Therapeutic Effects of Acivicin and N-(Phosphonacetyl)-l-aspartic Acid in a Biochemically Designed Trial against a N-(Phosphonacetyl)-l-aspartic Acid-resistant Variant of the Lewis Lung Carcinoma

摘要: Abstract The N -(phosphonacetyl)-l-aspartic acid (PALA)-resistant variant of the Lewis lung carcinoma, LL/PALA-C, has a target enzyme (l-aspartate transcarbamylase) activity identical to that its parent PALA-sensitive counterpart; however, antecedent de novo pyrimidine biosynthesis, carbamyl phosphate synthetase II (CPS II), is elevated two-fold in this resistant variant. Inasmuch as inhibition l-aspartate transcarbamylase by PALA competitive with respect substrate phosphate, investigations were conducted determine effects depletion, provoked CPS II, on biochemical and therapeutic tumor line. Towards end, spectrum l-glutamine antagonists screened vitro possible inhibitors crude extracts (a l-glutamine-utilizing amidotransferase) prepared from LL/PALA-C tumors. Acivicin was found be best inhibitors. kinetics established. Doses greater than 10 mg per kg inhibit tumors up 85% assessed direct assay measuring orotate orotidine accumulation pyrazofurin-treated mice. Restitution following single treatment rapid ( t 1/2 = 24 hr). Estimation impact biosynthesis used singly combination made pyrazofurin. Combinations 25 200 significantly enhanced over single-drug activities. On basis these collateral studies PALA, trial set evaluate against results show that, agents, neither drug active line; combinations 5 or (every day, Days 1 9) other showed >80% growth 21. Long-term cures (3/10) 50% increase life span observed 10-mg plus 200-mg group. Higher doses e.g. , mg/kg) given toxic. These experiments suggested ) production an important modulator b rigorous definition rationally designed protocol can provide results.