The effect of low dose Ara‐C in acute non‐lymphoblastic leukaemias and atypical leukaemia

Abstract

Nine patients with nonlymphocytic leukaemia and one patient with refractory anaemia with excess of blasts (RAEB) were treated subcutaneously with Ara-C at a low dose of 10 mg/m2/12 h; complete remission was obtained in seven patients. In all cases severe pancytopenia was observed during treatment. We measured the concentration of Ara-C in serum, and found that the maximum concentration reached a peak (52-132 ng/ml; mean 84.2 ng/ml) at 15 min following injection. These concentrations can be considered sufficient to inhibit DNA synthesis. Primary short-term culture of human leukaemic cells with low dose Ara-C was also performed, and differentiation of leukaemic cells was observed for several types of leukaemic cells. The in vitro findings corresponded to the observed clinical effects. From the above results, the action of low dose Ara-C may have resulted from a combination of two different mechanisms, its cytostatic effect and its differentiation-inducing effect.

In Vitro Characterization of Valproic Acid, ATRA, and Cytarabine Used for Disease-Stabilization in Human Acute Myeloid Leukemia: Antiproliferative Effects of Drugs on Endothelial and Osteoblastic Cells and Altered Release of Angioregulatory Mediators by Endothelial Cells

“…The effect of cytarabine on cell proliferation was in addition tested at two different concentrations (0.1 and 1  μ M) in combination with VPA (0.3 and 0.6 mM) and/or ATRA (1  μ M). Serum levels corresponding to these Ara-C concentrations can be reached during low-dose Ara-C therapy [30]. A similar antiproliferative effect of Ara-C was observed also in the presence of VPA as well as ATRA for both cell types, and VPA/ATRA did not alter the proliferation compared to treatment with cytarabine alone at these concentrations (Figure 1(c), results shown for HUVECs).…”

“…The serum levels of Ara-C depend on the dose and administration of the drug: (i) conventional doses vary from 100 to 200 mg/m 2 given by intermittent injection of continuous infusion over 5–10 days and result in steady-state plasma levels of 0.1–1  μ M [42]; (ii) high-dose protocols administering the drug as 1–3 g/m 2 results in peak concentrations of 100  μ M (up to 300  μ M in children) but a rapid fall to 0.11–8.25  μ M [19, 43, 44]; and (iii) low-dose therapy with 10–20 mg/m 2 once or twice daily reaches maximal levels of 0.2–0.6  μ M 15 minutes after the injection when using 10 mg/m 2 [30] and this is well above 0.1 pM that is assumed to be required for cytotoxicity [19]. Furthermore, the active metabolite uracil arabinoside may show 5–8-fold higher serum levels than Ara-C and has a relatively long half-life [43].…”

Flow Cytometric Analysis of the Cell Cycle of the Leukemic Cell Lines Treated with Etoposide and Cytosine Arabinoside.

“…In this study, Ara-C arrested HL-60 cells in the early S phase at lower concentrations (1 and 10 ng/ml). The peak plasma concentration obtained from a patient after subcutaneous injection of low dose Ara-C is about 50 to 100 ng/ml (Ishikura et al 1984), and the plasma concentration obtained by continuous infusion of standard dose Ara-C is about 10 to 100 ng/ml (Hirschmann et al 1968). So the perturbation of the cell cycle by Ara-C revealed at much lower concentrations than those obtained by clinical doses.…”

Treatment of patients with myelodysplastic syndromes: A review

“…It was thought that the improvement was the result of the differentiation of myeloid leukaemic cells. Since then, several reports on low dose cytarabine in patients with MDS have been published (11)(12)(13)(14)(15)(16)(17)(18). In our study (17), we have observed improvement in peripheral blood parameters and/or reduction in bone marrow blasts after 50 070 of the courses administered; a complete response as defined for AML was seen only after 8 070 of the courses; the median duration of response for the whole group of responders was 19.5 weeks, but it was clearly longer in good responders than in partial responders (26 and 10 weeks respectively).…”