Urethane-Caused Blood and Bone Marrow Changes in Agranulocytosis and Panmyelopathy of the Cat

The investigations reported in the present paper deal with the behavior of the peripheral blood and the bone marrow in urethane-produced agranulocytosis and panmyelopathy in the cat. The principal conclusions follow:

1. A severe panmyelopathy can be produced regularly in cats by the administration of relatively small doses of urethane: viz., 0.05 to 0.1 Gm. per Kg. per day. The panmyelopathy is still reversible if the urethane is stopped early enough and if the animal is maintained with antibacterial therapy.

2. The time required for recovery of the bone marrow after cessation of urethane administration depends on the total dosage of the drug. After small doses recovery occurs rapidly; after large doses much more slowly. Individual sensitivity of the experimental animal also plays a role, however.

3. The effect of smaller doses of urethane (0.05 Gm./Kg./day) on the bone marrow is to produce inhibition of maturation of granulocytopoiesis, and, to a lesser degree, of thrombocytopoiesis. To a still lesser extent, there is also inhibition of maturation of the red cell series.

4. The effect of larger doses of urethane (0.1 Gm./Kg./day) on the bone marrow, the effect on maturation is overshadowed by a generalized depletion of all marrow cells. Part of this effect is due to a decrease in the number of mitoses, with reduction of the mitotic index; as well as qualitative alterations in the mitotic patterns. It is probable that the effect on mitoses results in the formation of cells which are incapable of life as well as in an overall decrease in the formation of cells.

5. In the cat, the neutrophilic granulocytes are most sensitive to the action of urethane. The lymphocytes are next most sensitive; then the megakaryocytes, finally the erythroblasts. The eosinophils were remarkably insensitive.

6. The normal plasmacellular reticulum cells are relatively insensitive to urethane. This is in contrast to the neoplastic myeloma cells in human beings which have been reported to be sensitive to urethane.

7. The administration of folic acid or of vitamin B₆ to the experimental animals had no effect on the course of urethane agranulocytosis.

8. The normal granulocytopoiesis of the cat is about as sensitive towards urethane as the pathologic granulocytopoiesis of chronic myeloid leukoses of human beings. This is in contrast to the findings in other animals, and to normal granulocytopoiesis of man. The variation in behavior possibly indicates variations in enzyme systems in the various types of granulocytopoiesis, with only certain enzymes being affected by urethane.

9. Further experiments are in progress to determine if the effect of urethane on the bone marrow can be counteracted by means of other growth substances. It is hoped that better insight may thus be gained into the mechanism of action of urethane.