Induction of rat leukemias and thymic lymphoma by N-nitrosoureas

Some of the recent advances in experimental research on leukemogenesis have been due to the use of various N-nitrosoureas. Specifically, N-ethyl-, N-n-propyl-, N-n-butyl-, and N-n-butyl-N',N'-dimethyl-N-nitrosoureas have been found to be effective for inducing leukemias in rats. The induced leukemias are divided into four major types; myeloblastic, myelocytic, erythroblastic, and lymphoblastic, and each type is hematologically and pathologically characteristic. Four possible pathways for the induction process of leukemia by N-nitrosoureas are proposed and discussed. 1) Normal hematopoietic cell(s) mutate directly into leukemic cell(s) by the direct action of N-nitrosourea. 2) Hematopoietic cell(s) recover from chemically or physiologically induced cytotoxic effects and undergo proliferation into leukemic cell(s) by secondary N-nitrosourea action. 3) Bone marrow cell(s) are altered by chemical or physical agents and exhibit genetic instability to become leukemic cell(s) by secondary N-nitrosourea action. 4) The bone marrow cells upon interaction with chemical or physical agents become altered cells, which may undergo intensive clonal proliferation. These proliferating cells may subsequently interact with additional N-nitrosourea to develop into leukemic cell(s). In addition, the immunosuppressive state of the host, various growth factors, and promotors may also act on the newly induced leukemic cell(s) to produce and apparent leukemia. Experiments on rat thymic lymphoma are also briefly reviewed.