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Pharmacodynamic properties of methotrexate and AminotrexateTM during weekly therapy

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An Erratum to this article was published on 10 May 2006

Abstract

4-amino-pteroyl-glutamic acid (AminotrexateTM; AMT) has several advantages over the related antifolate methotrexate (MTX), including greater potency, complete oral bioavailability, and greater accumulation by leukemic blasts in vitro. We compared the pharmacodynamic properties of AMT (given orally at 4 mg/m2 in two divided doses per week) and MTX (100 mg/m2 in four divided doses per week) among children with acute lymphoblastic leukemia. We find AMT and MTX to have equivalent penetration into the bone marrow compartment of these patients, as indicated by the steady-state concentrations within mature red blood cells (RBCs). However, MTX concentrations in the cerebrospinal fluid after oral dosage are significantly greater than AMT. To confirm these clinical observations, mice were treated four weekly injections of AMT or MTX, at a 1:20 dosage ratio, and tissue antifolate content was then determined over the subsequent 22 days. We confirm the selective exclusion of AMT from the CNS compartment, while showing equivalent accumulation of AMT and MTX in the RBCs, liver, spleen, kidneys and testes. Finally, we demonstrate that AMT, MTX, and their predominant polyglutamate species are equipotent inhibitors of their target intracellular enzyme dihydrofolate reductase, emphasizing the critical nature of steady-state tissue accumulation in determining the relative cytotoxic potency of these two antifolates.

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Acknowledgments

PDC is a Damon Runyon-Lilly Clinical Investigator, supported in part by the Damon Runyon Cancer Research Foundation (CI −16-03). BAK is an American Cancer Society Professor. This work was supported in part by an FDA Orphan Products Development grant (FD-R-001832-03) and by the Institute for Children with Cancer and Blood Disorders, New Brunswick, NJ.

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Authors and Affiliations

  1. Department of Pediatric Hematology/Oncology , The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA

    Peter D. Cole, Angela K. Smith & Barton A. Kamen

  2. Department of Pharmacology, University of Valencia, Av Vicent Andres Estelles, 46100, Burjasot Valencia, Spain

    María José Alcaraz

  3. Robert Wood Johnson Medical School, UMDNJ, New Brunswick, NJ, USA

    John Tan

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  1. Peter D. Cole
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  2. María José Alcaraz
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  3. Angela K. Smith
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  4. John Tan
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  5. Barton A. Kamen
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Correspondence to Peter D. Cole.

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An erratum to this article can be found at http://dx.doi.org/10.1007/s00280-006-0234-5

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Cole, P.D., Alcaraz, M.J., Smith, A.K. et al. Pharmacodynamic properties of methotrexate and AminotrexateTM during weekly therapy. Cancer Chemother Pharmacol 57, 826–834 (2006). https://doi.org/10.1007/s00280-005-0115-3

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