Autologous marrow rescue in the treatment of leukemia is limited by the presence of occult viable leukemic cells in the marrow inoculum. The differential sensitivity of neoplastic versus normal hemopoietic cells supports the concept that ex vivo incubation of autologous marrow suspensions with selected cytotoxic agents may eliminate leukemic cells yet spare normal hemopoietic """"""""stem' cells. The proposed research will evaluate pharmacologic treatment of normal marrow and leukemic cell suspensions in a model of acute myelogenous leukemia (AML) in the Lewis-Brown Norway hybrid (LBN) rat. Four different agents will be studied: 4-hydroperoxycyclophos-phamide (4HC), bleomycin (BLEO), VP- 16, and m-AMSA. First, normal LBN marrow or AML cells will be incubated with increasing concentrations of each test drug. The treated normal marrow cells will be injected into lethally- irradiated syngeneic rats to assess drug effects on normal hemopoietic stem cells and hematologic reconstitution. Drug- treated AMl cells will be injected into unprepared LBN rats, and times to death from leukemia or leukemia-free survival, indicative of magnitude of elimination of AML cells by the drug treatment, will be determined. These dose-response curves will provide a range of drug concentrations with which mixtures of normal marrow and AML cells (to approximate a """"""""remission"""""""" marrow) will be incubated and injected into lethally-irradiated syngeneic rats to observe hematologic reconstitution, time to development of leukemia, and /or leukemia-free survival. Second, examination of sequential incubation of normal marrow. AML cells, and mixtures thereof with two of the above drugs will determine whehter combined sequential treatment with sub- curative doses of either durg alone may eradicate all clonogenic tumor yet not be toxic to normal rat marrow stem cells. In addition, complementary studies of the effects of incubation with these antineoplastic agents (singly and in combination) on the sensitivity of committed marrow-derived hemopoietic progenitor cells (granulocyte-macrophage colony-forming cells; GM-CFC) and a recently-described subline of LBN AML (the IPC-81 subline) will be conducted by in vitro clonogenic assays. These preclinical studies, which will develop principles for chemotherapeutic """"""""purging"""""""" of leukemic cells from syngeneic marrow, are germane to the development of therapeutic strategies in autologous marrow transplantation for human lymphohemopoietic malignancies.
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