Cancer Chemotherapy and Pharmacology

, Volume 29, Issue 2, pp 89–94 | Cite as

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

  • Yoshiaki Takada
  • Nigel H. Greig
  • David T. Vistica
  • Stanley I. Rapoport
  • Quentin R. Smith
Original Articles Blood Brain Barrier, Amino Acid Transport, Brain Tumor


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 (Ki, 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 aKi value of ∼0.2 μM. The relative affintty (1/Ki) 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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Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • Yoshiaki Takada
    • 1
  • Nigel H. Greig
    • 1
  • David T. Vistica
    • 2
  • Stanley I. Rapoport
    • 1
  • Quentin R. Smith
    • 1
  1. 1.Laboratory of Neurosciences, National Institute on AgingNational Institute of HealthBethesdaUSA
  2. 2.Laboratory of Drug Discovery, Research and DevelopmentNational Cancer Institute, Frederick Cancer Research CenterFrederickUSA

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