The overall goal of the proposed research is to explore mechanisms of activation and regulation of function in normal and neoplastic cells. The studies involve (a) cytoplasmic control of cell replication, (b) modification of tumor cell properties by non-cytotoxic lymphokines, (c) regulation of lymphokine production and the expression of lymphokine activity, and (d) the effects of non-immunologic growth factors on the immune response. Studies in the first category are based on our observation that mitogen- or interleukin-activated normal lymphocytes contain a cytoplasmic protein (ADR) that can induce DNA synthesis in isolated nuclei in a cell-free system. We have also found that this factor is produced consitutively by neoplastic cells. We propose to investigate this regulatory system for cell proliferation by purifying ADR, studying the mechanisms involved in its reaction with the cell nucleus, and determining the abnormalities of ADR, nucleus, and inhibitory systems in neoplastic cells. Studies in the second category are based on the premise that modification of functional properties of tumor cells by immunologic mediators may be as useful a form of tumor therapy as the more commonly attempted strategies desighed to kill tumor cells. To this end, we are studying the ability of lymphokines to inhibit tumor cell migration and inhibit binding of tumor cells to endothelium, as well as the effects of lymphokines on other aspects of tumor cell behavior. Studies in the last two categories are designed to provide insight into novel ways in which immune regulation may be achieved, with special attention to lymphokine production and the expression of lymphokine activity. To this end, various immunologic regulatory macromolecules as well as hormonal growth and regulatory factors not generally considered to be part of the immune system will be investigated. Our overall approach for this aim involves the purification and characterization of responsible factors, elucidation of their mechanism of action, investigation of possible alterations in neoplastic states, and, ultimately, attempts to manipulate the systems in which they participate for possible therapeutic effort. It is hoped that these studies will provide insights into basic mechanisms of cell growth and regulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA039723-05
Application #
3478978
Study Section
Special Emphasis Panel (SRC)
Project Start
1987-06-01
Project End
1993-05-31
Budget Start
1990-06-01
Budget End
1991-05-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Hahnemann University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Coffman, Frederick D; He, Mai; Diaz, Mai-Ling et al. (2006) Multiple initiation sites within the human ribosomal RNA gene. Cell Cycle 5:1223-33
Baloch, Z; Cohen, S; Fresa, K et al. (1995) Modulation of topoisomerase activities by tumor necrosis factor. Cell Immunol 160:98-103
Bereta, M; Bereta, J; Georgoff, I et al. (1994) Methylxanthines and calcium-mobilizing agents inhibit the expression of cytokine-inducible nitric oxide synthase and vascular cell adhesion molecule-1 in murine microvascular endothelial cells. Exp Cell Res 212:230-42
Fresa, K L; Autieri, M V; Coffman, F D et al. (1993) A cytosolic activator of DNA replication is tyrosine phosphorylated in its active form. Exp Cell Res 205:302-10
Bereta, J; Bereta, M; Cohen, S et al. (1993) Regulation of VCAM-1 expression and involvement in cell adhesion to murine microvascular endothelium. Cell Immunol 147:313-30
Coffman, F D; Georgoff, I; Fresa, K L et al. (1993) In vitro replication of plasmids containing human ribosomal gene sequences: origin localization and dependence on an aprotinin-binding cytosolic protein. Exp Cell Res 209:123-32
Ye, X; Georgoff, I; Fleisher, S et al. (1993) The mechanism of epipodophyllotoxin-induced thymocyte apoptosis: possible role of a novel Ca(2+)-independent protein kinase. Cell Immunol 151:320-35
Coffman, F D; Fresa, K L; Hameed, M et al. (1993) Characteristics of DNA replication in isolated nuclei initiated by an aprotinin-binding protein. J Cell Biochem 51:157-64
Bereta, M; Bereta, J; Cohen, S et al. (1992) Low density lipoprotein inhibits accumulation of nitrites in murine brain endothelial cell cultures. Biochem Biophys Res Commun 186:315-20
Bereta, J; Bereta, M; Coffman, F D et al. (1992) Inhibition of basal and tumor necrosis factor-enhanced binding of murine tumor cells to murine endothelium by transforming growth factor-beta 1. J Immunol 148:2932-40

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