Studies completed during the tenure of the expiring grant have demonstrated that the ability of DNA-specific anticancer agents to induce the differentiation of human myeloblastic leukemia (ML-1) cells depends upon the presence of natural differentiation- inducing factors. They have also shown that a myb oncogene- product, p75, controls the expression of some proliferation- related transcription. The research plan proposed is designed to expand on these topics by examining the mechanism by which ML- 1 specific growth-(GF) and differentiation factors (DF), in conjunction with pertinent oncogene (c-myb, c-myc, c-fos) products cause the expression of the cellular proliferation and differentiation programs. Specific GF and DF are to be characterized, and their cell receptors and intracellular targets are to be determined. Changes in oncogene expression during GF- and DF-initiated growth or differentiation are to be assessed, and the identity of p75 and of the mRNAs that are expressed in its presence are to be determined. Finally, the therapeutic potential that derives from the GF- and DF-mediated control of tumor growth and differentiation is to be examined, by using molecularly cloned DF for treating ML-1 leukemia cells in the nude mouse model, in the presence and absence of DNA-specific antineoplastic agents. As part of this examination, methods are to be developed for detecting the levels of DF in vivo. The proposed evaluation of the dynamic interactions that exist between GF, DF and antineoplastic drugs, and the effect these have on the molecular processes involved in growth and differentiation, should provide new insights useful for the more rational and effective use of these drugs and for the application of natural growth and differentiation factors in cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036241-06
Application #
3173756
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1984-06-01
Project End
1991-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14263
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Li, Z R; Hromchak, R; Mudipalli, A et al. (1998) Tumor suppressor proteins as regulators of cell differentiation. Cancer Res 58:4282-7
Li, Z; Hromchak, R; Bloch, A (1997) Differential expression of proteins regulating cell cycle progression in growth vs. differentiation. Biochim Biophys Acta 1356:149-59
Bloch, A; Liu, X M; Wang, L G (1995) Regulation of c-myb expression in ML-1 human myeloblastic leukemia cells by c-ets-1 protein. Adv Enzyme Regul 35:35-41
Wang, L G; Liu, X M; Li, Z R et al. (1994) Differential binding of nuclear c-ets-1 protein to an intron I fragment of the c-myb gene in growth versus differentiation. Cell Growth Differ 5:1243-51
Wikiel, H; Zhao, L; Gessner, T et al. (1994) Differential effect of growth- and differentiation-inducing factors on the release of eicosanoids and phospholipids from ML-1 human myeloblastic leukemia cells. Biochim Biophys Acta 1211:161-70
Bloch, A (1993) Dynamics of interaction between DNA-specific antitumor agents and serum-contained cytokines in the initiation of ML-1 human myeloblastic leukemia cell differentiation. Leukemia 7:1219-24
Denstman, S; Hromchak, R; Guan, X P et al. (1991) Identification of transferrin as a progression factor for ML-1 human myeloblastic leukemia cell differentiation. J Biol Chem 266:14873-6
Guan, X P; Hromchak, R A; Takuma, T et al. (1991) Tumor necrosis factor-alpha, transforming growth factor-beta, and tetradecanoylphorbol acetate: competence factors for ML-1 human myeloblastic leukemia cell differentiation. Cancer Commun 3:11-4
Fujii, Y; Takuma, T; Bloch, A (1990) A regulatory role for tumor necrosis factor (TNF) in ML-1 human myeloblastic leukemia cell maturation. Leuk Res 14:941-7

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