Seiter K, Kemeny N, Martin D, Schneider A, Williams L, Colofiore J, Sawyer R
Gastrointestinal Tumor Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Cancer. 1993 Mar 1;71(5):1875-81. doi: 10.1002/1097-0142(19930301)71:5<1875::aid-cncr2820710526>3.0.co;2-9.
In a previous trial in which methotrexate and N-phosphonacetyl-L-aspartate (PALA) were used to modulate 5-fluorouracil (5-FU), four of six patients could not tolerate treatment at the 600 mg/m2 5-FU dose level because of mucositis, diarrhea, and a decrease in performance status. The current study examines the ability of uridine rescue to prevent such toxic effects in the same regimen and, thereby, allow additional dose escalation of 5-FU.
Twenty-nine patients with advanced malignant neoplasms received PALA and MTX, each at 250 mg/m2, followed 24 hours later by increasing bolus doses of 5-FU (600-750 mg/m2) with a leucovorin rescue (10 mg orally every 6 hours for eight doses) and uridine rescue (3 g/m2/hour, for a 72-hour infusion, 3 hours on, 3 hours off). Treatment was repeated weekly with either 2 weeks on, 2 weeks off, or 3 weeks on, 1 week off.
Mucositis, which occurred in 4 of 12 patients treated at the 750 mg/m2 5-FU dose level, was the only significant chemotherapy-induced toxic effect. However, uridine-related central venous catheter complications (cellulitis in six patients and superior vena cava syndrome in one patient) precluded additional treatment on this protocol.
In the current regimen, uridine allowed dose escalation of 5-FU to 750 mg/m2, which some patients tolerated on a 3-week on, 1-week off schedule. Because of the vascular toxic effects associated with intravenous uridine, the authors recommend additional studies with oral uridine to determine whether the increase in 5-FU dose that uridine allows is associated with improved response rates.
在之前一项使用甲氨蝶呤和N-磷乙酰-L-天冬氨酸（PALA）来调节5-氟尿嘧啶（5-FU）的试验中，6名患者中有4名因黏膜炎、腹泻和体能状态下降，无法耐受600mg/m² 5-FU剂量水平的治疗。本研究探讨尿苷解救在同一方案中预防此类毒性作用的能力，从而使5-FU能够进一步增加剂量。
29例晚期恶性肿瘤患者接受PALA和MTX治疗，剂量均为250mg/m²，24小时后给予递增剂量的5-FU推注（600 - 750mg/m²），同时进行亚叶酸解救（每6小时口服10mg，共8剂）和尿苷解救（3g/m²/小时，持续输注72小时，输注3小时，停3小时）。治疗每周重复一次，采用2周治疗、2周休息或3周治疗、1周休息的方案。
在接受750mg/m² 5-FU剂量水平治疗的12例患者中，有4例出现黏膜炎，这是唯一显著的化疗诱导毒性作用。然而，与尿苷相关的中心静脉导管并发症（6例患者发生蜂窝织炎，1例患者发生上腔静脉综合征）使该方案无法继续进行额外治疗。
在当前方案中，尿苷使5-FU剂量增加至750mg/m²，部分患者在3周治疗、1周休息的方案下能够耐受。由于静脉注射尿苷存在血管毒性作用，作者建议进一步开展口服尿苷的研究，以确定尿苷允许增加的5-FU剂量是否与缓解率提高相关。
