These studies will continue to evaluate the role of colony stimulating factors (CSFs) in the regulation of granulopoiesis. They will examine the activity of the known CSFs in the control of baseline neutrophil and monocyte production. Experiments will be extended to determine both beneficial as well as potential deleterious effects when these factors are used as pharmacologic agents. Antibodies will e produced to the purified or recombinant growth factors and to the specific cellular receptors for these factors. These antibodies will be used not only in mice but in agar gel cultures, in long-term marrow cultures and in experiments utilizing peritoneal diffusion chambers in irradiated mice. The latter approaches will help determine the degree of CSF production by the local microenvironment and the role of such factors in cellular proliferation. Unique experiments will examine the access, after injection, of the various CSF preparations to the responsive hemopoietic progenitor cells in vivo. These findings will indicate how many receptors need to be saturated in order to induce effects and should provide guidelines for the optimal administration of these agents. The beneficial effects of the CSFs will then be explored in animals after high dose chemotherapy or irradiation and marrow transplantation. Experiments will determine whether the CSFs can induce stem cell exhaustion when administered after minimal doses of bone marrow cells in the transplantation model. Possible marrow protection with Interleukin-1 (IL-1) and additive or synergistic actions of IL-1 with the CSFs will be determined after irradiation and chemotherapy. Potential additive or synergistic effects of the know CSFs with each other will be explored in normal and in myelosuppressed animals. Experiments will determine whether the synergy of CSF-1 with GM-CSF and IL-3 that is seen in vitro will have potential therapeutic benefits in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA015237-18
Application #
3164139
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-09-01
Project End
1994-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
18
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Western Pennsylvania Hospital
Department
Type
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15224
Shadduck, R K; Fischer, B C; DePasquale, D K et al. (1996) Paradoxical stimulation of normal and leukemic rat hematopoiesis by monoclonal antibody to CSF-1 receptor. Exp Hematol 24:314-7
Logan, T F; Gooding, W; Kirkwood, J M et al. (1996) Tumor necrosis factor administration is associated with increased endogenous production of M-CSF and G-CSF but not GM-CSF in human cancer patients. Exp Hematol 24:49-53
Gilmore, G L; Shadduck, R K (1995) Inhibition of day-12 spleen colony-forming units by a monoclonal antibody to the murine macrophage/monocyte colony-stimulating factor receptor. Blood 85:2731-4
Jones, C M; Poddar, S; Goldstein, R et al. (1994) Human MCF activates monocytes to produce IL-1 but not TNF or CSF-1. Immunobiology 190:303-16
Shadduck, R K; Waheed, A; Mangan, K F et al. (1993) Preparation of a monoclonal antibody directed against the receptor for murine colony-stimulating factor-1. Exp Hematol 21:515-20
Greenberger, J S; Sakakeeny, M A; Leif, J et al. (1992) Expression of M-CSF and its receptor (C-FMS) during factor-independent cell line evolution from hematopoietic progenitor cells cocultivated with gamma irradiated marrow stromal cell lines. Leukemia 6:626-33
Greenberger, J; Leif, J; Crawford, D et al. (1992) Humoral and cell surface interactions during gamma-irradiation leukemogenesis in vitro. Exp Hematol 20:92-102
Shadduck, R K (1992) Granulocyte-macrophage colony-stimulating factor: present use and future directions. Semin Hematol 29:38-42
Shadduck, R K (1992) Granulocyte-macrophage colony-stimulating factor: present status. Semin Hematol 29:1-3
Gonzales-Chambers, R; Przepiorka, D; Shadduck, R K et al. (1991) Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide-purged marrow for acute lymphoblastic leukemia. Med Pediatr Oncol 19:160-4

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