Inhibitors of DNA topoisomerase (topo) I and II are some of the newer agents used in the treatment of human malignancies. The cytotoxic effect of these is dependent on the nuclear activity of the target enzyme. The more topoisomerase in the nucleus the more effective the inhibitor. Recent preclinical data suggest that there is an optimal sequence of administration of anti-neoplastic agents (i.e., DNA-damaging agent->topo I inhibitor->topo II inhibitor) determined by levels of topo I and II. This hypothesis will be examined in vivo. Several mechanisms of drug resistance to topo inhibitors have been defined in vitro. A hypothesis to be examine din this project of the MOPP application is that alterations in the amount, activity, or location or location of topo I and II are involved in drug resistance in multiple myeloma, NHL, AML and ovarian cancer. Recent studies in the laboratory of the applicant suggest that changes in trafficking of topo IIalpha, which are growth phase- or adhesion- dependent, may also determine drug sensitivity Further studies in vitro to examine the shuttling of topoisomerases at a molecular level, as well as experiments to define mechanisms of resistance to sequential alkylator- >topo I inhibitor or topo I inhibitor-> II inhibitor exposure, may suggest other mechanisms that are operational in vivo. These hypotheses and mechanisms will be addressed through the following specific aims. 1. To determine if a specific sequence of anti-tumor agents has a biochemical justification in vivo in the high-dose chemotherapy of both multiple myeloma and NHL, as well as in the induction chemotherapy of AML. 2. To define the roles of an altered subcellular distribution of attenuation of the expression/activity of topo I or II in the drug resistance of selected hematologic malignancies and ovarian cancer. 3. To compare the mechanisms of drug resistance of selected hematologic malignancies and ovarian cancer. 3. To compare the mechanisms of drug resistance in human multiple myeloma cell lines isolated in the presence of a single drug versus a specific sequence of drugs. 4. To examine the modulation of topo IIalpha trafficking in models of drug resistance that are dependent on either growth stage or fibronectin adhesion. By examining both the molecular basis of anti-tumor drug sequencing and the role of alterations of topo I and II in the drug resistance both the molecular basis of anti- tumor drug sequencing and the role of alterations of topo I and II in the drug resistance of myeloma, NHL and ovarian cancer, these studies may suggest more effective approaches to the treatment of these diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA082533-01A1
Application #
6401797
Study Section
Subcommittee E - Prevention &Control (NCI)
Project Start
2000-05-01
Project End
2005-04-30
Budget Start
Budget End
Support Year
1
Fiscal Year
2000
Total Cost
Indirect Cost
Name
University of South Florida
Department
Type
DUNS #
City
Tampa
State
FL
Country
United States
Zip Code
33612
Daud, Adil I; Dawson, Jana; DeConti, Ronald C et al. (2009) Potentiation of a topoisomerase I inhibitor, karenitecin, by the histone deacetylase inhibitor valproic acid in melanoma: translational and phase I/II clinical trial. Clin Cancer Res 15:2479-87
Shain, Kenneth H; Yarde, Danielle N; Meads, Mark B et al. (2009) Beta1 integrin adhesion enhances IL-6-mediated STAT3 signaling in myeloma cells: implications for microenvironment influence on tumor survival and proliferation. Cancer Res 69:1009-15
Turner, Joel G; Marchion, Douglas C; Dawson, Jana L et al. (2009) Human multiple myeloma cells are sensitized to topoisomerase II inhibitors by CRM1 inhibition. Cancer Res 69:6899-905
Vultur, Adina; Buettner, Ralf; Kowolik, Claudia et al. (2008) SKI-606 (bosutinib), a novel Src kinase inhibitor, suppresses migration and invasion of human breast cancer cells. Mol Cancer Ther 7:1185-94
Buettner, Ralf; Huang, Mei; Gritsko, Tanya et al. (2007) Activated signal transducers and activators of transcription 3 signaling induces CD46 expression and protects human cancer cells from complement-dependent cytotoxicity. Mol Cancer Res 5:823-32
Nam, Sangkil; Williams, Ann; Vultur, Adina et al. (2007) Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Mol Cancer Ther 6:1400-5
Gritsko, Tanya; Williams, Ann; Turkson, James et al. (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12:11-9
Turner, Joel G; Gump, Jana L; Zhang, Chunchun et al. (2006) ABCG2 expression, function, and promoter methylation in human multiple myeloma. Blood 108:3881-9
Song, Lanxi; Morris, Mark; Bagui, Tapan et al. (2006) Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res 66:5542-8
Simon, George R; Lush, Richard M; Gump, Jana et al. (2006) Sequential oral 9-nitrocamptothecin and etoposide: a pharmacodynamic- and pharmacokinetic-based phase I trial. Mol Cancer Ther 5:2130-7

Showing the most recent 10 out of 40 publications