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Phenester [acetic acid, (p-(bis (2 chlorethyl)-amino)-phenyl) ethyl ester] is known to produce marked oncolytic activity against the mammary adenocarcinoma 13,762 in rats. For evaluation of toxicity, 17 dogs were treated with single doses of 120, 80, 20, or 5 mg/kg, with 5 consecutive daily doses of 80, 28, 14, 7, or 3.5 mg/kg, or with 11 treatments of 7 mg/kg, at 4-day intervals. The essential toxicity consisted of centrally induced salivation, vomiting, muscle twitches, tremors, and finally clonic and tonic convulsions. EEG recordings (2 dogs) from the thalamus and cerebral cortex demonstrated subcortical and cortical spikes and 3–4 cps hypersynchronous slow waves which during tonic convulsions, progressed into cortical and subcortical seizures followed by postictal silence. Six of the 8 dogs that developed tonic convulsions died or became moribund during the seizures or a few days thereafter. Mortality resulted from treatment with up to 5 daily doses of 28 mg/kg ( 2 2 ), 14 mg/kg ( 1 2 ), or 7 mg/kg ( 2 5 ). The other dogs survived. Tonic convulsions were also noted in one of 2 dogs receiving 11 treatments at 4-day intervals with 7 mg/kg/day, and in 1 dog treated with a single dose of 80 mg/kg. Dogs treated with 5 daily doses of 3.5 mg/kg or with a single dose of 20 mg/kg did not manifest convulsions. The 6 dogs which became critically ill exhibited very severe or severe hypocellularity of the bone marrow ( 5 6 dogs), severe hypocellularity of the lymphoid tissues ( 6 6 dogs), severe bronchopneumonia ( 2 6 dogs) or intestinal toxicity ( 1 6 dogs). Hepatic and renal toxicity were negligible. In contrast to other alkylating agents, phenester failed to produce degenerative changes of the spermatogenic cells or important intestinal histopathologic changes; convulsive properties predominated. Treatment with 3.5 mg/kg/day for 5 consecutive days elicited vomiting, but was otherwise tolerated without adverse side effects (maximum tolerated dose).

The toxicity of chromomycin A3, a potent antitumor antibiotic derived from Streptomyces griseus , was assessed in mice, dogs and monkeys. In mice, the LD50 after 5 daily iv doses was 603 μg/kg. In dogs and monkeys, the single-dose iv minimal lethal dose was 200 and 330 μg/kg, respectively, while this value after 5 daily iv doses was 100 μg/kg for both species. The principal clinicopathologic findings in dogs and monkeys that became moribund or died included emesis, hemorrhagic diarrhea, fever, dehydration, and necrosis of intestinal and lymphoid tissues with occasional necrosis in other organs. Laboratory findings were consistent with clinical signs. Dogs and monkeys that survived treatment exhibited mild, reversible toxic alterations.

cis-Dichlorodiammineplatinum(II), a compound with antineoplastic and antimitotic activity, which inhibited the synthesis of DNA and to a lesser extent of RNA and proteins, was submitted to a preclinical pharmacologic evaluation in 16 dogs, 10 monkeys, and 120 mice. The LD50 following a single dose iv in Swiss mice was 13.4 mg/kg for males and 12.32 mg/kg for females. The minimum lethal dose for the dog was a single iv injection of 2.5 mg/kg or 5 daily consecutive injections of 0.75 mg/kg and for the monkey, 5 daily doses of 2.5 mg/kg. The treatment elicited severe morbidity within 5–17 days and the time of onset was dose related. Toxic signs included severe hemorrhagic enterocolitis, severe hypocellularity of the bone marrow and lymphoid tissues and marked renal lesions (renal tubular necrosis in the dog and nephrosis in the monkey). Dogs also showed occasional pancreatitis and monkeys myocarditis and occasional degeneration of the spermatogenic cells. Renal lesions were the most severe toxic changes in survivors and were manifested by azotemia, hypochloremia, proteinuria, appearance of urinary erythrocytes, leukocytes and decreased 24-hr excretion of lactate dehydrogenase in dogs and by protracted polyuria in monkeys. Occasional hypocalcemia also occurred. In dogs and monkeys that survived the treatment, toxicity regressed entirely within 55–124 days. Treatment affected primarily tissues with a high rate of cell division (intestines, bone marrow, lymphoid tissues and occasionally testes) and tissues known for primary excretion of the compound (intestines and kidneys).

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