Abstract

Ara-C is one of the most effective agents in the treatment of acute myelogenous leukemia. The mechanism(s) of action of ara-C and the basis for selectivity against leukemic cells, however, remains unclear. We have previously studied the effects of ara-C incorporation into leukemic cell DNA. The incorporated ara-C residue acts as a relative chain terminator and the extent of incorporation correlates with inhibition of DNA synthesis. Cytostatic concentrations of ara-C induce human leukemic cell differentiation in vitro and alter specific gene expression. Lethal effects at higher ara-C concentration are associated with termination of DNA chain elongation. The work will extend these findings by studying the mechanism(s) responsible for ara-C induced globin gene expression in human K562 erythroleukemia cells. We will extend preliminary studies demonstrating that ara-C alters proto-oncogene expression in human leukemic cells. These effects on specific gene expression will be further studied by monitoring ara-C induced changes in chromatin structure. The effects of ara-C on gene amplification, rereplication of previously replicated DNA segments and chromosomal aberrations will also be studied as events related to the accumulation of DNA replication intermediates. Finally, we will study the in vivo metabolism of ara-C during high dose continuous infusion therapy.
The specific aims are: 1) To study the molecular mechanisms of ara-C induced K562 cell differentiation by monitoring specific globin gene expression, DNA methylation and nuclease hypersensitive sites; 2) To monitor the effects of ara-C on proto-oncogene expression in human leukemic cell lines; 3) To study the effects of ara-C on DNA chain elongation, histone expression and chromatin structure; 4) To study the effects of ara-C on gene amplification, endoreduplication and chromosomal aberrations; 5) To study the pharmacodynamics of ara-C in a Phase II trial of high dose continuous infusion therapy for myeloid leukemia.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA029431-07
Application #
3168711
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1981-01-01
Project End
1991-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Kawano, Takeshi; Ito, Masaki; Raina, Deepak et al. (2007) MUC1 oncoprotein regulates Bcr-Abl stability and pathogenesis in chronic myelogenous leukemia cells. Cancer Res 67:11576-84
Wei, Xiaolong; Xu, Hai; Kufe, Donald (2007) Human mucin 1 oncoprotein represses transcription of the p53 tumor suppressor gene. Cancer Res 67:1853-8
Raina, Deepak; Ahmad, Rehan; Kumar, Shailendra et al. (2006) MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage. EMBO J 25:3774-83
Wei, Xiaolong; Xu, Hai; Kufe, Donald (2005) Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response. Cancer Cell 7:167-78
Yoshida, Kiyotsugu; Yamaguchi, Tomoko; Natsume, Tohru et al. (2005) JNK phosphorylation of 14-3-3 proteins regulates nuclear targeting of c-Abl in the apoptotic response to DNA damage. Nat Cell Biol 7:278-85
Agata, Naoki; Nogi, Hiroko; Bamberg, Michael et al. (2005) The angiogenesis inhibitor NM-3 is active against human NSCLC xenografts alone and in combination with docetaxel. Cancer Chemother Pharmacol 56:610-4
Raina, Deepak; Pandey, Pramod; Ahmad, Rehan et al. (2005) c-Abl tyrosine kinase regulates caspase-9 autocleavage in the apoptotic response to DNA damage. J Biol Chem 280:11147-51
Huang, Lei; Chen, Dongshu; Liu, Derek et al. (2005) MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin. Cancer Res 65:10413-22
Raina, Deepak; Kharbanda, Surender; Kufe, Donald (2004) The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts. J Biol Chem 279:20607-12
Li, Quan; Ren, Jian; Kufe, Donald (2004) Interaction of human MUC1 and beta-catenin is regulated by Lck and ZAP-70 in activated Jurkat T cells. Biochem Biophys Res Commun 315:471-6

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