title: Prevention of central nervous system toxicity of the antitumor antibiotic acivicin by concomitant infusion of an amino acid mixture.
abstract: Acivicin is an investigational amino acid antitumor antibiotic currently being evaluated in Phase II clinical trials. In humans acivicin causes reversible, dose-limiting central nervous system (CNS) effects including somnolence, ataxia, personality changes, and hallucinations. We have observed and reported previously that acivicin-treated cats exhibit symptoms (ataxia, sedation, somnolence) resembling CNS toxicity reported in humans. We hypothesized that if acivicin uptake into brain were mediated by a saturable transport system common to endogenous amino acids, drug uptake and CNS toxicity might be blocked by elevation of normal amino acid concentrations in circulating plasma. To test this hypothesis, cats received constant-rate i.v. infusions of either saline or Aminosyn, 10% (a commercially available mixture of 16 amino acids not containing glutamine, glutamate, aspartate, or cysteine) for 4 h prior to and 18 h subsequent to administration of acivicin at a dose producing marked behavioral changes in control cats. Presence or absence of ataxia and sedation were noted at intervals after acivicin treatment. Results showed that Aminosyn infusion prevented CNS symptoms in six of eight cats. Subsequent experiments showed that acivicin levels in brain tissue of Aminosyn-treated cats were 13% of the drug levels in saline-infused cats. Acivicin levels in most peripheral tissues were also decreased significantly by Aminosyn infusion but not to the extent observed in brain. Decreased brain uptake was shown to be due to a combination of amino acid blockade of drug transport into that organ and of increased total body clearance of drug. Concomitant Aminosyn treatment did not alter the efficacy of acivicin in mice bearing L1210 leukemia or MX-1 human mammary carcinoma. Further studies demonstrated that a solution containing only four large neutral amino acids (leucine, isoleucine, phenylalanine, and valine) could also protect cats from acivicin-induced CNS toxicity, apparently without increasing acivicin total body clearance. However, a mixture of several other amino acids contained in Aminosyn (alanine, arginine, tyrosine, histidine, proline, serine, and glycine) failed to prevent CNS toxicity. We conclude that cotreatment with Aminosyn or a mixture of large neutral amino acids could protect cancer patients from acivicin-induced CNS toxicity without ablating antitumor efficacy.
authors.affiliation: Cancer and Infectious Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
authors.forename: M G
authors.initials: MG
authors.lastname: Williams
authors.forename: R H
authors.initials: RH
authors.lastname: Earhart
authors.forename: H
authors.initials: H
authors.lastname: Bailey
authors.forename: J P
authors.initials: JP
authors.lastname: McGovren
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy; D002415:Cats; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology*; D004573:Electrolytes; D005260:Female; D005947:Glucose; D006801:Humans; D007262:Infusions, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D010080:Oxazoles / Q000633:toxicity*; D057947:Parenteral Nutrition Solutions; D012016:Reference Values; D012996:Solutions; D014183:Transplantation, Heterologous
chemical_list: D000596:Amino Acids; D000964:Antimetabolites, Antineoplastic; D004573:Electrolytes; D007555:Isoxazoles; D010080:Oxazoles; D057947:Parenteral Nutrition Solutions; D012996:Solutions; C545824:amino-acid, glucose, and electrolyte solution; D005947:Glucose; C006303:acivicin