Bibliographic Details
| Title: |
Pericyte-targeting prodrug overcomes tumor resistance to vascular disrupting agents. |
| Authors: |
Minfeng Chen1,2, Xueping Lei1,2, Changzheng Shi3, Maohua Huang1,2, Xiaobo Li1,2, Baojian Wu1,2, Zhengqiu Li1,2, Weili Han1,4, Bin Du3, Jianyang Hu1,2, Qiulin Nie1,2, Weiqian Mai1,2, Nan Ma1,2, Nanhui Xu1,2, Xinyi Zhang1,2, Chunlin Fan1,2, Aihua Hong5, Minghan Xia3, Liangping Luo3, Ande Ma4 |
| Source: |
Journal of Clinical Investigation. Oct2017, Vol. 127 Issue 10, p3689-3701. 13p. 5 Color Photographs, 1 Graph. |
| Subject Terms: |
*PERICYTES, *BLOOD vessels, *DISEASE relapse, *TUMOR treatment, *DRUG toxicity, *ANIMAL experimentation, *ANIMALS, *CELLS, *DRUG resistance in cancer cells, *EPITHELIAL cells, *MEMBRANE proteins, *MICE, *NEOVASCULARIZATION inhibitors, *PRODRUGS, *PROTEOLYTIC enzymes, *TUMORS, *VINBLASTINE, *PATHOLOGIC neovascularization, *PHARMACODYNAMICS, *METABOLISM |
| Abstract: |
Blood vessels in the tumor periphery have high pericyte coverage and are resistant to vascular disrupting agents (VDAs). VDA treatment resistance leads to a viable peripheral tumor rim that contributes to treatment failure and disease recurrence. Here, we provide evidence to support a hypothesis that shifting the target of VDAs from tumor vessel endothelial cells to pericytes disrupts tumor peripheral vessels and the viable rim, circumventing VDA treatment resistance. Through chemical engineering, we developed Z-GP-DAVLBH (from the tubulin-binding VDA desacetylvinblastine monohydrazide [DAVLBH]) as a prodrug that can be selectively activated by fibroblast activation protein α (FAPα) in tumor pericytes. Z-GP-DAVLBH selectively destroys the cytoskeleton of FAPα-expressing tumor pericytes, disrupting blood vessels both within the core and around the periphery of tumors. As a result, Z-GP-DAVLBH treatment eradicated the otherwise VDA-resistant tumor rim and led to complete regression of tumors in multiple lines of xenografts without producing the drug-related toxicity that is associated with similar doses of DAVLBH. This study demonstrates that targeting tumor pericytes with an FAPα-activated VDA prodrug represents a potential vascular disruption strategy in overcoming tumor resistance to VDA treatments. [ABSTRACT FROM AUTHOR] |
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| Database: |
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