Creagan E T, O'Connell M J, Kovach J S
Cancer. 1983 Aug 15;52(4):615-8. doi: 10.1002/1097-0142(19830815)52:4<615::aid-cncr2820520407>3.0.co;2-o.
This article reports a Phase I study of combined therapy with N-(phosphonacetyl)-L-aspartate (PALA) and L-alanosine in 26 patients with advanced cancer. Each agent exhibits antitumor effect by enzyme inhibition: PALA blocks pyrimidine biosynthesis by impeding aspartate transcarbamylase and L-alanosine depletes purine nucleotides by interfering with adenylosuccinate synthetase. These agents were selected for clinical investigation in light of synergistic cytotoxicity in vitro against human tumor cell lines and in vivo against P-388 murine leukemia resistant to cytosine arabinoside. Dose-limiting toxicities were stomatitis and diarrhea to a lesser extent. There was no substantial myelosuppression. The authors recommend either of two intravenous regimens for studies of therapeutic activity in selected patients with neoplastic diseases: a one-day treatment repeated of PALA, 5.0 g/m2 and L-alanosine, 3.0 g/m2, repeated every 3 weeks; or a monthly program of PALA, 500 mg/m2/d 1-5 and L-alanosine, 60 mg/m2/d 1-5.
本文报道了一项针对26例晚期癌症患者，使用N-（膦酰乙酰基）-L-天冬氨酸（PALA）和L-丙氨菌素联合治疗的I期研究。每种药物都通过抑制酶发挥抗肿瘤作用：PALA通过抑制天冬氨酸转氨甲酰酶来阻断嘧啶生物合成，而L-丙氨菌素则通过干扰腺苷琥珀酸合成酶来消耗嘌呤核苷酸。鉴于这两种药物在体外对人肿瘤细胞系以及在体内对耐阿糖胞苷的P-388小鼠白血病具有协同细胞毒性，故而选择它们进行临床研究。剂量限制性毒性为口腔炎，腹泻程度较轻。未出现明显的骨髓抑制。作者推荐两种静脉给药方案中的任意一种，用于对选定的肿瘤疾病患者进行治疗活性研究：一种是一天的治疗方案，即PALA 5.0 g/m²和L-丙氨菌素3.0 g/m²，每3周重复一次；另一种是每月方案，即PALA 500 mg/m²/d，第1 - 5天给药，L-丙氨菌素60 mg/m²/d，第1 - 5天给药。
