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.