Melton R G, Wiblin C N, Baskerville A, Foster R L, Sherwood R F
Biochem Pharmacol. 1987 Jan 1;36(1):113-21. doi: 10.1016/0006-2952(87)90388-1.
The in vivo fate of the therapeutic enzyme, carboxypeptidase G2 (CPG2) in native form and covalently-linked to soluble dextrans was studied in the mouse using radiolabelled compounds. Clearance, from the blood, of all compounds tested was found to be as intact, active material, whilst excreted radiolabel was associated in all cases with low molecular weight substances. The clearance and excretion rates of native CPG2 were found to balance, but this was not so for dextran-CPG2 conjugate or CNBr-activated dextran. Tissue distribution studies demonstrated that there was little or no tissue uptake of native CPG2, whereas dextran-CPG2 conjugate, and CNBr-activated dextran were retained in the liver. Within the liver, the CPG2 component of dextran-CPG2 conjugate was degraded more rapidly than the dextran moiety. Blockade of reticulo-endothelial system (RES) led to increased half-lives of dextran CPG2 conjugate and CNBr-activated dextran, demonstrating the involvement of the RES in the clearance of these compounds. Impairment of RES activity did not affect the clearance rate of native CPG2. These results are discussed in relation to the potential use of dextran-CPG2 conjugates in cancer chemotherapy.
利用放射性标记化合物在小鼠体内研究了天然形式的治疗性酶羧肽酶G2（CPG2）以及与可溶性葡聚糖共价连接的CPG2的体内命运。发现所有测试化合物从血液中的清除均为完整的活性物质，而排泄出的放射性标记在所有情况下均与低分子量物质相关。发现天然CPG2的清除率和排泄率达到平衡，但葡聚糖-CPG2缀合物或溴化氰活化的葡聚糖并非如此。组织分布研究表明，天然CPG2几乎没有或没有组织摄取，而葡聚糖-CPG2缀合物和溴化氰活化的葡聚糖则保留在肝脏中。在肝脏内，葡聚糖-CPG2缀合物的CPG2成分比葡聚糖部分降解得更快。网状内皮系统（RES）的阻断导致葡聚糖CPG2缀合物和溴化氰活化的葡聚糖的半衰期延长，表明RES参与了这些化合物的清除。RES活性受损并不影响天然CPG2的清除率。结合葡聚糖-CPG2缀合物在癌症化疗中的潜在用途对这些结果进行了讨论。
