Effect of the interval between high dose 1-beta-D-arabinofuranosylcytosine injections on leukemic cell load, intestinal toxicity, and normal hematopoietic stem cells in a rat model for acute myelogenous leukemia

Abstract

One injection of 1-beta-D-arabinofuranosylcytosine (ara-C) in BN rats bearing myelocytic leukemia induces recruitment and synchronization of the leukemic cells. A second ara-C injection, given when the largest fraction of cells is in S phase, causes the largest reduction in leukemic clonogenic cells. The relevance of recruitment and synchronization of leukemic cells after high dose ara-C (200 mg/kg) by rapid i.v. injection (comparable with 1 g/m2 in patients) has been tested in rats with respect to survival time and toxicity. Several groups of leukemic rats have been treated with seven injections of ara-C; the intervals between the injections per group were 4, 6, 9, 12, 15, 18, and 24 h, respectively. The longest mean survival time is observed in the group treated every 9 h which is 70.8 days compared to 22.6 days in nontreated leukemic controls. This 9-h interval of ara-C administration corresponds with the moment when DNA synthesis of the leukemic cells resumes after its inhibition by the ara-C. The most severe toxic side effects on the gastrointestinal system are observed in the group that received ara-C every 6 h; no toxic death has occurred in the animals treated with 15-h or longer intervals. The effect of the increasing interval between two ara-C injections on the normal hematopoietic stem cells has been measured with the colony forming unit spleen assay. This study showed that the reduction of normal stem cells due to ara-C is independent of the interval of administration. This differential effect of ara-C on leukemic and normal hematopoietic stem cell kinetics might in part explain the mechanisms of achieving a complete remission in acute leukemia.