Animal behavioral and neurochemical effects of the CNS toxic amino acid antitumor agent, acivicin.
The investigational amino acid antitumor agent, acivicin, has been reported to cause dose-related and reversible CNS toxicity in humans characterized by sedation, ataxia, hallucinations, personality changes, and other symptoms. In a series of studies aimed at characterizing this toxicity, we investigated several species as potential animal models, determined the effects of acivicin on neuronal action potentials, and measured drug effects on the brain content of several putative amino acid neurotransmitters. In mice, we were unable to demonstrate any effects of acivicin in a battery of tests used in identifying and classifying CNS-active agents of potential therapeutic utility. In rats, unlike phencyclidine and certain other psychotomimetic drugs, acivicin produced no impairment of shock avoidance or brightness discrimination in animals trained on an automated Y-maze. In contrast to the rodent species, acivicin effects were perceived as resembling those of cyclazocine by rhesus monkeys trained to discriminate between psychoactive drugs and saline by food reinforcement. Cats treated with acivicin exhibited dose-related symptoms of sedation, somnolence, and ataxia. Iontophoretically applied acivicin was shown to have no effect on the spontaneous firing rate of dorsal horn interneurones in spinal cats. At the time of peak CNS symptoms in cats treated with 100 mg/kg acivicin, content of gamma-aminobutyric acid (GABA; nmoles/mg protein) was elevated from 57-140% in cerebellum, diencephalon, midbrain, and corpus callosum compared to control animals. Brain contents of glutamate, glutamine, and aspartate were not altered in cats experiencing neurotoxicity. These studies have shown that some symptoms of acivicin CNS toxicity are shared by humans and higher non-human species such as the cat and the monkey but not by rodents. Acivicin itself is apparently not a CNS excitant or depressant, but metabolites of the drug could be. Acivicin may also cause increases in the GABA content of localized regions of brain.
McGovren
J P
JP
Cancer and Infectious Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Williams
M G
MG
Tang
A H
AH
VonVoigtlander
P F
PF
Piercey
M F
MF
Einspahr
F J
FJ
Schreur
P J
PJ
D000200:Action Potentials / Q000187:drug effects; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D002415:Cats; D004192:Discrimination, Psychological / Q000187:drug effects; D005260:Female; D007478:Iontophoresis; D007555:Isoxazoles / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D000596:Amino Acids; D000903:Antibiotics, Antineoplastic; D007555:Isoxazoles; D010080:Oxazoles; D005680:gamma-Aminobutyric Acid; C006303:acivicin