Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma
Assessment of normal and tumor tissue uptake of MAG-CPT, a polymer-bound prodrug of camptothecin, in patients undergoing elective surgery for colorectal carcinoma
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DOI：
10.1007/s00280-003-0685-x
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发表时间：
2003-11-01
影响因子：
3
通讯作者：
Nygren, P
中科院分区：
文献类型：
--
作者：
Sarapa, N;Britto, MR;Nygren, P
目的.喜树碱（MAG-CPT）是一种新型药物传递系统的先导化合物，它是将喜树碱（CPT）的活性部分与可溶性载体（MAG）共价连接，形成无活性的前药。CPT的作用机制保持不变，但递送系统被认为允许载体结合的药物在肿瘤组织中积聚并局部释放活性CPT。该概念验证临床研究旨在确定与邻近正常组织或血浆相比，MAG-CPT是否优先递送至肿瘤组织或保留在肿瘤组织中，并估计CPT的组织内释放程度。方法.这是一项在10名计划接受择期结直肠癌手术的成人患者中进行的开放、非随机研究。患者在手术前24小时、3天或7天接受60 mg/m2（CPT当量）的MAG-CPT单次给药。在手术时同时收集血浆、肿瘤和邻近正常组织样品，并分析MAG结合和释放的CPT浓度。结果给药后24 h，血浆、肿瘤和正常组织中MAG结合和游离CPT浓度达到平衡，给药后7天平行下降。MAG结合的CPT被递送至与肿瘤和正常组织相似的水平。给药后24小时，肿瘤中平均+/-SD MAG结合CPT浓度为861+/-216 ng/g，邻近正常组织中为751+/-215 ng/g，肿瘤中游离CPT浓度低于正常组织（分别为12.2+/-4.7 ng/g和21.9+/-6.7 ng/g）。在给药后24小时，肿瘤和血浆中MAG结合和游离CPT的平均+/-SD比值分别为0.13+/-0.03和0.22+/-0.09，并且该比值在给药后长达7天没有变化，表明肿瘤中MAG结合CPT的优先保留或游离CPT的释放缺乏。这些结果与来自动物肿瘤异种移植研究的先前数据形成鲜明对比，其中在单次静脉内给药后3天和7天，组织中的MAG-CPT水平高于血浆中的水平。结论.通过MAG-CPT聚合物结合的递送系统可实现CPT向靶肿瘤组织的递送，在给药后24小时内建立释放的CPT的血浆和肿瘤组织浓度之间的平衡。然而，在给药后7天内，未检测到MAG结合或释放的CPT相对于正常组织或血浆在肿瘤中的优先保留。在我们的研究中采用的方法可能是有用的，在抗癌药物的进一步发展的“去/不去”的决定。
Purpose. MAG-camptothecin (MAG-CPT) is the lead compound of a novel drug delivery system in which an active cytotoxic moiety, camptothecin (CPT), is covalently linked to a soluble polymeric carrier (MAG) to form an inactive prodrug. The mechanism of action of CPT remains unaltered, but the delivery system is thought to allow the carrier-bound drug to accumulate in tumor tissues and release the active CPT locally. This proof-of-concept clinical study was designed to determine whether MAG-CPT was preferentially delivered to or retained in tumor tissue compared to adjacent normal tissue or plasma, and to estimate the degree of intratissue release of CPT. Methods. This was an open, non-randomized study in ten adult patients scheduled for elective surgery for colorectal cancer. Patients received a single dose of 60 mg/m(2) (CPT equivalent) of MAG-CPT 24 h, 3 days or 7 days prior to surgery. Plasma, tumor, and adjacent normal tissue samples were collected simultaneously at the time of surgery and analyzed for MAG-bound and released CPT concentrations. Results. MAG-bound and free CPT concentrations in plasma, tumor, and normal tissue achieved equilibrium by 24 h after dosing, declining in parallel up to 7 days after dosing. MAG-bound CPT was delivered to similar levels to tumor and normal tissue. At 24 h after dosing, the mean+/-SD MAG-bound CPT concentrations were 861+/-216 ng/g in tumor and 751+/-215 ng/g in adjacent normal tissue, and free CPT concentrations were lower in tumor than in normal tissue (12.2+/-4.7 ng/g and 21.9+/-6.7 ng/g, respectively). At 24 h after dosing, mean+/-SD ratios of MAG-bound and free CPT in tumor and plasma were 0.13+/-0.03 and 0.22+/-0.09, respectively, and the ratios did not change for up to 7 days after dosing, indicating a lack of preferential retention of MAG-bound CPT or release of free CPT in tumor. These results are in marked contrast to previous data from animal tumor xenograft studies, where MAG-CPT levels were higher in tissue than in plasma at 3 and 7 days after a single i.v. dose. Conclusions. Delivery of CPT to the target tumor tissue is achievable by means of the MAG-CPT polymer-bound delivery system, with the equilibrium between plasma and tumor tissue concentrations of released CPT being established within 24 h after dosing. However, preferential retention of MAG-bound or released CPT in the tumor relative to normal tissue or plasma was not detected during the 7 days after dosing. The methods employed in our study could be of use in making 'go/no-go' decisions on further development of anticancer drugs.