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Effect of Colloidal Au¹⁹⁶ on the Growth Cycle of Leukemic Cells and on the Survival of Their Host^*

( Cancer Research Laboratories, Meharry Medical College, Nashville, Tenn.)

1. Various numbers of leukemic spleen cells were inoculated intraperitoneally into Akm mice. Blood and, in several series, peritoneal fluid were withdrawn from these mice repeatedly, at various intervals. The total number of cells and the percentage of leukemic cells were counted in each specimen, and the results were reviewed in tables illustrating the growth cycle of leukemic cells.

2. It was found that after the intraperitoneal inoculation of 1,000,000 of these cells they multiplied in the peritoneal fluid and reached their maximum number on the fourth day, while only few leukemic cells appeared in the blood during this period (aleukemic stage). However, on the fifth day, the number of leukemic cells in the peritoneal fluid suddenly decreased, whereas leukemic cells appeared at that time in blood in large numbers (true leukemia) and continued to multiply at a very high rate, invading the spleen, liver, and lymph nodes, until the death of the animal.

3. The reduction in size of the inoculum (to 10,000 cells) or the use of 1 million cells from peritoneal fluid delayed the change of the aleukemic stage into leukemia and the death of the animal; increase of the inoculum to 10,000,000 or more shortened the aleukemic stage and reduced the life span of the animal. Thus, the three stages of growth occurred in all inoculated animals. The occurrence of death was not correlated with the level of leukemic cells in the blood but with the invasion of organs by these cells.

4. Evidence is presented to show that during the three stages of the growth cycle the growth potency of leukemic cells increased. However, the inversion of cell distribution initiating the second and the third stages was induced apparently by disturbances of the regulatory mechanism of the host.

5. Intravenous injection of colloidal Au¹⁹⁸ considerably prolonged the survival of leukemic mice and reduced the number of leukemic cells in the blood and the organs (slightly in the fluid). It is concluded that the therapeutic effect of this agent is due (a) to its direct cytotoxic action on the leukemic cell, (b) to improvement of the regulating mechanism of the host, and (c) to stimulation of reticulo-endothelial elements.

6. Treatment with repeated small doses of aminopterin drastically reduced the cellular content of the blood and the peritoneal fluid but allowed the replacement of destroyed leukocytes by production of the hematopoietic organs and, therefore, extended the survival of mice.

7. Combined treatment with Au¹⁹⁸ and aminopterin demonstrated a synergistic cytotoxic effect on leukemic cells. Moreover, mice survived longer than mice treated with aminopterin alone. This is attributable to the compensation of the antianabolic effect of aminopterin by stimulation of reticulo-endothelial elements with colloidal gold.

^* This work was carried out under Contract At-(40-1)-269 with the Division of Biology and Medicine of the United States Atomic Energy Commission.

Received 6/30/51.

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