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Kethoxal Bis(thiosemicarbazone)

II. Toxic and Pathologic Effects¹

Department of Experimental Therapeutics, Roswell Park Memorial Institute, New York State Department of Health, Buffalo 3, New York

The marked activity of kethoxal bis(thiosemicarbazone) against several experimental tumors prompted the preclinical pharmacologic study of this compound in mice, rats, dogs, and monkeys prior to its clinical trial. Hepatic changes related to drug toxicity were prominent in rats, dogs, and monkeys. In rats, such changes were delayed and consisted primarily of a characteristic enlargement of the common bile duct and secondary proliferation of the intrahepatic biliary system associated with atrophy of the parenchyma. In dogs and monkeys, the hepatic injury was associated with abnormalities of several blood biochemical parameters of liver function and consisted primarily of fat accumulation in the parenchyma. In dogs necrosis also occurred. Moderate to severe hypoglycemia was observed in rats, dogs, and monkeys. Abnormal vacuolation in cells of the adrenal cortex and atrophy of the exocrine pancreas were also found in these 3 species and were most consistent in rats. Both pancreatic and adrenal changes were partially reversible. Foci of myocardial necrosis were found in dogs and monkeys. In dogs the cardiac lesion was most frequent in incidence and multiple in nature, and it was localized primarily in the ventricles. In this species pulmonary edema was observed and appeared to be associated with generalized vascular effects leading to multiple internal hemorrhages, which were elicited mostly under acute conditions. Giant cells in the testis were also found in dogs. Hematologic abnormalities were seen in all 3 species but were not consistent among them. Delayed marrow hypoplasia occurred in rats. Neutropenia was consistent in monkeys, whereas hemoconcentration and leukocytosis were apparent in dogs. Minor and inconsistent renal abnormalities were observed in dogs and monkeys. In rats reversible paralysis was followed in some cases by a persistent retardation of growth and by the development of cataracts. Gastric ulcers were also noted in this species. These findings are discussed in relation to toxicity, which might be encountered in clinical trial of this drug.

¹ This investigation was supported in part by a research grant (CA-04130) from the National Cancer Institute, USPHS.

Received 3/ 5/65.