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Experimental Studies with Actinomycin D^*

( Roswell Park Memorial Institute, Buffalo 3, N.Y.)

1. A single intraperitoneal injection of 2050 µg/kg of a 100 µg/ml solution of actinomycin D killed 50 per cent of the animals, while with a 50 µg/ml solution 2400 µg/kg were required for 50 per cent mortality. A preliminary experiment indicated decreased toxicity in hypoxic environment.

2. Actinomycin D reduced spleen weight in mice beyond the loss caused by food and water deprivation. The interaction of actinomycin D and food deprivation on spleen weight was not demonstrated in this acute experiment.

3. Although solutions as old as 6 weeks and new ethanol-water solutions had the same degree of microbial inhibition, the same spectra and animal toxicity, there was unexplainable variance in antitumor effect.

4. Actinomycin D was excreted in the urine of dogs within 30 hours following an intravenous injection of either 75 µg/kg or 15 µg/kg. The blood level of actinomycin D in the dog that received 75 µg/kg was similar to its urinary excretion. The dosage of 15 µg/kg was too low to accurately determine the degree of inhibition in blood by this method.

5. Of the tumors tested, the antibiotic was most effective against mammary adenocarcinomas C-755 and C3HBA and Krebs-2 ascites. Single massive intraperitoneal injections caused the complete disappearance of solid thymomas with diameters of 12–13 mm.

6. The associated ascites of an ovarian carcinoma in a dog was successfully controlled by several courses of Actinomycin D.

7. Actinomycin D at 100 µg/ml produced a blue zone of inhibition averaging 18 mm., with a maximum of 25 mm. on an agar pour plate containing Ehrlich ascites. No anticell action was noted with a concentration of actinomycin D of 10 µg/ml.

8. Studies with mice do not support the hypothesis that the action of the antibiotic may be reversed by pantothenate. Combinations of actinomycin D and calcium pantothenate failed to decrease the survival time of animals bearing Krebs-2 ascites when compared with animals which had received actinomycin D.

^* This investigation was supported in part by a research grant from the Rosenstiel Foundation.

Received 7/16/57.

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