Pharmacokinetic characteristics and therapeutic effects of mitomycin C dextran conjugates after intratumoural injection
Pharmacokinetic characteristics and therapeutic effects of mitomycin C dextran conjugates after intratumoural injection
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DOI：
10.1016/s0168-3659(97)00185-5
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发表时间：
1998-03-31
影响因子：
10.8
通讯作者：
Hashida, M
中科院分区：
文献类型：
--
作者：
Nomura, T;Saikawa, A;Hashida, M
研究了丝裂霉素C大分子前药（MMC）、MMC-葡聚糖缀合物（MMC-D）在荷瘤Walker 256癌肉瘤大鼠瘤内注射后的药代动力学和治疗效果。第一步，使用组织分离的肿瘤制剂在灌注实验中描述了这些药物的肿瘤内分布特征。虽然直接肿瘤内注射后MMC立即从肿瘤制剂中消失，但阳离子和阴离子MMC-D在肿瘤中保留更长时间，这表明葡聚糖缀合可以大大延迟MMC的肿瘤内清除。在阳离子缀合物的情况下，效果更为明显。灌注实验中的静脉流出数据是基于隔室模型进行分析的，其中假设肿瘤组织由两个隔室组成，一个是灌注良好的，另一个是灌注不良的。药代动力学分析显示，大分子缀合减少了MMC从灌注不良区域而不是灌注良好区域的消除，使用计算参数模拟组织中的缀合和游离MMC水平清楚地表明，肿瘤内注射MMC-D，特别是阳离子形式，可以在组织中维持一定水平的活性游离MMC更长的时间。体内药代动力学研究和皮下 Walker 256 癌肉瘤大鼠的全身放射自显影也证实了肿瘤内注射后阳离子 MMC-D 在肿瘤中的长期保留。此外，在肿瘤内注射后，观察到阳离子MMC-D对皮下肿瘤具有优异的抗肿瘤活性。连同MMC在低浓度下对缺氧肿瘤细胞具有选择性毒性的发现一起，这些药代动力学研究有力地支持了大分子前药的治疗功效。 (C) 1998 Elsevier Science B.V.
The pharmacokinetics and therapeutic effects of macromolecular prodrugs of mitomycin C (MMC), MMC-dextran conjugates (MMC-D) were studied after intratumoural injection in rats bearing Walker 256 carcinosarcoma. As the first step, the intratumoural disposition characteristics of these drugs were delineated in perfusion experiments employing a tissue-isolated tumour preparation. While MMC immediately disappeared from the tumour preparation following direct intratumoural injection, cationic and anionic MMC-D were retained in the tumour longer, demonstrating that the intratumoural clearance of MMC can be greatly retarded by dextran conjugation. The effect was more pronounced in the case of the cationic conjugate, Venous outflow data in the perfusion experiments were analyzed based on a compartment model in which the tumour tissue was assumed to consist of two compartments, one well- and the other poorly-perfused. The pharmacokinetic analysis revealed that macromolecular conjugation reduced elimination of MMC from the poorly-perfused region rather than well-perfused region, Simulation of conjugated and free MMC levels in the tissue using the calculated parameters clearly showed that intratumoural injection of MMC-D, especially the cationic form, can maintain a certain level of active free MMC in the tissue for a much longer time period. The long retention of cationic MMC-D in tumour after intratumoural injection was also confirmed by an in vivo pharmacokinetic study and whole body autoradiography in rats bearing subcutaneous Walker 256 carcinosarcoma. In addition, superior antitumour activity of cationic MMC-D was observed against subcutaneous rumours after intratumoural injection. Together with the finding that MMC is selectively toxic to hypoxic tumour cells at low concentrations, these pharmacokinetic studies strongly support the therapeutic efficacy of the macromolecular prodrugs. (C) 1998 Elsevier Science B.V.