Potentiation of 1-beta-D-arabinofuranosylcytosine metabolism and cytotoxicity by 2,3-dihydro-1H-imidazolo[1,2-b]pyrazole in the human promyelocytic leukemic cell, HL-60.
The effect of IMPY (2,3-dihydro-1H-imidazolo[1,2-b]pyrazole) on the metabolism and cytotoxicity of subsequently administered 1-beta-D-arabinofuranosylcytosine (ara-C) was examined in the human promyelocytic leukemic cell line HL-60. Cells exposed to 3 mM IMPY for 12 hr followed by a 1-hr exposure to 1 microM [3H]ara-C accumulated 27.5 +/- 4.8 (S.D.) pmol ara-C/10(6) cells compared to 14.0 +/- 3.5 pmol/10(6) cells in untreated controls. Cells experienced greater than a 2-fold increment in 1-beta-D-arabinofuranosylcytosine 5'-triphosphate generation and retention following this same IMPY exposure and nearly a 4-fold increment in incorporation of ara-C into HL-60 nucleic acids. These alterations in ara-C metabolism were associated with a 36% reduction in the intracellular concentration of deoxycytidine 5'-triphosphate and reductions in deoxyadenosine 5'-triphosphate and deoxyguanosine 5'-triphosphate concentrations to undetectable levels. Coincubation of cells with IMPY along with other pyrimidine antagonists such as thymidine, N-(phosphonacetyl-L-aspartate), deoxyadenosine, and deoxyguanosine, produced up to 4-fold increments in ara-C intracellular accumulation. Pretreatment of HL-60 cells with 3 mM IMPY followed by a continuous exposure to 10 nM ara-C produced synergistic inhibitory effects on both suspension culture growth and soft agar clonogenicity. In contrast, exposure of normal human bone marrow progenitor cells (CFU-GM) to the same schedule of IMPY and ara-C produced subadditive or antagonistic effects on the growth of these cells in soft agar. These findings may have implications for the design of in vivo regimens using IMPY and ara-C.
D000970:Antineoplastic Agents / Q000633:toxicity*; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D003561:Cytarabine / Q000378:metabolism / Q000633:toxicity*; D004261:DNA Replication / Q000187:drug effects; D003853:Deoxyribonucleosides / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000503:physiopathology*; D011720:Pyrazoles / Q000633:toxicity*
D000970:Antineoplastic Agents; D003853:Deoxyribonucleosides; D011720:Pyrazoles; D003561:Cytarabine; C000971:2,3-dihydro-1H-imidazo(1,2-b)pyrazole