| Research Abstract |
The IC_<50> value for acivicin that yielded the 50% growth inhibition of logarithmically growing Crithidia fasciculata in a serum-free medium at 27^ﾟC was 1.5 uM, and the value for allopurinol was 10 uM. Acivicin (20 uM) inhibited the growth by 84%, and this inhibition was antagonized by 10 uM each of cytidine plus guanosine (or deoxyguanosine) ; guanosine or deoxyguanosine alone was slightly antagonistic. At 10 uM allopurinol, 200 uM each of uracil, uridine, cytidine or deoxycytidine reversed the inhibition of cell growth. Coadministration of acivicin and allopurinol resulted in a synergistic inhibition of cell growth, and this inhibition was protected by the simultaneous addition of cytidine, guanosine, and hypoxanthine. These results are consistent with the view that acivicin targets GMP and CTP synthetases and that allopurinol targets de novo pyrimidine synthesis in C. Fasciculata. Extraordinarily low concentration of acivicin (IC_<50> = 10 nM) was effective to inhibit the growth of Leishmania mexicana amazonesis.
Acivicin causes the selective, time-dependent, irreversible intracellular inactivation of glutamine-dependent activity of carbamoyl-p synthetase II (CPS II). Inactivation was protected by high concentration of glutamine, but the incomplete protection from inactivation suggests a very high affinity of the drug for CPS II, indicating that acivicin causes an affinity labeling of glutamine-dependent CPS II activity intracellularly. Similar mechanism is also suggested for CTP and GMP synthetases, probably resulting in the reduced CTP, GTP, and dGTP levels that cause the decreases in RNA and DNA syntheses and consequently the inhibition of cell growth.
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