Studies on the mechanism of resistance of selected murine tumors to L-alanosine

Abstract

Sublines of P388 and L1210 leukemia were rendered resistant to L-alanosine [L-2-amino-3-(N-hydroxy-N-nitrosamino) propionic acid] and designated P388/LAL and L1210/LAL. Assessments were made of certain biochemical and pharmacological determinants of the sensitivity or resistance to L-alanosine of these sensitive and resistant lines. It was observed that the antibiotic strongly inhibited adenylosuccinate synthetase and DNA synthesis only in the parent or sensitive lines; moreover, after a therapeutic dose of the drug, the concentration of L-alanosyl-AICOR (L-alanosyl-5-amino-4-imidazole carboxylic acid ribonucleotide), the putative active anabolite of L-alanosine, was dramatically higher in these parent lines as compared with the resistant variants. Enzymologic studies established that, in P388/LAL, the specific activity of the enzyme SAICAR synthetase (5-amino-4-imidazole-N-succinocarboxamide ribonucleotide synthetase), which is believed to conjugate L-alanosine with the nascent purine AICOR (5-amino-4-imidazole carboxylic acid ribonucleotide), was depressed significantly; the same was not true for L1210/LAL. In both resistant lines, however, the enzymes of purine salvage were present at levels about 200 per cent higher than those measured in the native strains. These studies establish that resistance to L-alanosine is very likely pluricausal, but that the ability of susceptible cells to synthesize or retain L-alanosyl-AICOR is an element important to the process.