title: Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier.
abstract: 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 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-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 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.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Y
authors.initials: Y
authors.lastname: Takada
authors.forename: N H
authors.initials: NH
authors.lastname: Greig
authors.forename: D T
authors.initials: DT
authors.lastname: Vistica
authors.forename: S I
authors.initials: SI
authors.lastname: Rapoport
authors.forename: Q R
authors.initials: QR
authors.lastname: Smith
mesh_terms: D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D026905:Amino Acid Transport Systems; D000818:Animals; D001377:Azaserine / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D019328:Buthionine Sulfoximine; D002352:Carrier Proteins / Q000493:pharmacokinetics*; D003980:Diazooxonorleucine / Q000493:pharmacokinetics*; D007555:Isoxazoles / Q000493:pharmacokinetics*; D008297:Male; D008558:Melphalan / Q000493:pharmacokinetics*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D026905:Amino Acid Transport Systems; D002352:Carrier Proteins; D007555:Isoxazoles; D009588:Nitrogen Mustard Compounds; D003980:Diazooxonorleucine; C051625:2-amino-7-(bis(2-chloroethyl)amino)-1,2,3,4-tetrahydro-2-naphthoic acid; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D001377:Azaserine; D015081:2-Naphthylamine; C006303:acivicin; D008558:Melphalan