Resistance of tumor interstitial pressure to the penetration of intraperitoneally delivered antibodies into metastatic ovarian tumors
Resistance of tumor interstitial pressure to the penetration of intraperitoneally delivered antibodies into metastatic ovarian tumors
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DOI：
10.1158/1078-0432.ccr-04-2332
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发表时间：
2005-04-15
影响因子：
11.5
通讯作者：
Henderson, K
中科院分区：
文献类型：
--
作者：
Flessner, MF;Choi, J;Henderson, K
目的：尽管有证据表明区域化疗改善了转移性腹膜卵巢癌的治疗，但单抗在腹腔注射方面并未显示出显著的成功。送货。本研究旨在解决这样一种假设，即大分子抗肿瘤药物的对流穿透取决于IP之间的正压差。治疗液与肿瘤。实验设计：采用裸鼠腹壁种植人卵巢异种移植瘤，以便于体内测量肿瘤压力并进行瘤体内注射治疗。高压下的溶液。结果：12例SKOV3肿瘤(9.7+/-8.3)和15例OVCAR3肿瘤(12.5+/-7.0)肿瘤压力谱显示峰值压力为32 mm Hg，平均压力(+/-SD，mm Hg)。L.P.在6-8毫米汞柱(最大可行压力)的治疗中，曲妥珠单抗在邻近正常肌肉中的渗透率显著低于邻近的正常肌肉。为了建立对流进入肿瘤的驱动力，尝试了各种方法来降低肿瘤压力，包括使用紫杉烷或前列腺素E-1治疗，消除肿瘤循环，以及移除肿瘤包膜。肿瘤去包膜后压力降至零，但不能增强抗体的穿透能力。与每个肿瘤上特定的曲妥珠单抗受体的结合并不是抗体穿透的显著障碍。结论：结果仅部分支持我们的假设，并暗示肿瘤的微环境本身是带电大分子输送的主要障碍。
Purpose: Despite evidence that regional chemotherapy improves the treatment of metastatic peritoneal ovarian carcinoma, monoclonal antibodies have not shown significant success in i.p. delivery. The present study was designed to address the hypothesis that convective penetration of macromolecular antineoplastic agents depends on a positive pressure difference between the i.p. therapeutic solution and the tumor.Experimental Design: Nude rats with human ovarian xenografts implanted in the abdominal wall were used in experiments to facilitate in vivo measurement of tumor pressure and the treatment of the tumor with i.p. solutions at high pressures. Penetration of I-125-labeled trastuzumab was measured with quantitative autoradiography.Results: Tumor pressure profiles showed peak pressures of 32 mm Hg with mean pressures (+/- SD, mm Hg) in 12 SKOV3 tumors of 9.7 +/- 8.3 and in 15 OVCAR3 tumors of 12.5 +/- 7.0. l.p. therapeutic dwells at 6 to 8 mm Hg (maximum feasible pressure) showed significantly less penetration of trastuzumab than in adjacent normal muscle. To establish a driving force for convection into the tumor, various maneuvers were attempted to reduce tumor pressure, including treatment with taxanes or prostaglandin E-1, elimination of tumor circulation, and removal of the tumor capsule. Tumor decapsulation decreased the pressure to zero but did not enhance the penetration of antibody. Binding to specific trastuzumab receptors on each tumor was shown to be not a significant barrier to antibody penetration.Conclusions: The results only partially support our hypothesis and imply that the microenvironment of the tumor is in itself a major barrier to delivery of charged macromolecules.