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Rodent Leukemia: Recent Biological Studies. A Review^*

Arthur Kirschbaum

( Departments of Anatomy, University of Minnesota Medical School, Minneapolis 14, Minn., and of the College of Medicine, University of Illinois, Chicago 12, Ill.)

1. Morphologic types of lymphoblastoma simulating those seen in man appear in rodents.

2. Interaction of genetic and extrinsic factors determine the time of appearance and type of lymphoblastoma. A nongenetic factor contributing towards resistance is transmitted from mother to offspring and may be supplied before birth or by nursing alone. Susceptibility to the development of "spontaneous" leukemia is not determined by genes identical with those involved in reactions to leukemogenic agents such as ionizing radiations, carcinogenic hydrocarbons, and estrogenic hormones. Specific genes may control susceptibility to each leukemogen. Leukemogenic agents may act synergistically in strains of mice susceptible to the independent action of each agent.

3. Leukemic cells of certain transfer lines may harbor a virus which is not an etiologic agent for leukemia, but which causes an illness hastening death from leukemia and alters the antigenicity of cells or the immune reaction of the host. Preliminary experiments have suggested that noncellular extracts of either leukemic tissue or of embryonic cells from a high leukemic strain may cause leukemia to appear "spontaneously" if injected into mice of a low-leukemia strain. Freezing and lyophilization of mouse leukemic cells render them inactive for transmitting leukemia.

4. Estrogen favors, androgen inhibits leukemogenesis in mice in certain situations. The leukemogenic effects of both x-rays and carcinogenichydrocarbons may be potentiated by estrogenic hormone.

5. Susceptibility to the development of mouse leukemia may represent a property of the thymus, which serves not only as a primary locus for the development of the disease, but may influence its genesis in some unknown manner.

6. A humoral factor may be involved in the development of x-ray-induced leukemia. Radiation of the thymus alone, or of the whole body except the thymus, did not result in the induction of thymic tumors in animals which develop such neoplasms following whole body radiation. Since shielding of an extremity reduced the incidence of x-ray-induced thymoma, it appears that nonirradiated tissue may inactivate a humoral factor produced by radiation.

7. In a strain of mice susceptible to a particular leukemogenic agent, the younger the animal is at the time of exposure, the more the susceptibility is enhanced.

8. Nutritional factors such as caloric restriction or cystine deficiency may delay the development and reduce the incidence of spontaneous or carcinogen-induced leukemia. Pyridoxine or riboflavin deficiency are associated with the inhibition of growth of certain transplanted lymphosarcomas. It has been postulated that guanine is essential for the growth of neoplastic cells and that the growth of certain lymphosarcomas may be inhibited by the administration of 8-azaguanine, a guanine analog. The inhibitory effect of folic acid analogs on transplanted leukemia is attributed to interference with folic acid metabolism resulting in diminished nucleic acid synthesis.

9. Genetic factors control the transplantation of leukemic cells. The malignant transplantable elements are only the lymphoblastic round cells and not mesenchymal stromal elements. Antigen-antibody reactions may be involved in transplant-ability, since the gene presumably controls immunologic physiology. Homologous and heterologous immune sera may inactivate leukemic cells in vitro. Cytoplasmic constituents of leukemic cells are more highly antigenic than nuclei. Temporary growth of leukemic cells in foreign strains may be accelerated or inhibited by multiple prior injections of frozen, lyophilized tissue. Heterologous transplantation of leukemic cells can be accomplished by previous radiation of the foreign host, but not by inoculation into the anterior chamber of the eye. Humoral factors passing from normal to radiated rats joined by parabiosis may nullify radiation-induced susceptibility. Immunity towards transplanted leukemia can be passively transferred by inoculation of spleen or liver of immune animals. Resistance to homologous transplantation of leukemic cells may be overcome by inoculation of large doses of cells into very young animals.

10. Various agents may inhibit or delay the growth of certain lines of transplanted leukemic cells. Among these are "radiomimetic drugs," folic acid antagonists, cortical hormones, ionizing radiations, trivalent arsenic, benzene. Although the most active agents are those which have given the most encouraging clinical results, transplanted leukemia as generally used can at most be considered a helpful but not a critical testing medium. Wide variation exists in the response of different lines of leukemic cells to the same agent. Of greatest significance are the studies on refractoriness of leukemic cells and host to drug therapy.

^* The investigations of the author, providing a background for the writing of this review, were supported by grants from the National Cancer Institute, Public Health Service, the American Cancer Society, the Jane Coffin Childs Memorial Fund for Medical Research, the Donner Foundation, and the Graduate School of the University of Minnesota. For the most part publications of the last 7 years are considered, this review constituting a continuation of one appearing in the Yale Journal of Biology and Medicine in 1944.

Present address: College of Medicine, University of Illinois, Chicago 12, Ill.

Received 7/12/51.

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