Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors Journal Article
| Authors: | Escorcia, F. E.; Henke, E.; McDevitt, M. R.; Villa, C. H.; Smith-Jones, P.; Blasberg, R. G.; Benezra, R.; Scheinberg, D. A. |
| Article Title: | Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors |
| Abstract: | Antiangiogenic therapies are frequently used with concomitantly administered cancer chemotherapy to improve outcomes, but the mechanism for the benefit of the combination is uncertain. We describe a mechanism by which a specific, cytotoxic antivascular agent causes vascular remodeling and improved chemotherapy results. By selectively killing tumor neovasculature using short-ranged α-particles targeted to vascular endothelial (VE)-cadherin on vascular endothelial cells (by use of 225Ac-labeled E4G10 antibody) we were able both to reduce tumor growth and to increase the efficacy of chemotherapy, an effect seen only when the chemotherapy was administered several days after the vascular targeting agent, but not if the order of administration was reversed. Immunohistochemical and immunofluorescence studies showed that the vasculature of 225Ac-E4G10-treated tumors was substantially depleted; the remaining vessels appeared more mature morphologically and displayed increased pericyte density and coverage. Tumor uptake and microdistribution studies with radioactive and fluorescent small molecule drugs showed better accumulation and more homogenous distribution of the drugs within 225Ac-E4G10-treated tumors. These results show that 225Ac-E4G10 treatment leads to ablation and improvement of the tumor vascular architecture, and also show that the resulting vascular remodeling can increase tumor delivery of small molecules, thus providing a process for the improved outcomes observed after combining antivascular therapy and chemotherapy. This study directly shows evidence for what has long been a speculated mechanism for antiangiogenic therapies. Moreover, targeting the vessel for killing provides an alternative mode of improving chemotherapy delivery and efficacy, potentially avoiding some of the drawbacks of targeting a highly redundant angiogenic pathway. ©2010 AACR. |
| Keywords: | immunohistochemistry; cancer chemotherapy; controlled study; unclassified drug; human cell; fluorouracil; drug efficacy; nonhuman; treatment duration; antineoplastic agent; neoplasms; animal cell; mouse; animals; mice; animal tissue; antineoplastic combined chemotherapy protocols; animal experiment; animal model; antineoplastic activity; immunofluorescence; xenograft model antitumor assays; cell line, tumor; angiogenesis; neovascularization, pathologic; drug synergism; endothelium cell; antibodies, monoclonal; indium radioisotopes; drug uptake; isotope labeling; vascular endothelium; mice, nude; tumor burden; folinic acid; radioactivity; positron-emission tomography; antiangiogenic therapy; radiopharmaceutical agent; tumor growth; radioimmunotherapy; angiogenesis inhibitors; tumor vascularization; leucovorin; colon adenocarcinoma; vascular targeting agent; neovascularization (pathology); drug delivery system; pentetate indium in 111; fluorine radioisotopes; monoclonal antibody e4610 ac 225; vascular endothelial cadherin; alpha radiation; dideoxynucleosides |
| Journal Title: | Cancer Research |
| Volume: | 70 |
| Issue: | 22 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2010-11-15 |
| Start Page: | 9277 |
| End Page: | 9286 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-10-2029 |
| PUBMED: | 21045141 |
| PROVIDER: | scopus |
| PMCID: | PMC3058681 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 20 April 2011" - "CODEN: CNREA" - "Source: Scopus" |
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272Blasberg -
144Mcdevitt -
14Henke -
499Scheinberg -
146Benezra -
67
Smith-Jones -
13
Villa -
17Escorcia
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