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Cancer Chemotherapy and Pharmacology

, Volume 66, Issue 4, pp 653–658 | Cite as

The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia

  • T. Adam de Beaumais
  • T. Dervieux
  • M. Fakhoury
  • Y. Medard
  • S. Azougagh
  • D. Zhang
  • K. Yakouben
  • E. Jacqz-Aigrain
Original Article

Abstract

Purpose

Low-dose methotrexate (MTX) therapy is the cornerstone treatment of acute lymphoblastic leukemia (ALL) and may enhance the activation of 6-mercaptopurine (6-MP) to 6-thioguanine nucleotides (6-TGN). Yet, data have established that high-dose MTX (HDMTX) hampers the accumulation of 6-TGN in red blood cells (RBC) and lymphoblasts.

Methods

To clarify the pharmacokinetic interactions between these two antimetabolites, we serially measured RBC 6-TGN and MTX polyglutamates (MTXPG) levels following repeated courses of HDMTX (5 g/m² over 24 h) with daily oral 6-MP (25 mg/m²) during interval therapy in 20 children with ALL.

Results

HDMTX produced a rapid reduction in RBC 6-TGN 24 h after the start of MTX, and this effect was sustained at least by the third day (median decrease −21%; P < 0.001). However, a return to pre-infusion of 6-TGN levels was observed by the time of the following HDMTX course 14 days later (P < 0.001). RBC MTX polyglutamates accumulation followed Michaelis–Menten kinetics but was not associated with the change in pre-infusion 6-TGN levels which remained stable during the interval period.

Conclusion

HDMTX does not appear to enhance 6-MP activation to 6-TGN. Moreover, given that the deleterious effect of HDMTX on intracellular 6-MP disposition has been shown to be several folds greater in lymphoblasts than in RBC. Our data warrant additional studies elucidating the optimal MTX dose synergizing with 6-MP.

Keywords

Methotrexate Methotrexate polyglutamates Mercaptopurine Leukemia Thioguanine nucleotides 

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • T. Adam de Beaumais
    • 1
  • T. Dervieux
    • 2
  • M. Fakhoury
    • 1
  • Y. Medard
    • 1
  • S. Azougagh
    • 1
  • D. Zhang
    • 1
  • K. Yakouben
    • 3
  • E. Jacqz-Aigrain
    • 1
  1. 1.Department of Pediatric Pharmacology and PharmacogeneticsRobert Debre HospitalParisFrance
  2. 2.Cypress BioscienceSan DiegoUSA
  3. 3.Department of HematologyRobert Debre HospitalParisFrance

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