Vokes E E, Raschko J W, Vogelzang N J, Warfield E E, Ratain M J, Doroshow J H, Schilsky R L
Department of Medicine, University of Chicago Pritzker School of Medicine, IL 60637.
Cancer Chemother Pharmacol. 1991;28(1):69-73. doi: 10.1007/BF00684960.
Fluorodeoxyuridine (FUdR) interferes with cellular metabolism by inhibiting thymidylate synthase. Therefore, we sought to modulate its activity with leucovorin (LV) and to identify the maximally tolerated dose given as a 5-day continuous intravenous infusion in combination with oral administration of LV at a dose of 100 mg every hour for four doses immediately preceding the start of the FUdR infusion and then every 4 h for the entire duration of FUdR treatment. Patients were evaluated at six FUdR dose levels ranging from 0.1 to 0.375 mg/kg per day. Severe or life-threatening mucositis was first observed in two of six patients treated at 0.25 mg/kg daily. Further escalation of the dose to 0.3 mg/kg per day resulted in grade 2 mucositis in four of six patients and in grade 3 mucositis in two cases. A dose of 0.375 mg/kg daily resulted in grade 3 toxicity in all three patients treated. Other types of toxicities included skin rash and hand-foot syndrome, but no hematologic toxicities were observed. Stable disease was observed in 11 of 24 evaluable patients, including 3 subjects with renal cell carcinoma. Our recommended dose for phase II trials is 0.3 mg/kg FUdR per day.
氟脱氧尿苷（FUdR）通过抑制胸苷酸合成酶来干扰细胞代谢。因此，我们试图用亚叶酸（LV）调节其活性，并确定在5天连续静脉输注时的最大耐受剂量，同时在开始输注FUdR前立即口服LV，剂量为每小时100mg，共4剂，然后在FUdR治疗的整个期间每4小时口服一次。对患者进行了评估，FUdR的剂量水平有6个，范围为每天0.1至0.375mg/kg。在每天接受0.25mg/kg治疗的6名患者中，有2名首次出现严重或危及生命的粘膜炎。将剂量进一步增至每天0.3mg/kg，导致6名患者中有4名出现2级粘膜炎，2名出现3级粘膜炎。每天0.375mg/kg的剂量使接受治疗的3名患者均出现3级毒性。其他类型的毒性包括皮疹和手足综合征，但未观察到血液学毒性。在24名可评估患者中的11名中观察到疾病稳定，其中包括3名肾细胞癌患者。我们推荐的II期试验剂量为每天0.3mg/kg FUdR。
