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

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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.

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Authors and Affiliations

  1. Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debre Hospital, 48 Boulevard Serurier, 75019, Paris, France

    T. Adam de Beaumais, M. Fakhoury, Y. Medard, S. Azougagh, D. Zhang & E. Jacqz-Aigrain

  2. Cypress Bioscience, San Diego, CA, USA

    T. Dervieux

  3. Department of Hematology, Robert Debre Hospital, Paris, France

    K. Yakouben

Authors
  1. T. Adam de Beaumais
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  2. T. Dervieux
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  3. M. Fakhoury
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  4. Y. Medard
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  5. S. Azougagh
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  6. D. Zhang
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  7. K. Yakouben
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  8. E. Jacqz-Aigrain
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Corresponding author

Correspondence to E. Jacqz-Aigrain.

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Adam de Beaumais, T., Dervieux, T., Fakhoury, M. et al. The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol 66, 653–658 (2010). https://doi.org/10.1007/s00280-009-1205-4

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  • DOI: https://doi.org/10.1007/s00280-009-1205-4

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