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 triphosphate (Ara-CTP) and subsequent incorporation into DNA is regulated by the pyrimidine nucleotides UTP, CTP and dCTP. Inhibition of the de novo synthesis of these pyrimidine nucleotides by N-(phosphon)-acetyl-L-aspartate (PALA) may enhance the cytotoxicity of Ara-C. We therefore studied the effect of PALA on Ara-C cytotoxicity and on Ara-CTP accumulation and incorporation into DNA on cell lines and patient samples. Fifty micromolar PALA increased the growth inhibitory effect of Ara-C in U937 cells several fold both with pre- and coincubation. Ara-C cytotoxicity was not potentiated by PALA in Hl60 cells. However, coincubation 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 concentrations in only two cases. Ara-CTP accumulation in leukemic blast cells varied from non-detectable levels to 200 pmol/10(6) cells. Fifty micromolar PALA enhanced the accumulation of Ara-CTP significantly in only one patient with no apparent effect on UTP and CTP levels. Raising PALA to 500 microM decreased UTP and CTP levels to 50% but had no effect on Ara-CTP levels. In conclusion, modulation by PALA of Ara-C cytotoxicity and metabolism is limited in leukemic cells, both in culture and from patients. This suggests the possibility for selective modulation of other agents by PALA on non-hematological cells.
Noordhuis
P
P
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Kazemier
K M
KM
Kasperrs
G J
GJ
Peters
G J
GJ
D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology*; D001085:Arabinofuranosylcytosine Triphosphate / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D003561:Cytarabine / Q000378:metabolism* / Q000494:pharmacology*; D003570:Cytidine Triphosphate / Q000378:metabolism; D004273:DNA, Neoplasm / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000378:metabolism / Q000473:pathology*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014544:Uridine Triphosphate / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D001224:Aspartic Acid; D003570:Cytidine Triphosphate; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D014544:Uridine Triphosphate