Amino acid-conferred resistance to melphalan. I. Structure-activity relationship in cultured murine L1210 leukemia cells

Abstract

Melphalan cytotoxicity to murine L1210 leukemia cells in culture was reduced in growth medium containing amino acids. Investigation of the effect of single amino acids revealed that the L-isomers of glutamine and leucine, but not the D-isomers, were the most active in decreasing cytotoxicity. Protection was concentration dependent, with maximum protection occurring at approximately 0.25 mM, a physiologic concentration. The LD90 for melphalan in the presence of 0.1 mM L-glutamine or L-leucine was increased by 7.3- and 10.8-fold respectively, under conditions where the cells had been pre-incubated with the amino acids. These results are interpreted to suggest that melphalan transport by the L1210 leukemia cell is mediated by a system also responsible for the transport of glutamine and leucine and that interaction with such a system may play a significant role in the chemotherapeutic activity of this alkylating agent.