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Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier

  • Original Articles
  • Blood Brain Barrier, Amino Acid Transport, Brain Tumor
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Summary

The relative affinity of six anticancer amino acid drugs for the neutral amino acid carrier of the blood-brain barrier was examined in rats using an in situ brain perfusion technique. Affinity was evaluated from the concentration-dependent inhibition ofl-[14C]-leucine uptake into rat brain during perfusion at tracer leucine concentrations and in the absence of competing amino acids. Of the six drugs tested, five, including melphalan, azaserine, acivicin, 6-diazo-5-oxo-l-norleucine, and buthionine sulfoximine, exhibited only low affinity for the carrier, displaying transport inhibition constants (K i, concentrations producing 50% inhibition) ranging from 0.09 to 4.7 mM. However, one agent −d,l-2-amino-7-bis[(2-chloroethyl)amino]-1,2,3,4-tetrahydro-2-naphthoic acid (d,l-NAM) — demonstrated remarkably high affinity for the carrier, showing aK i value of ∼0.2 μM. The relative affintty (1/K i) ofd,l-NAM was >100-fold that of the other drugs and >10-fold that of any compound previously tested. As the blood-brain barrier penetrability of most endogenous neutral amino acids is related to their carrier affinity, the results suggest thatd,l-NAM may be a promising agent which may show enhanced uptake and distribution to brain tumors.

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Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging, National Institute of Health, NIH Bldg 10 Room 6C-103, 20892, Bethesda, MD, USA

    Yoshiaki Takada, Nigel H. Greig, Stanley I. Rapoport & Quentin R. Smith

  2. Laboratory of Drug Discovery, Research and Development, National Cancer Institute, Frederick Cancer Research Center, P.O. Box B, 21702, Frederick, MD, USA

    David T. Vistica

Authors
  1. Yoshiaki Takada
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  2. Nigel H. Greig
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  3. David T. Vistica
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  4. Stanley I. Rapoport
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  5. Quentin R. Smith
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Takada, Y., Greig, N.H., Vistica, D.T. et al. Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier. Cancer Chemother. Pharmacol. 29, 89–94 (1991). https://doi.org/10.1007/BF00687316

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  • DOI: https://doi.org/10.1007/BF00687316

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