Zaharevitz D W, Anderson L W, Malinowski N M, Hyman R, Strong J M, Cysyk R L
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
Eur J Biochem. 1992 Nov 15;210(1):293-6. doi: 10.1111/j.1432-1033.1992.tb17420.x.
The relative contribution of de-novo and salvage synthesis to tissue pyrimidine nucleotide pools is an important parameter in the rational design of anti-pyrimidine therapies, but has not been measured in vivo. We have measured the contribution of de-novo synthesis to the total acid-soluble uracil nucleotide pool in mouse tissues by analysis of the incorporation of label after intra-peritoneal infusion of L-[15N]alanine. The contribution of salvage synthesis was measured by the incorporation of radiolabel after intravenous infusion of [14C]uridine. The results show that de-novo synthesis makes the larger contribution to the intestine uracil nucleotide pool, salvage synthesis makes the larger contribution to the kidney pool, and de-novo and salvage synthesis make roughly equal contributions to the liver pool. In tumors studied (L1210, P388, B16, Nettesheim), the contribution of de-novo synthesis was at least five times the contribution of salvage synthesis. The measurements were repeated 24 hours after a 400-mg/kg dose of N-phosphonacetyl-L-aspartic acid. De-novo synthesis was substantially inhibited in all tissues and tumors after this treatment, although significant residual activity was observed in the intestine and L1210 cells. Nettesheim carcinoma was the only tumor or tissue to show a significant increase in salvage synthesis after N-phosphonacetyl-L-aspartic acid treatment.
从头合成和补救合成对组织嘧啶核苷酸库的相对贡献是抗嘧啶疗法合理设计中的一个重要参数，但尚未在体内进行测量。我们通过分析腹腔注射L-[15N]丙氨酸后标记物的掺入情况，测量了从头合成对小鼠组织中总酸溶性尿嘧啶核苷酸库的贡献。通过静脉注射[14C]尿苷后放射性标记物的掺入来测量补救合成的贡献。结果表明，从头合成对肠道尿嘧啶核苷酸库的贡献更大，补救合成对肾脏库的贡献更大，而从头合成和补救合成对肝脏库的贡献大致相等。在所研究的肿瘤（L1210、P388、B16、内特海姆）中，从头合成的贡献至少是补救合成贡献的五倍。在给予400mg/kg剂量的N-膦酰乙酰-L-天冬氨酸24小时后重复进行测量。治疗后，所有组织和肿瘤中的从头合成均受到显著抑制，尽管在肠道和L1210细胞中观察到了显著的残余活性。内特海姆癌是唯一在N-膦酰乙酰-L-天冬氨酸治疗后补救合成显著增加的肿瘤或组织。
