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

Abstract:  Erratum in: Cancer Chemother Pharmacol 1992;30(2):164. Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier. Takada Y, Greig NH, Vistica DT, Rapoport SI, Smith QR. Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892. 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-depend ent inhibition of L-[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-norl eucine, 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 a Ki value of approximately 0.2 microM. The relative affinity (1/Ki) of D,L-NAM was greater than 100-fold that of the other drugs and greater than 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 that D,L-NAM may be a promising agent which may show enhanced uptake and distribution to brain tumors. PMID: 1760863 [PubMed - indexed for MEDLINE]