Phase 2 Report of Preclinical Lethality Studies in Mice, Pharmacokinetic Study in Rats and Dogs, 'In vitro' Protein Binding Study in Rat, Mouse, Dog, and Human Sera, and Toxicity Studies in Dogs and Rats of Chlorsulfaquinoxaline (NSC-339004)

摘要

The antineoplastic Chlorsulfaquinoxaline (CSQ, NSC-339004) was given intravenously to CD2Fl mice, beagle dogs and Fischer 344 rats as a single (x1) or as five consecutive daily (x5) doses. In mice, the x1 LD50 was estimated to be 1,821 mg/sq. m. for males and the x5 LD90, LD50 and LD10 were 1,650, 1,401 and 1,191 mg/sq. m./day for the combined sexes. Doses used were 1,200, 480, 240, 180 and 120 mg/sq. m. for the x1 dogs, 1,200 and 120 mg/sq. m/day for the x5 dogs, and 3,600, 2,700, 1,800 and 1,200 mg/sq. m for the x1 rats. Plasma levels of CSQ from 2 min to 4 hr after a dose of 1,200 mg/sq. m. were 149-212 microgram/m in the dog and 373-495 microgram/ml in the rat. Clinical signs observed were immediate toxic effects on the central nervous system and local irritation of the injection site in all three species and gastrointestinal disturbance and body weight loss in dogs and rats. Clinical pathologic and histopathologic data in dogs and rats indicated that the target organs of toxicity were lymphoid tissues, testes, bone marrow, adrenal gland, pancreas, intestinal tract, liver and kidney. The dog was more severely affected than the rat. Males and females were similarly affected for mice and dogs but male rats were more severely affected than female rats. Except for testicular atrophy, which had a late occurrence, reversibility was evident in surviving animals. Very few indications of toxicity were observed following a single dose of 120 mg/sq. m. in dogs and 1,800 mg/sq. m. in rats.