Kanter P M, Schwartz H S, West C R
Cancer Drug Deliv. 1983;1(1):11-20. doi: 10.1089/cdd.1983.1.11.
A study was conducted to elucidate functional or chemical parameters that may be useful for in vivo toxicologic and pharmacokinetic analysis of PCNU. The growth-inhibitory and DNA-related parameters of this agent and its serum breakdown products in murine leukemia L1210 cells were carried out in direct comparison with BCNU. In human and dog sera, the T1/2 of intact PCNU (5-12 min) was similar to BCNU (5-16 min). However, much larger T1/2 values for PCNU (140 min) and BCNU (110 min) were determined for drug incubated in dog brain homogenates. Uptake of 14C-labeled PCNU in L1210 cells was rapid, and tenfold higher than in CCRF-CEM, a human leukemia cell line naturally resistant to BCNU and PCNU. BCNU was shown to induce DNA strand damage in L1210 and to inhibit radioactive thymidine incorporation into DNA and cross-link proteins with DNA in L1210. PCNU, by comparison, only weakly inhibited thymidine incorporation and did not induce DNA strand breakage or produce DNA-protein cross-links in L1210 at reasonable concentrations. The compounds are further differentiated in fetal calf serum by the breakdown products derived from initial concentrations of intact drug that are equipotent; those of BCNU inhibit L1210 growth whereas those of PCNU do not. PCNU, which is rapidly broken down into inactive metabolites, may have a selective therapeutic advantage if infused directly to the target site.
开展了一项研究以阐明可能有助于对PCNU进行体内毒理学和药代动力学分析的功能或化学参数。将该药物及其血清分解产物在鼠白血病L1210细胞中的生长抑制和DNA相关参数与BCNU进行了直接比较。在人血清和犬血清中，完整PCNU的T1/2（5 - 12分钟）与BCNU（5 - 16分钟）相似。然而，在犬脑匀浆中孵育的药物，PCNU（140分钟）和BCNU（110分钟）的T1/2值要大得多。14C标记的PCNU在L1210细胞中的摄取迅速，比CCRF - CEM细胞（一种对BCNU和PCNU天然耐药的人白血病细胞系）高十倍。已证明BCNU可诱导L1210细胞中的DNA链损伤，并抑制放射性胸苷掺入L1210细胞的DNA以及与DNA交联蛋白质。相比之下，在合理浓度下，PCNU仅微弱抑制胸苷掺入，且在L1210细胞中不诱导DNA链断裂或产生DNA - 蛋白质交联。在胎牛血清中，这些化合物还可通过来自等效力的完整药物初始浓度的分解产物进一步区分；BCNU的分解产物抑制L1210细胞生长，而PCNU的分解产物则不然。PCNU迅速分解为无活性代谢物，如果直接注入靶位点，可能具有选择性治疗优势。
