Analogs of L-aspartic acid in chemotherapy for cancer.
The interaction of analogs of L-aspartic acid with adenylosuccinic acid synthetase, L-asparagine synthetase, and L-aspartic acid transcarbamylase is discussed. Each of these enzymes is of critical importance in the economy of certain types of tumor cells. L-Alanosine, a new antitumor antibiotic, is shown to be accepted as a substrate by the enzymes of de novo purine biosynthesis which ordinarily use L-aspartic acid as a substrate; as a consequence of this interaction, an anabolite is thought to be produced which impairs the formation of adenine nucleotides by inhibiting adenylosuccinate synthetase, leading to an interruption in DNA synthesis. Homoserine-beta-adenylate, guanidinosuccinic acid, and PA2LA [3-(phosphonacetylamido)-L-alanine] are shown to be inhibitors of L-asparagine synthetase from murine lymphoblasts; each of these analogs of L-aspartic acid exhibits novel structural properties which can be used by synthetic chemists in the design of molecules with an even greater ability to block the biosynthesis of L-asparagine. Certain aspects of the mechanism of action of PALA (N-phosphonacetyl-L-aspartic acid) were examined. This agent, which is a potent inhibitor of mammalian L-aspartic acid transcarbamylase, is capable of stimulating the homologous enzyme from Escherichia coli under certain circumstances. In vivo the duration of inhibition produced by this agent is shown to be unusually protracted; for example, L-aspartic acid transcarbamylase in mouse liver remains at 30% of treatment levels for greater than or equal to 20 days after a single therapeutic dose of PALA. This long-lasting effect reflects either sluggish synthesis of new enzyme molecules in this organ or shuttling of the inhibitor from old to new molecules. It is suggested that new and still more potent analogs of L-aspartic acid be sought, and that they be screened, inter alia, against these target enzymes.
D000265:Adenylosuccinate Synthase / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors; D001217:Aspartate-Ammonia Ligase / Q000037:antagonists & inhibitors; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002478:Cells, Cultured; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D001217:Aspartate-Ammonia Ligase; D000265:Adenylosuccinate Synthase; D010746:Phosphonoacetic Acid