Mechanisms of sensitivity or resistance of murine tumors to N-(phosphonacetyl)-L-aspartate (PALA).

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.