Many agents used in the treatment of human malignancy are known to induce chromosome aberrations, resulting in cell death of the tumor cells and clinical response. At the same time, chromosome aberrations are also produced in normal tissue, and this can result in treatment-associated morbidity (e.g. myelosuppression and mucositis) and increased risk for the development of second malignancy. The long-term goal of this research is to improve the therapeutic index of the treatment of malignant disease, i.e. maximize damage to tumor tissue and minimize damage to normal tissue. To achieve this goal, it is important to better understand the molecular mechanisms involved in chromosome aberration formation and repair after treatment with therapeutic agents. This proposal focuses on two general issues. First, the relationship between chromatin structure and sensitivity to therapeutic agents is addressed by examining Ataxia telangiectasia cells for alterations in chromatin structure that impact initial levels of DNA and chromosome damage and the cell's ability to repair this damage. In addition, the chromatin of cells is altered by Topoisomerase II antagonists and its effects on chromosome damage, repair and survival of irradiated normal and tumor cells is determined. The working hypothesis behind this approach is that the manner in which DNA is folded up into chromatin can affect the efficiency of conversion of DNA double strand breaks into chromosome breaks as well as their repairability. DNA and chromosome damage and repair is determined by the DNA filter elution and premature chromosome condensation techniques, and chromatin organization is probed at the nucleoid level. The second focus of the proposal is a determination of the consequences of inhibition of chromosome repair with metabolic inhibitors such as F-AraA, with regard to its long term consequences on residual levels of chromosome damage as well as cell survival. Chromosome studies here will be enhanced with fluorescence in situ hybridization using chromosome-specific probes ('chromosome painting'). These latter-studies will yield significant new information regarding the molecular mechanisms of chromosome damage and repair as well as provide a potential approach to increasing the therapeutic ratio in the treatment of malignant disease. Overall, the proposed studies will provide basic insights into chromosome aberration mechanisms as well as clinically relevant information for therapeutic strategies and the long term effect of therapy on normal tissues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA027931-13
Application #
2087661
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1980-05-01
Project End
1995-11-30
Budget Start
1993-12-01
Budget End
1994-11-30
Support Year
13
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Milas, L; Fujii, T; Hunter, N et al. (1999) Enhancement of tumor radioresponse in vivo by gemcitabine. Cancer Res 59:107-14
Gregoire, V; Hunter, N R; Brock, W A et al. (1996) Improvement in the therapeutic ratio of radiotherapy for a murine sarcoma by indomethacin plus fludarabine. Radiat Res 146:548-53
Vyas, R C; Frankel, S R; Agbor, P et al. (1996) Probing the pathobiology of response to all-trans retinoic acid in acute promyelocytic leukemia: premature chromosome condensation/fluorescence in situ hybridization analysis. Blood 87:218-26
Pandita, T K; DeRubeis, D (1995) Spontaneous amplification of interstitial telomeric bands in Chinese hamster ovary cells. Cytogenet Cell Genet 68:95-101
Pandita, T K; Hittelman, W N (1995) Evidence of a chromatin basis for increased mutagen sensitivity associated with multiple primary malignancies of the head and neck. Int J Cancer 61:738-43
Gregoire, V; Ruifrok, A C; Price, R E et al. (1995) Effect of intra-peritoneal fludarabine on rat spinal cord tolerance to fractionated irradiation. Radiother Oncol 36:50-5
Gregoire, V; Hunter, N; Milas, L et al. (1994) Potentiation of radiation-induced regrowth delay in murine tumors by fludarabine. Cancer Res 54:468-74
Gregoire, V; Van, N T; Stephens, L C et al. (1994) The role of fludarabine-induced apoptosis and cell cycle synchronization in enhanced murine tumor radiation response in vivo. Cancer Res 54:6201-9
Pandita, T K; Gregoire, V; Dhingra, K et al. (1994) Effect of chromosome size on aberration levels caused by gamma radiation as detected by fluorescence in situ hybridization. Cytogenet Cell Genet 67:94-101
Kuo, M T; Vyas, R C; Jiang, L X et al. (1994) Chromosome breakage at a major fragile site associated with P-glycoprotein gene amplification in multidrug-resistant CHO cells. Mol Cell Biol 14:5202-11

Showing the most recent 10 out of 32 publications