O'Dwyer P J
Fox Chase Cancer Center, Philadelphia, PA.
Pharmacol Ther. 1990;48(3):371-80. doi: 10.1016/0163-7258(90)90055-7.
Phosphonacetyl-L-aspartate (PALA) is a rationally-synthesized analog of the transition-state intermediate in the formation of carbamyl aspartate from carbamyl phosphate and aspartic acid by aspartate carbamyl transferase (ACTase). PALA is thus a potent inhibitor of the enzyme (Ki about 10(-8) M for ACTases of various origins), which in whole cells blocks the de novo synthesis of pyrimidines. In vivo, low doses of PALA inhibit whole body pyrimidine synthesis. While this action is cytotoxic in vitro, extensive human testing demonstrates that PALA alone is devoid of selective antitumor activity. Recent interest in the therapeutic action of PALA derives from the demonstration that its action potentiates the cytotoxicity of several cytotoxic drugs, notably 5-fluorouracil (5-FU). Results from clinical trials of PALA and 5-FU in combination in colorectal cancer suggest that biochemical modulation with regimens which follow the principles determined in preclinical studies may enhance the efficacy of current therapy.
膦乙酰-L-天冬氨酸（PALA）是一种通过理性合成得到的类似物，它模拟了天冬氨酸氨甲酰基转移酶（ACTase）催化磷酸氨甲酰和天冬氨酸生成氨甲酰天冬氨酸过程中的过渡态中间体。因此，PALA是该酶的一种强效抑制剂（对于各种来源的ACTase，其抑制常数Ki约为10^(-8) M），在完整细胞中它能阻断嘧啶的从头合成。在体内，低剂量的PALA会抑制全身嘧啶的合成。虽然这种作用在体外具有细胞毒性，但广泛的人体试验表明，单独使用PALA没有选择性抗肿瘤活性。最近对PALA治疗作用的关注源于其能增强几种细胞毒性药物（尤其是5-氟尿嘧啶（5-FU））的细胞毒性这一发现。PALA与5-FU联合用于治疗结直肠癌的临床试验结果表明，遵循临床前研究确定原则的生化调节方案可能会提高当前治疗的疗效。
