Sullivan M P, Nelson J A, Feldman S, Van Nguyen B
Division of Pediatrics, University of Texas M.D. Anderson Hospital and Tumor Institute, Houston 77030.
Cancer Chemother Pharmacol. 1988;21(1):78-84. doi: 10.1007/BF00262746.
DON (6-diazo-5-oxo-L-norleucine), a glutamine antagonist, has been subjected to limited clinical trials since 1957. Use of the drug in adults has been curtailed due to sparse reports of effectiveness as well as its dose-limiting toxicities, i.e., severe nausea, vomiting and mucositis. In earlier studies, children given DON orally in combination with 6-mercaptopurine had significant prolongation of remission of acute leukemias during maintenance therapy. As DON is acid-labile and relatively unstable in solution, oral administration does not appear to be ideal for DON. In the trial described in this report, i.v. DON therapy was studied, using i.v. chlorpromazine to control vomiting, in 20 children, 17 of whom were evaluable following treatment at DON dose levels ranging from 150 mg/m2 to 520 mg/m2. Nausea and vomiting, the dose-limiting toxicity for adults, was controlled with chlorpromazine. Mucositis, which has also been observed in adults, did not occur in the children given DON i.v. A maximum tolerated dose was not defined; however, the projected maximum tolerated dose appears to be in excess of 450 mg/m2. DON was measured in plasma using a rapid-sampling HPLC procedure. The total body clearance, plasma t1/2, and area under the plasma concentration curve (AUC) were calculated using a noncompartmental method. The drug is rapidly cleared from plasma (t 1/2 = 3 h), and its volume of distribution is approximately twice that of total body water in children. These pharmacokinetic data, differ from that of adults reported by others. Specifically, the plasma t 1/2 for children is longer: total body clearance (Cl), and volume of distribution at steady state (Vss) are greater. In addition, no dose dependency of t 1/2, Cl or Vss was observed in this study, and the DON pharmacokinetics were linear and predictable. Five of nine children with acute leukemia showed improvement, though insufficient for classification as partial response, and five of eight children with solid tumors also showed improvement. Further trials using DON in combination with thiopurines or other agents appear indicated.
重氮丝氨酸（6-重氮-5-氧代-L-正亮氨酸）是一种谷氨酰胺拮抗剂，自1957年以来已进行了有限的临床试验。由于关于其有效性的报道稀少以及存在剂量限制性毒性，即严重的恶心、呕吐和粘膜炎，该药物在成人中的使用已受到限制。在早期研究中，口服重氮丝氨酸联合6-巯基嘌呤的儿童在维持治疗期间急性白血病的缓解期显著延长。由于重氮丝氨酸对酸不稳定且在溶液中相对不稳定，口服给药似乎并非重氮丝氨酸的理想给药方式。在本报告所述的试验中，对20名儿童进行了静脉注射重氮丝氨酸治疗的研究，使用静脉注射氯丙嗪控制呕吐，其中17名儿童在重氮丝氨酸剂量水平为150mg/m²至520mg/m²治疗后可进行评估。恶心和呕吐是成人的剂量限制性毒性，用氯丙嗪得到了控制。在成人中也观察到的粘膜炎在接受静脉注射重氮丝氨酸的儿童中未发生。未确定最大耐受剂量；然而，预计最大耐受剂量似乎超过450mg/m²。使用快速采样高效液相色谱法测定血浆中的重氮丝氨酸。采用非房室方法计算总体清除率、血浆半衰期和血浆浓度曲线下面积（AUC）。该药物从血浆中迅速清除（半衰期=3小时），其分布容积在儿童中约为总体液的两倍。这些药代动力学数据与其他人报道的成人数据不同。具体而言，儿童的血浆半衰期更长：总体清除率（Cl）和稳态分布容积（Vss）更大。此外，在本研究中未观察到半衰期、Cl或Vss的剂量依赖性，重氮丝氨酸的药代动力学呈线性且可预测。9名急性白血病儿童中有5名病情有所改善，尽管不足以分类为部分缓解，8名实体瘤儿童中有5名也有改善。似乎有必要进一步开展重氮丝氨酸联合硫嘌呤或其他药物的试验。
