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Potentiation of 1-ß-D-Arabinofuranosylcytosine Metabolism and Cytotoxicity by 2,3-Dihydro-1H-imidazolo[1,2-b]pyrazole in the Human Promyelocytic Leukemic Cell, HL-60¹

Division of Hematology/Oncology, Columbia University College of Physicians and Surgeons, New York, New York [S. G., K. B.], and the Department of Medicine and Pharmacology, Yale University School of Medicine, New Haven, Connecticut [F. R., E. C.]

The effect of IMPY (2,3-dihydro-1H-imidazolo[1,2-b]pyrazole) on the metabolism and cytotoxicity of subsequently administered 1-ß-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 µM [³H]ara-C accumulated 27.5 ± 4.8 (S.D.) pmol ara-C/10⁶ cells compared to 14.0 ± 3.5 pmol/10⁶ cells in untreated controls. Cells experienced greater than a 2-fold increment in 1-ß-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.

¹ Supported by NIH Grants CA-27130, CA-08341, and CA-13696-11, ACS Grant CH-145; the William J. Matheson Foundation; the Cele Butwin Foundation, Inc.; and the Pharmaceutical Manufacturers' Association. Dr. Cadman is a recipient of a Faculty Research Award from the American Cancer Society.

² Special Fellow of the Leukemia Society of America. To whom requests for reprints should be sent.

Received 7/12/82. Accepted 8/ 1/83.