MODULATION OF METABOLISM AND CYTOTOXICITY OF CYTOSINE-ARABINOSIDE WITH N-(PHOSPHON)-ACETYL-L-ASPARTATE IN HUMAN LEUKEMIC BLAST CELLS AND CELL-LINES

Cytosine arabinoside (Ara-C) activation to cytosine arabinoside tripho sphate (Ara-CTP) and subsequent incorporation into DNA is regulated by the pyrimidine nucleotides UTP, CTP and dCTP. Inhibition of the de no vo synthesis of these pyrimidine nucleotides by N-(phosphon)-acetyl-L- aspartate (PALA) may enhance the cytotoxicity of Ara-C. We therefore s tudied the effect of PALA on Ara-C cytotoxicity and on Ara-CTP accumul ation and incorporation into DNA on cell lines and patient samples. Fi fty micromolar PALA increased the growth inhibitory effect of Ara-C in U937 cells several fold both with pre- and coincubation. Ara-C cytoto xicity was not potentiated by PALA in HL60 cells. However, coincubatio n with PALA did not enhance Ara-CTP accumulation both in HL60 and U937 cells, nor affect Ara-C incorporation into DNA. Ara-C cytotoxicity to leukemic blast cells from 11 untreated patients with different types of leukemia was only modulated to a small extent by high PALA concentr ations in only two cases. Ara-CTP accumulation in leukemic blast cells varied from non-detectable levels to 200 pmol/10(6) cells. Fifty micr omolar PALA enhanced the accumulation of Ara-CTP significantly in only one patient with no apparent effect on UTP and CTP levels. Raising PA LA to 500 mu M decreased UTP and CTP levels to 50% but had no effect o n Ara-CTP levels. In conclusion, modulation by PALA of Ara-C cytotoxic ity and metabolism is limited in leukemic cells, both in culture and f rom patients. This suggests the possibility for selective modulation o f other agents by PALA on non-hematological cells.