Kreis W, Budman D R, Chan K, Allen S L, Schulman P, Lichtman S, Weiselberg L, Schuster M, Freeman J, Akerman S
Don Monti Division of Oncology, Department of Medicine, North Shore University Hospital, Cornell University Medical College, Manhasset, New York 11030.
Leukemia. 1991 Nov;5(11):991-8.
Thirty two patients with refractory or recurrent acute leukemia or blast crisis of chronic myelocytic leukemia were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight doses. Two of 13 (15.3%) evaluable patients in group I achieved a complete response, both of whom had acute myelocytic leukemia. In group II, seven of 14 evaluable patients (50%) obtained objective responses--six with complete responses (42.8%) and one with partial response (7%). Myelosuppression was seen in all patients with a median duration of 32.5 days (group I) and 36.3 days (group II), respectively. Non-hematologic toxicity consisted of nausea, vomiting, diarrhea, conjunctivitis, skin rash, hepatocellular toxicity, hemorrhage, and renal toxicity. Pharmacokinetic studies revealed, for group I, mean peak plasma Ara-C levels at 3 h (Cp3h) of 1254 ng/ml, area under the curve (AUC) 4651 ng x h/ml, total body clearance (TBC) 32.65 l/h/m2, renal clearance (RC) 7.04 l/h/m2 with a mean of 12.36% of the injected amount of Ara-C excreted unchanged in urine over the first 24 h. The corresponding mean values for group II are Cp3h 3305 ng/ml, AUC 15080 ng x h/ml, TBC 20.48 l/h/m2, RC 7.02 l/h/m2 and 26.23%. Ara-C 200 mg/m2 combined with THU gave serum Ara-C levels and response rates comparable to those achieved with high dose Ara-C (HiDAC) (greater than or equal to 1 g/m2). Central nervous system toxicity associated with HiDAC was not seen. Pharmacokinetics for uracil arabinoside (Ara-U) in patients treated with Ara-C 200 mg/m2 plus THU, were comparable to values seen with Ara-C for Cp3h, AUC and 24 h urine, amounting to 3160 ng/ml, 21717 ng x h/ml and 23.62% whereas TBC was significantly lower (p less than 0.001) for Ara-U than for Ara-C (3.02 versus 20.48 l/h/m2).
32例难治性或复发性急性白血病或慢性粒细胞白血病急变期患者接受了1-β-D-阿拉伯呋喃糖基胞嘧啶（阿糖胞苷，Ara-C）治疗，100mg/m²[第一组（n = 15）]或200mg/m²[第二组（n = 18）]，并同时给予四氢尿苷（THU）350mg/m²，以12小时的间隔进行3小时持续静脉输注，共8剂。第一组13例可评估患者中有2例（15.3%）获得完全缓解，这2例均为急性髓细胞白血病。在第二组中，14例可评估患者中有7例（50%）获得客观缓解——6例完全缓解（42.8%），1例部分缓解（7%）。所有患者均出现骨髓抑制，第一组和第二组的中位持续时间分别为32.5天和36.3天。非血液学毒性包括恶心、呕吐、腹泻、结膜炎、皮疹、肝细胞毒性、出血和肾毒性。药代动力学研究显示，对于第一组，3小时时血浆阿糖胞苷平均峰值水平（Cp3h）为1254ng/ml，曲线下面积（AUC）为4651ng·h/ml，全身清除率（TBC）为32.65l/h/m²，肾清除率（RC）为7.04l/h/m²，在最初24小时内，平均有12.36%的注入量阿糖胞苷以原形从尿中排出。第二组的相应平均值为Cp3h 3305ng/ml，AUC 15080ng·h/ml，TBC 20.48l/h/m²，RC 7.02l/h/m²和26.23%。200mg/m²阿糖胞苷联合四氢尿苷所获得的血清阿糖胞苷水平和缓解率与大剂量阿糖胞苷（HiDAC）（≥1g/m²）相当。未观察到与HiDAC相关的中枢神经系统毒性。接受200mg/m²阿糖胞苷加四氢尿苷治疗的患者中，阿糖尿苷（Ara-U）的药代动力学参数Cp3h、AUC和24小时尿排泄量与阿糖胞苷的值相当，分别为3160ng/ml、21717ng·h/ml和23.62%，而Ara-U的TBC显著低于阿糖胞苷（p＜0.001）（3.02对20.48l/h/m²）。
