) The overall objective of this application is to study a new approach to improve chemotherapeutic effectiveness of topoisomerase (Topo) I inhibitors by inhibition of intercellular contact. This hypothesis is based on previous observations that show sensitization of cells to topotecan by interference with cell adhesion in vitro. To test this hypothesis the investigator has designed a strategy to induce cell detachment in solid tumors rendering cells more sensitive to Topo I inhibitors. Briefly, the strategy is the use of an anti-sense oligonucleotide to the focal adhesion kinase pl25FAK shown to cause cell detachment in cells expressing high levels of pl25FAK. This application is directed: A) to demonstrate in tissue culture that inhibition of intercellular contact by the chosen strategy enhances susceptibility of breast cancer cell lines to Topo I inhibitors; B) to test in vivo in nude mice bearing breast cancer xenografts that inhibition of intercellular contact sensitizes breast tumors to Topo I inhibitors; and C) to investigate the mechanism by which inhibition of intercellular contact sensitizes cells to Topo I inhibitors in vitro and in vivo. The first step of this aspect of the study will be focused in evaluating changes in Topo I levels and activity by inhibition of intercellular contact. If changes only in activity are detected then post-translational modifications of Topo I by inhibition of intercellular contact will be evaluated. In addition, the levels and activity of proteins controlling cell survival and cell death, known to be important factors in response to therapy, such as PARP, p53 and members of the bcl-2 family, will be considered as prime candidates in this study.
| Satoh, Taroh H; Surmacz, Tatiana A; Nyormoi, Okot et al. (2003) Inhibition of focal adhesion kinase by antisense oligonucleotides enhances the sensitivity of breast cancer cells to camptothecins. Biocell 27:47-55 |
| Whitacre, Cecilia M; Satoh, Taroh H; Xue, Liang yan et al. (2002) Photodynamic therapy of human breast cancer xenografts lacking caspase-3. Cancer Lett 179:43-9 |
| Whitacre, C M; Feyes, D K; Satoh, T et al. (2000) Photodynamic therapy with the phthalocyanine photosensitizer Pc 4 of SW480 human colon cancer xenografts in athymic mice. Clin Cancer Res 6:2021-7 |
