo Health Science Campus
2001-2006 Associate Professor, Dept. of Biochemistry & Cancer Biology, Medical University of Ohio (MUO)
1997-2001 Associate Professor, Biomedical Program, Univ. of Alaska Anchorage (UAA)
1994-present Affiliate faculty, Dept. of Pathology, University of Washington School of Medicine, Seattle, WA
1991-1997 Assistant Professor, Biomedical Program & Dept. of Biological Sciences, UAA
Kaliyaperumal, S., Patrick, S.M., Williams, K.J. (2011) Phosphorylated hMSH6: DNA mismatch versus DNA damage recognition. Mut. Res. 706:36-45.
Mueser, T.C., Hinerman, J.M., Devos, J.M., and Williams, K.J. (2010) Structural analysis of bacteriophage T4 DNA replication: a review in the Virology Journal series on bacteriophage T4 and its relatives. Virol J 7:359.
Mueser, T.C., Williams, K.J. (2011) Alkylation chemotherapy: Mechanistic potential and pitfalls. In: Advances in Genetics Research (K.V. Urbano, ed.), Nova Science Publishers, pp. 179-196.
Schroering, A., Kothandapani, A., Patrick, S.M., Kaliyaperumal, S., Sharma, V.P., Williams, K.J. (2009) Prolonged cell cycle response of HeLa cells to low-level alkylation exposure. Cancer Res. 69:6307-6314.
Edelbrock, M.A., Kaliyaperumal, S., Williams, K.J. (2009) DNA mismatch repair efficiency and fidelity are elevated during DNA synthesis in human cells. Mutat. Res. 662:59-66.
Schroering, A., Williams, K.J. (2008) Rapid induction of chromatin-associated DNA mismatch repair proteins after MNNG treatment. DNA Repair 7:951-969.
Schroering, A., Edelbrock, M.A., Richards, T.J., Williams, K.J. (2007) The cell cycle and DNA mismatch repair. Exp. Cell Res. 313:292-304.
Edelbrock, M., He, H., Schroering, A., Fernstrom, M. Bathala, S., Williams, K.J. (2005) Recognition and binding of mismatch repair proteins at an oncogenic hot spot. BMS Molecular Biology 6:6.
Edelbrock, M., Fernstrom, M., Williams, K.J. p,p'-DDE and HCB: Mechanisms of toxicity to fetal and embryonic mammalian cells. In: Endocrine Disruptors (Naz, R., ed.), CRC Press, 2005.
*Kelley, M.R., *Tompkinson, A.E., *Williams, K.J., (equal contributors) Drinkwater, N.R., Fung, V.A. (2004) Frontiers of mutagenesis and DNA repair: a workshop. Cancer Res. 64:3357-3360.
Anderson, J., Simonetti, J., Fisher, D.G., Williams, J., Yasuhiro, Y., Rodrigues, N., Sullivan, D.G., Gretch, DR., McMahon, B., and Williams, K.J. (2003) Comparison of different HCV viral load and genotyping assays.. J. Clin. Virol. 28:27-37.
Williams, K.J. Fidelity of DNA synthesis as a molecular biomarker. IN: Biomarkers of Environmentally Associated Disease Technologies, Concepts, and Perspectives. S.H. Wilson, W.A. Suk, eds., CRC Press, Chapter 12, 2002.
Salmon M., Blando R., Anderson J., Berner J. and Williams, K.J. (2002) Effects of hexachlorobenzene on embryonic mammalian cells.Toxicology In Vitro, 16:539-548.
Simonetti, J., Berner, J., and Williams, K.J. (2001) Effects of p,p'-DDE on immature cells in culture at concentrations relevant to the Alaskan environment. Toxicology in Vitro, 15(2), 169-179.
Matton, N., Simonetti, J. and Williams, K.J. (2000) Identification of mismatch repair protein complexes in HeLa nuclear extracts and their interaction with heteroduplex DNA. Journal of Biological Chemistry, 275:17808-17813.
Matton, N., Simonetti, J. and Williams, K.J. (1999) Inefficient in vivo repair of mismatches at an oncogenic hotspot correlated with lack of binding by mismatch repair proteins and with phase of the cell cycle. Carcinogenesis, 20(8), 1417-1424.
Arcangeli, A., Simonetti, J., Pongratz, C. and Williams, K.J. (1997) Site- and strand-specific mismatch repair of human H-ras genomic DNA in a mammalian cell line. Carcinogenesis, 18, 1311-1318.
Arcangeli, L. and Williams, K.J. (1995) Mammalian assay for site-specific DNA damage processing using the human H-ras proto-oncogene. Nucleic Acids Research , 23, 2269-2276.