Pharmacology of intracellular cytosine-arabinoside-5'-triphosphate in malignant cells of pediatric patients with initial or relapsed leukemia and in normal lymphocytes.

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.

• Authors: U Koehl, G Hollatz, E Rohrbach, K Visschedyk, J Cinatl, B Kornhuber, J Kreuter, E Mutschler, D Schwabe
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 60 Issue 4 Pg. 467-77 (Sep 2007) ISSN: 0344-5704 [Print] Germany
• PMID: 17171362 (Publication Type: Journal Article)

Chemical References

• Cytarabine
• Arabinofuranosylcytosine Triphosphate

Topics

• Adolescent
• Arabinofuranosylcytosine Triphosphate (metabolism, pharmacology)
• Cell Line
• Cell Line, Tumor
• Child
• Child, Preschool
• Chromatography, High Pressure Liquid
• Cytarabine (pharmacokinetics, pharmacology)
• Half-Life
• Humans
• Infant
• Inhibitory Concentration 50
• Lymphocytes (metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
• Recurrence