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.