Selective killing of tumor neovasculature paradoxically improves chemotherapy delivery to tumors.
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.
Molecular Pharmacology and Chemistry Program, Cancer Biology and Genetics Program, and Departments of Medicine and Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Freddy E
FE
Escorcia
Erik
E
Henke
Michael R
MR
McDevitt
Carlos H
CH
Villa
Peter
P
Smith-Jones
Ronald G
RG
Blasberg
Robert
R
Benezra
David A
DA
Scheinberg
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015224:Dideoxynucleosides / Q000493:pharmacokinetics; D004357:Drug Synergism; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D049268:Positron-Emission Tomography / Q000379:methods; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D007205:Indium Radioisotopes; C002854:alovudine; D002955:Leucovorin; D005472:Fluorouracil