Molecular Pharmacology, Vol 14, 1136-1142, Copyright © 1978 by the American Society for Pharmacology and Experimental Therapeutics

Amino Acid Conferred Protection against Melphalan: Interference with Leucine Protection of Melphalan Cytotoxicity by the Basic Amino Acids in Cultured Murine L1210 Leukemia Cells

¹ Laboratory of Medicinal Chemistry and Biology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20014

Melphalan cytotoxicity to murine L1210 leukemia cells in culture is influenced by the amino acid composition of the incubation medium. Deletion of glutamine or leucine from RPMI 1630 medium increased the cytotoxicity produced during a 35 min exposure of L1210 cells to melphalan by 10-fold and 2-fold, respectively, indicating that a substantial proportion of the protection afforded L1210 cells from melphalan cytotoxicity in an amino acid environment can be attributed to these amino acids. However, protection from melphalan cytotoxicity in cells first incubated with leucine in a balanced salt solution containing bovine serum albumin and glucose was 10 times better than that in cells incubated with leucine in RPMI 1630 medium containing all amino acids except glutamine. This difference was due to an increase in the accumulation of intracellular melphalan in medium containing leucine and the basic amino acids. The increases in intracellular drug and resulting cytotoxicity decrease with increasing carbon chain length within the arginine homologous series (-amino--guanidinobutyric acid > arginine > homoaginine). However, the lowest arginine homologue, -amino--guanidinopropionic acid, was ineffective. Maximum promotion of melphalan cytotoxicity by -amino--guanidinobutyric acid occurred at concentrations equimolar with leucine and was not substantially influenced by the length of prior incubation with the homologue. Interaction between melphalan and the basic amino acids with the leucine-preferring transport system in L1210 cells plays a significant role in melphalan cytotoxicity.

Note:
ACKNOWLEDGMENTS The authors express their appreciation to Ms. Charlotte Thomas for preparation of the manuscript.

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