Toxicologic and biochemical properties of the antitumor
antibiotic,
alanosine [L-2-amino-3-(N-hydroxy,N-nitrosamino)
propionic acid], were studied in mice. The LD50 of
L-alanosine (given intraperitoneally) was approximately 2 g/kg; L-5178Y/AR
tumor, small intestine, liver, and lung were the tissues more consistently or severely damaged by the
drug. L-5178Y/AR
tumor, small intestine, liver, and lung, which were more susceptible to damage by
L-alanosine, showed high concentrations of the putative active
antimetabolite of
L-alanosine, "L-
alanosyl-AICOR", and either high concentrations of
SAICAR synthetase, which forms this conjugate or low specific activities of
adenylosuccinate lyase, the
enzyme believed to decompose it. In addition, a low specific activity of the
enzyme,
adenylosuccinate synthetase, appeared to predispose an organ to the toxicity of
alanosine. These data are compatible with the hypothesis that "L-
alanosyl-AICOR" is the molecule responsible both for the therapeutic and toxicologic effects of
L-alanosine and suggest that it is the dynamic interplay of the synthesizing
enzyme, the catabolizing
enzyme, and the target
enzyme which determines whether this anabolite accumulates to a concentration capable of inflicting cellular damage.