Kemeny N, Schneider A, Martin D S, Colofiore J, Sawyer R C, Derby S, Salvia B
Department of Developmental Chemotherapy, Memorial Sloan Kettering Cancer Institute, New York 10021.
Cancer Res. 1989 Aug 15;49(16):4636-9.
Based on an animal model to improve the antitumor activity of 5-fluorouracil (FUra), a Phase I study of N-(phosphonacetyl)-L-aspartate, methotrexate, FUra, and leucovorin was conducted on 44 patients. Methotrexate was given in an intermediate dose (250 mg/m2) to overcome potential drug resistance, and N-(phosphonacetyl)-L-aspartate was given at a low dose (250 mg/m2) in order to allow escalation of FUra to toxicity. These two drugs were given 24 h before FUra to enhance maximal incorporation of FUra into RNA. Two schedules of administration were used; one every other week and one weekly for 2 weeks. The every other week schedule was well tolerated, with minimal gastrointestinal and hematological toxicity. However, the weekly for 2 weeks schedule was more toxic with increased mucositis, diarrhea requiring therapy, and decreased performance status of 20% in 4 of 6 patients. There were no responders in the every other week schedule. There was one partial response and three patients with stable disease in four evaluable patients on the weekly for 2 weeks schedule. At 24 h post-N-(phosphonacetyl)-L-aspartate-methotrexate treatment, PRPP levels were doubled in bone marrow biopsies, and increased 2.5- to 25-fold in tumor biopsies. We have currently added uridine rescue to this combination with the hope of further escalating the dose of FUra.
基于一种改善5-氟尿嘧啶（FUra）抗肿瘤活性的动物模型，对44例患者进行了N-（膦酰基乙酰基）-L-天冬氨酸、甲氨蝶呤、FUra和亚叶酸钙的I期研究。给予甲氨蝶呤中等剂量（250mg/m²）以克服潜在的耐药性，给予N-（膦酰基乙酰基）-L-天冬氨酸低剂量（250mg/m²）以便将FUra剂量提升至毒性水平。这两种药物在FUra前24小时给予，以增强FUra最大程度地掺入RNA。使用了两种给药方案；一种是每隔一周给药，另一种是每周给药2周。每隔一周的给药方案耐受性良好，胃肠道和血液学毒性最小。然而，每周给药2周的方案毒性更大，粘膜炎增加，需要治疗的腹泻，6例患者中有4例（20%）体能状态下降。每隔一周的给药方案中没有缓解者。在每周给药2周的方案中，4例可评估患者中有1例部分缓解，3例病情稳定。在N-（膦酰基乙酰基）-L-天冬氨酸-甲氨蝶呤治疗后24小时，骨髓活检中的PRPP水平加倍，肿瘤活检中增加了2.5至25倍。我们目前已在该联合方案中加入尿苷解救，希望进一步提高FUra的剂量。
