Abstract

The biological response modifier and activator of protein kinase C - bryostatin is a natural product purified to homogeneity which has been demonstrated to stimulate normal hematopoiesis at the same concentrations which inhibit tumor cell growth. We plan experimental studies which will continue to dissect the mechanisms of action of bryostatin with simultaneous studies which will lead to a clinical trial with this agent.
Our specific aims i nclude determination of the functional response of primitive hematopoietic progenitor target populations to bryostatin. We will utilize murine and parallel human in vitro model systems to study the experimental therapeutic properties of bryostatin. The in vivo animal studies will be performed as a preclinical model in preparation for the clinical trial. We will also establish the utility of a transplantation model to study the effects in vivo on leukemic cell growth and determine if bryostatin can be used in purging bone marrow of minimal residual disease. Finally, we will attempt to determine the molecular biochemical mechanisms of action of bryostatin on both normal and malignant hematopoietic cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047993-09
Application #
2007728
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1988-07-01
Project End
1997-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Deng, X; Ruvolo, P; Carr, B et al. (2000) Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Proc Natl Acad Sci U S A 97:1578-83
Ruvolo, P P; Deng, X; Ito, T et al. (1999) Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J Biol Chem 274:20296-300
Deng, X; Ito, T; Carr, B et al. (1998) Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J Biol Chem 273:34157-63
Ruvolo, P P; Deng, X; Carr, B K et al. (1998) A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 273:25436-42
Sharkis, S J; Collector, M I; Barber, J P et al. (1997) Phenotypic and functional characterization of the hematopoietic stem cell. Stem Cells 15 Suppl 1:41-4; discussion 44-5
Ito, T; Deng, X; Carr, B et al. (1997) Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem 272:11671-3
May, W S; Tyler, P G; Ito, T et al. (1994) Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis. J Biol Chem 269:26865-70
Carroll, M P; May, W S (1994) Protein kinase C-mediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells. J Biol Chem 269:1249-56
Ito, T; Jagus, R; May, W S (1994) Interleukin 3 stimulates protein synthesis by regulating double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci U S A 91:7455-9
Kennedy, M J; Prestigiacomo, L J; Tyler, G et al. (1992) Differential effects of bryostatin 1 and phorbol ester on human breast cancer cell lines. Cancer Res 52:1278-83

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