Paul David Foglesong, Ph.D.

My laboratory is determining the levels of human DNA topisomerases (Topo I, Topo II a , Topo II b, Topo III a ) in normal and tumor tissures by imunohistochemistry, in situ hybridization, and catalytic assays. We have characterized over 250 tumor tissues to date. In most of the tumors there are markedly elevated levels of Topo II a and Topo II b . These results have been compared to similar studies using monoclonal antibodies against Ki-67, proliferating cell nuclear antigen (PCNA), p53 and other markers. These observations are highly relevant to chemotherapy since cells containing higher levels of Topo II are more sensitive to anti-tumor drugs which inhibit them.

We are also characterizing the effects of interleukin-2 (IL-2) upon the levels of DNA topoisomerases in HuT 78 cells (human T cell lymphoma which respond mitogenically to IL-2). Topo I activity is induced in HuT 78 cells rapidly after IL-2 treatment in three distinct peaks. The first occurs 15-30 minutes after treatment, then another peak of activity was observed after 2-4 h, and lastly, a peak was seen at 12-24 h after treatment. We have discovered that IL-2 induces the activity of Topo II in HuT 78 cells. We are characterizing the molecular mechanism(s) of the induction of Topo activity (i.e., increased transcription, translation, phosphorylation). Also, we are investigating the possible role of DNA topoisomerases in the transcription of genes following treatment of cells by IL-2.