Several biochemical parameters were examined relative to the sensitivity or resistance of representative rodent
tumors to
N-(phosphonacetyl)-L-aspartate (
PALA). The activity of the target
enzyme,
L-aspartate transcarbamylase (ATCase), was evaluated in homogenates of a spectrum of murine
neoplasms. ATCase activity was significantly lower in
PALA-sensitive as opposed to
PALA-refractory
tumors. However, among
tumors sensitive to
PALA, there was no clearcut relationship between ATCase activity and degree of sensitivity to
PALA. Thus, a number of hypotheses were proposed to explain differential sensitivity to
PALA in vivo.
Enzyme activities in the salvage pathway which phosphorylate
pyrimidine nucleosides and deoxynucleosides were found to be greater in refractory
tumors. The uptake of
PALA, in vitro, though quite slow, was found to be two to eight times greater in two sensitive
tumors as compared to the refractory
L1210 leukemia. However, in vivo, 24 hours following graduated doses of
PALA, nearly identical intratumoral
drug concentrations were observed in representative sensitive and refractory
tumors. Thus, ultimately,
PALA transport would not appear to correlate with differences in
drug sensitivity. A number of other biochemical parameters were also found to have no association with sensitivity to
PALA in vivo. These included: kinetics of inhibition of ATCase, capacity for restitution of ATCase activity after a dose of
PALA, degree of inhibition of ATCase at various doses of
PALA, detoxification of
PALA by
tumor cells, kinetics of uptake of
uridine, or catabolism of
pyrimidines or
pyrimidine nucleosides.