Cancer Chemotherapy and Pharmacology

, Volume 29, Issue 2, pp 89–94

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

DOI: 10.1007/BF00687316

Cite this article as:
Takada, Y., Greig, N.H., Vistica, D.T. et al. Cancer Chemother. Pharmacol. (1991) 29: 89. doi:10.1007/BF00687316

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 (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.

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