L-Phenylalanine mustard (L-PAM) uptake by tumor cells is mediated by two high-affinity amino acid transport systems. The observation that bone marrow progenitor cells either lack System L or exhibit reduced affinity for the System L specific substrate, 2-aminobicyclo [2.2.1] heptane-2-carboxylic acid (BCH) (Blood 56:427) suggested that preparation of new amino acid nitrogen mustards which are transported by System L may result in chemotherapeutic agents which exhibit less myelosuppression. These observations prompted the synthesis of the nitrogen mustard derivative of 2-amino-2-carboxylic-1,2,3,4-tetrahydronaphthalene. Inhibition analysis of the initial rate of transport of BCH by L1210 leukemia cells indicates that this amino acid nitrogen mustard, DL-2-amino-7-bis (2-chloroethyl) amino-1,2,3,4 tetrahydronaphthoic acid, is the most potent competitive inhibitor of System L (Ki=0.2MuM) described to date and has a 500-fold greater affinity for this transport system than phenylalanine mustard. Comparative evaluation of the antitumor and myelosuppressive activities of L-PAM and the System L specific nitrogen mustard indicates that the latter possesses both enhanced antitumor AND reduced myelosuppressive properties. This increased antitumor activity is reflected by a 2-fold improvement in the therapeutic index. In addition to the above mentioned marked differences in the mode of transport and selectivity, this amino acid nitrogen mustard also differs from L-PAM in its rate of dechlorination. These studies indicate a half life (t-1/2) of 45 minutes as compared to 120 minutes for phenylalanine mustard. This more rapid conversion to a non-cytotoxic derivative may also contribute to reducing host toxicity.
