ABSTRACT
PURPOSE: The prodrug cytosinearabinoside (ara-C) is widely used in the treatment of acute leukemias. The active drug is the intracellular metabolite cytosine-arabinoside-5'-triphosphate (ara-CTP). The purpose of the present study was to investigate the relation between sensitivity and pharmacokinetic parameters Cmax, t1/2 and AUC of ara-CTP. The obtained results were compared to previous studies. EXPERIMENTAL DESIGN: Cmax, t1/2 and AUC of ara-CTP were assessed in leukemic cells of 17 pediatric patients with acute lymphoblastic leukemia (ALL) and in 6 lymphoblastic cell lines and compared with normal lymphocytes of 9 healthy donors by high pressure liquid chromatography (HPLC). The sensitivity of the cells against ara-C was determined by the MTT assay. RESULTS: The intracellular accumulation of ara-CTP was significantly lower in normal lymphocytes (Cmax 47.7-60.9 pmol/10(6) cells) compared to leukemic cell lines (Cmax 11-1128 pmol/10(6) cells) and leukemic cells of our patients (Cmax 85.9-631 pmol/10(6) cells). Similar results were found for the AUC. There was no significant difference between initial and relapsed leukemias in our small cohort. A correlation between sensitivity in terms of IC50 values and the intracellular ara-CTP accumulation was observed in cell lines, but not in leukemic cells and normal lymphocytes from healthy donors. CONCLUSIONS: Pharmacokinetic parameters varied tremendously in leukemic cells in contrast to normal lymphocytes without a difference in sensitivity. It is worthwhile to compare literature data to assess an optimal dosage of ara-C in pediatric patients.
Subject(s)
Arabinofuranosylcytosine Triphosphate/pharmacology , Cytarabine/pharmacokinetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Adolescent , Arabinofuranosylcytosine Triphosphate/metabolism , Cell Line , Cell Line, Tumor , Child , Child, Preschool , Chromatography, High Pressure Liquid , Cytarabine/pharmacology , Half-Life , Humans , Infant , Inhibitory Concentration 50 , Lymphocytes/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , RecurrenceABSTRACT
Immunotherapy of childhood malignancies has a magic aura of promising an easy way to cure. It is not only the public, but also the medical community, which has caused this hope. Therefore, it was worthwhile to bring together a panel of experts working in the field of immunotherapy in order to discuss ongoing projects, and to show hopes and disappointments. The result was a fascinating symposium sponsored by The Kind Philipp Leukemia Foundation (Mönchengladbach, Germany). The symposium took place in the Reissensburg near Ulm (Germany) which gives the ideal location for such an event.
