Close correlation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate, an intracellular active metabolite, to the therapeutic efficacy of N(4)-behenoyl-1-beta-D-arabinofuranosylcytosine therapy for acute myelogenous leukemia.

Abstract

N(4)-Behenoyl-1-beta-D-arabinofuranosylcytosine (BHAC), a prodrug of 1-beta-D-arabinofuranosylcytosine, is used effectively for the treatment of leukemia in Japan. BHAC therapy may be more effective if it is delivered in conjunction with monitoring of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate (ara-CTP), the intracellular active metabolite of ara-C derived from BHAC. However, previous monitoring methods for ara-CTP were insufficiently sensitive. Here, using our new sensitive method, we evaluated the ara-CTP pharmacokinetics in relation to the therapeutic response in 11 acute myelogenous leukemia patients who received a 2-h infusion of BHAC (70 mg / m(2)) in combination remission induction therapy. ara-CTP could be monitored at levels under 1 mM. BHAC maintained effective levels of plasma ara-C and intracellular ara-CTP for a longer time, even compared with historical values of high-dose ara-C. The area under the concentration-time curve of ara-CTP was significantly greater in the patients with complete remission than in the patients without response. This greater amount of ara-CTP was attributed to the higher ara-CTP concentrations achieved in the responding patients. There was no apparent difference of plasma ara-C pharmacokinetics between the two groups. Thus, for the first time, the ara-CTP pharmacokinetics was evaluated in relation to the therapeutic effect of BHAC, and the importance of ara-CTP was proven. Administration of optimal BHAC therapy may require monitoring of the ara-CTP pharmacokinetics in each individual patient.

• Authors: T Yamauchi, Y Kawai, N Goto, S Kishi, S Imamura, A Yoshida, Y Urasaki, T Fukushima, H Iwasaki, H Tsutani, M Masada, T Ueda
• Journal: Japanese journal of cancer research : Gann (Jpn J Cancer Res) Vol. 92 Issue 9 Pg. 975-82 (Sep 2001) ISSN: 0910-5050 [Print] Japan
• PMID: 11572766 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Antimetabolites, Antineoplastic
• Prodrugs
• Cytarabine
• Arabinofuranosylcytosine Triphosphate
• enocitabine

Topics

• Acute Disease
• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Arabinofuranosylcytosine Triphosphate (analysis, blood, pharmacokinetics)
• Area Under Curve
• Biotransformation
• Cytarabine (administration & dosage, analogs & derivatives, blood, pharmacokinetics, pharmacology, therapeutic use)
• Female
• Humans
• Infusions, Intravenous
• Intracellular Fluid (chemistry)
• Leukemia, Myeloid (blood, drug therapy)
• Male
• Middle Aged
• Neoplastic Stem Cells (chemistry)
• Prodrugs (administration & dosage, pharmacokinetics, pharmacology, therapeutic use)
• Remission Induction
• Sensitivity and Specificity
• Treatment Outcome