CARRIER-MEDIATED TRANSPORT OF THE ANTITUMOR AGENT ACIVICIN ACROSS THEBLOOD-BRAIN-BARRIER

The cytotoxic agent acivicin has been shown to be effective against se veral types of tumors. However, the clinical utilization of acivicin h as been prohibited because of its dose-limiting neurotoxicity. Acivici n is believed to be transported into the brain by the large neutral am ino acid (LNAA) carrier, which is expressed at the blood-brain barrier (BBB). In this study, we used an in situ rat brain perfusion techniqu e to determine the kinetics of the LNAA carrier-mediated transport of acivicin across the BBB. We found that the V-max of acivicin (1.05 nmo l/sec/g) obtained in this study was comparable to the V-max of L-leuci ne (1.07 nmol/sec/g) and other LNAAs as determined by other investigat ors. The K-m was high compared with other LNAAs, but this could be exp lained by the low lipophilicity of acivicin. Acivicin transport across the BBB was inhibited by other LNAAs but not by acivicin derivatives with structural modifications at the amino or carboxyl group. The ASC (alanine, serine, cysteine) carrier system did not influence the trans port of acivicin across the BBB. These results suggest that the CNS to xicity of acivicin might be reduced by coadministration of other LNAAs . Acivicin derivatives with structural modifications at the amino or c arboxyl group of acivicin lack affinity for the LNAA carrier at the BB B and, therefore, will exhibit less CNS toxicity than acivicin.