Abstract

This project is an application to use genetic therapy directed against KS apoptotic mechanisms. Based on preliminary evidence found by this and other groups, the Bcl-2 and Bcl-xl gene products are expressed by KS cells in vivo and in vitro. The approach is to inactivate these gene products with a repressor, Bcl-xs. An adenovirus vector expressing Bcl-xs has been constructed. Thus far it has been lethal to all KS cells examined, presumably by induction of apoptosis. The hypothesis is that this or a similar virus vector may be a useful novel therapeutic agent for KS treatment.
The specific aims are to: (1) determine the molecular mechanism by which the Bcl-xs adenovirus kills KS cells; (2) to determine whether expression of Bcl-2, Bcl-xl or the HIV tat gene product in KS cells affect the efficiency of killing by the bcl-xs adenovirus vector; (3) to determine the effect of the bcl-xs adenovirus on a spectrum of normal cells and KS cells; and (4) to assess the possible in vivo therapeutic utility of the bcl-xs adenovirus in an animal model of KS.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070057-04
Application #
2748836
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Cremer, Kenneth J
Project Start
1995-09-30
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Song, W; Sun, Q; Dong, Z et al. (2005) Antiangiogenic gene therapy: disruption of neovascular networks mediated by inducible caspase-9 delivered with a transcriptionally targeted adenoviral vector. Gene Ther 12:320-9
Nor, J E; Hu, Y; Song, W et al. (2002) Ablation of microvessels in vivo upon dimerization of iCaspase-9. Gene Ther 9:444-51
Mitra, R S; Benedict, M A; Qian, D et al. (2001) Killing of sarcoma cells by proapoptotic Bcl-X(S): role of the BH3 domain and regulation by Bcl-X(L). Neoplasia 3:437-45
Foreman, K E; Wrone-Smith, T; Krueger, A E et al. (1999) Expression of costimulatory molecules CD80 and/or CD86 by a Kaposi's sarcoma tumor cell line induces differential T-cell activation and proliferation. Clin Immunol 91:345-53
Han, J S; Nunez, G; Wicha, M S et al. (1998) Targeting cancer cell death with a bcl-XS adenovirus. Springer Semin Immunopathol 19:279-88
Foreman, K E; Alkan, S; Krueger, A E et al. (1998) Geographically distinct HHV-8 DNA sequences in Saudi Arabian Iatrogenic Kaposi's sarcoma lesions. Am J Pathol 153:1001-4
Bonish, B K; Foreman, K E; Gutierrez-Steil, C et al. (1997) Phenotype and proliferation characteristics of cultured spindle-shaped cells obtained from normal human skin and lesions of dermatofibroma, Kaposi's sarcoma, and dermatofibrosarcoma protuberans: a comparison with fibroblast and endothelial cells of the de J Dermatol Sci 16:52-8
Foreman, K E; Bacon, P E; Hsi, E D et al. (1997) In situ polymerase chain reaction-based localization studies support role of human herpesvirus-8 as the cause of two AIDS-related neoplasms: Kaposi's sarcoma and body cavity lymphoma. J Clin Invest 99:2971-8
Foreman, K E; Friborg Jr, J; Kong, W P et al. (1997) Propagation of a human herpesvirus from AIDS-associated Kaposi's sarcoma. N Engl J Med 336:163-71
Dole, M G; Clarke, M F; Holman, P et al. (1996) Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells. Cancer Res 56:5734-40

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