Asselin B L, Whitin J C, Coppola D J, Rupp I P, Sallan S E, Cohen H J
Strong Children's Research Center, University of Rochester, NY.
J Clin Oncol. 1993 Sep;11(9):1780-6. doi: 10.1200/JCO.1993.11.9.1780.
As part of pharmacologic studies of asparaginase (ASNase), we determined the half-life of ASNase activity and protein, and the effect of dose, repeated doses, different drug preparations, and hypersensitivity reactions on the half-life (t1/2) of serum ASNase activity.
We measured ASNase activity (spectrophotometric assay) in serum samples obtained from patients with acute lymphoblastic leukemia (ALL) at various times during their therapy with intramuscular ASNase. ASNase protein was measured by enzyme-linked immunoadsorbent assay (ELISA).
Studies following the initial dose of Escherichia coli-derived ASNase demonstrated no difference in apparent t1/2 following 25,000 IU/m2 versus 2,500 IU/m2 (1.24 v 1.35 days, P = .2). The apparent t1/2s following maintenance doses of E coli ASNase (middle dose t1/2, 1.28 days, or last dose t1/2, 1.14 days) showed no difference when compared with the initial dose of ASNase (P = .3 to .9). There was no significant difference between the apparent t1/2s of ASNase activity and ASNase protein (n = 8, P = .2 to .6). The serum t1/2 was 0.65 and 5.73 days for patients receiving Erwinia or polyethylene glycol (PEG)-modified E coli ASNase, respectively, as the induction dose. ASNase activity was undetectable in sera of four patients studied in the week following an anaphylactic reaction to E coli ASNase and the t1/2 was significantly shorter in five patients with a history of allergic reaction to E coli ASNase who were studied following a dose of PEG ASNase, (t1/2, 1.80 days).
We conclude that (1) the apparent t1/2 of ASNase is dependent on enzyme preparation used, but is not affected by dose or by repeated use; (2) the apparent t1/2 of E coli ASNase as a protein is the same as the apparent t1/2 of enzymatic activity; and (3) patients who have had a hypersensitivity reaction to E coli ASNase have a decreased apparent t1/2 with both E coli and PEG ASNase.
作为天冬酰胺酶（ASNase）药理学研究的一部分，我们测定了ASNase活性和蛋白质的半衰期，以及剂量、重复给药、不同药物制剂和过敏反应对血清ASNase活性半衰期（t1/2）的影响。
我们在急性淋巴细胞白血病（ALL）患者接受肌肉注射ASNase治疗的不同时间，测量其血清样本中的ASNase活性（分光光度法测定）。通过酶联免疫吸附测定（ELISA）测量ASNase蛋白。
对初始剂量的大肠杆菌来源的ASNase进行研究发现，25000 IU/m²与2500 IU/m²剂量后的表观t1/2无差异（1.24天对1.35天，P = 0.2）。与ASNase初始剂量相比，维持剂量的大肠杆菌ASNase后的表观t1/2（中剂量t1/2为1.28天，或最后剂量t1/2为1.14天）无差异（P = 0.3至0.9）。ASNase活性和ASNase蛋白的表观t1/2之间无显著差异（n = 8，P = 0.2至0.6）。接受欧文氏菌或聚乙二醇（PEG）修饰的大肠杆菌ASNase作为诱导剂量的患者，其血清t1/2分别为0.65天和5.73天。在对大肠杆菌ASNase发生过敏反应后的一周内，研究的4例患者血清中检测不到ASNase活性，在接受一剂PEG ASNase治疗后进行研究的5例有大肠杆菌ASNase过敏反应史的患者中，其t1/2明显缩短（t1/2为1.80天）。
我们得出结论：（1）ASNase的表观t1/2取决于所用的酶制剂，但不受剂量或重复使用的影响；（2）大肠杆菌ASNase作为蛋白质的表观t1/2与酶活性的表观t1/2相同；（3）对大肠杆菌ASNase有过敏反应的患者，使用大肠杆菌和PEG ASNase时，其表观t1/2均降低。
