Abstract

This proposal is in response to RFA-DPCB-81-i, """"""""Mechanisms of biological and chemical prevention of carcinogenesis"""""""". The carcinogenesis systems to be investigated are, (1) patients previously exposed to leukemogenic agents such as irradiation or alkylating agents, (2) patients with preleukemia or chronic myeloid leukemia where anti promotion (and/or antiprogression) thereapy could be designed to prevent progression to acute leukemia, (3) murine long term bone marrow cultures infected with various oncogenic C type viruses where reproducible preleukemia and overtly leukemic transformation events can be induced. Basic experimental and applied clinical studies will be undertaken with, (1) Retinoids to investgate their role in inducing differentiation of malignant or premalignant hemopoietic cells: (2) Tumor necrosis factor as a potent selective anti-leukemic cytostatic (or cytotoxic) agent: (3) Serum leukemia-differentiation-inducing protein, (and its relationship to species of myeloid colony stimulating factors): (4) Prostaglandins: (5) Interferon. Synergism between these biological response modifiers has been documented and we intend to examine in detail the combination of these biological agents together with certain chemotherapeutic agents in vivo and in vitro with the aim of inhibiting leukemogenesis and preventing promotion, progression and expression of leukemia. Phase I clinical trials will be undertaken with retinoic acid in patients with preleukemia and chronic meyloid leukemia. Preleukemia and leukemic bone marrow in diffusion chambers implanted in mice or in long term bone marrow culture, will be used as experimental systems to monitor the influence of the biological response modifiers, either singely or in combination. The inducibility, origin and mechanism of action of leukemia differentiation protein will be studied following endotoxin administration in mice or in conjunction with a Phase I clinical trial of highly purified endotoxin in patients with advanced malignancy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA032516-03S1
Application #
3170414
Study Section
(SSS)
Project Start
1982-09-15
Project End
1986-02-28
Budget Start
1984-09-01
Budget End
1986-02-28
Support Year
3
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Muench, M O; Firpo, M T; Moore, M A (1993) Bone marrow transplantation with interleukin-1 plus kit-ligand ex vivo expanded bone marrow accelerates hematopoietic reconstitution in mice without the loss of stem cell lineage and proliferative potential. Blood 81:3463-73
Muench, M O; Gasparetto, C; Moore, M A (1992) The in vitro growth of murine high proliferative potential-colony forming cells is not enhanced by growth in a low oxygen atmosphere. Cytokine 4:488-94
Muench, M O; Guy, Z; Moore, M A (1992) Ex vivo differentiation therapy as a method of leukemic cell purging in murine bone marrow expansion cultures. Cancer Res 52:6576-82
Muench, M O; Schneider, J G; Moore, M A (1992) Interactions among colony-stimulating factors, IL-1 beta, IL-6, and kit-ligand in the regulation of primitive murine hematopoietic cells. Exp Hematol 20:339-49
Muench, M O; Moore, M A (1992) Accelerated recovery of peripheral blood cell counts in mice transplanted with in vitro cytokine-expanded hematopoietic progenitors. Exp Hematol 20:611-8
Steffen, M; Budde-Steffen, C; Gabrilove, J L et al. (1992) Modulation of leukemic cell growth by tumor necrosis factor: action and expression in myeloid leukemia. Leukemia 6:634-41
Moore, M A (1991) The future of cytokine combination therapy. Cancer 67:2718-26
Moore, M A (1991) Review: Stratton Lecture 1990. Clinical implications of positive and negative hematopoietic stem cell regulators. Blood 78:1-19
Slordal, L; Warren, D J; Moore, M A (1990) Protective effects of tumor necrosis factor on murine hematopoiesis during cycle-specific cytotoxic chemotherapy. Cancer Res 50:4216-20
Warren, D J; Slordal, L; Moore, M A (1990) Tumor-necrosis factor induces cell cycle arrest in multipotential hematopoietic stem cells: a possible radioprotective mechanism. Eur J Haematol 45:158-63

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