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Metabolism of 1-ß-D-Arabinofuranosylcytosine in Human Leukemic Cells¹

Laboratory of Pharmacology [T-C. C., F. S. P.] and Hematology/Lymphoma Service [Z. A., B. D. C.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The synthesis of nucleoside triphosphate (ara-CTP) from 1-ß-D-arabinofuranosylcytosine (ara-C) in leukemic cells of blood and bone marrow was measured in vitro. Blood samples from 74 patients and 12 healthy donors were compared. During initial periods of incubation (0 to 45 min), when ara-CTP synthesis was linear, cells from acute myelocytic or myelomonocytic leukemia patients, who were currently or previously sensitive to ara-C therapy, produced twofold more ara-CTP than did cells from chronic myelocytic, lymphocytic leukemic (acute or chronic), and normal subjects. In previously untreated acute myelocytic leukemia patients, particularly low levels of ara-CTP synthesis may have negative prognostic value. All synthesized ara-CTP was trapped intracellularly, and, at the level of 15 ng/10⁶ cells, ara-CTP inhibited incorporation of [methyl-³H]thymidine into DNA of myeloblasts by 94%. Negligible amounts of the total radioactivity of ara-C were incorporated into DNA or RNA during incubation. In the presence of the pyrimidine nucleoside deaminase inhibitor, tetrahydrouridine (THU), ara-CTP synthesis by acute myelocytic leukemia, chronic myelocytic leukemia, and acute lymphocytic leukemia was significantly increased. The THU effect was even more prominent during the nonlinear phases of synthesis (2 to 20 hr) in which THU not only inhibited the deamination of ara-C but also partially blocked the catabolic pathway from ara-CTP to ara-U. Samples from relapsed patients, previously sensitive to ara-C and currently showing secondary resistance, synthesized high levels of ara-CTP; this result indicates that secondary resistance is due to factors other than the lack of kinases that phosphorylate ara-C. Thus, high levels of ara-CTP appear to be a prerequisite, but not a sufficient condition, for determining the therapeutic efficacy of ara-C. The present data suggest that the combined use of THU with ara-C may increase the therapeutic efficacy of ara-C in humans.

¹ This study was supported in part by National Cancer Institute Grant CA 16534, American Cancer Society Grant CH 36, and by the Elsa U. Pardee Foundation.

Received 4/20/77. Accepted 7/ 6/77.

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