Monitoring vascular normalization induced by antiangiogenic treatment with F-18-fluoromisonidazole-PET Articles uri icon

authors

  • HERNÁNDEZ AGUDO, ELENA
  • DESCO MENENDEZ, MANUEL
  • QUINTELA FANDINO, MIGUEL
  • MONDEJAR, TAMARA
  • SOTO MONTENEGRO, Mª LUISA
  • MEGÍAS, DIEGO
  • MOURÓN, SILVANA
  • SÁNCHEZ, JESÚS
  • HIDALGO, MANUEL
  • LÓPEZ CASAS, PEDRO PABLO
  • MULERO, FRANCISCA

publication date

  • May 2016

start page

  • 704

end page

  • 718

issue

  • 5

volume

  • 10

international standard serial number (ISSN)

  • 1574-7891

electronic international standard serial number (EISSN)

  • 1878-0261

abstract

  • Background: Rationalization of antiangiogenics requires biomarkers. Vascular re normalization is one widely accepted mechanism of action for this drug class. The interstitium of tumors with abnormal vasculature is hypoxic. We sought to track vascular normalization with F-18-misonidazole ([F-18]-FMISO, a probe that detects hypoxia) PET, in response to window-of-opportunity (WoO) treatment with the antiangiogenic dovitinib. Methods: Two patient-derived pancreas xenografts (PDXs; Panc215 and Panc286) and the spontaneous breast cancer model MMTV-PyMT were used. Animals were treated during 1 week of WoO treatment with vehicle or dovitinib, preceded and followed by [F-18]-FMISO-PET, [F-18]-FDG-PET, and histologic assessment (dextran extravasation, hypoxia and microvessel staining, and necrosis, cleaved caspase-3 and Ki67 measurements). After WoO treatment, gemcitabine (pancreas)/adriamycin (breast) or vehicle was added and animals were treated until the humane endpoint. Tumor growth inhibition (TGI) and survival were the parameters studied. Results: [F-18]-FMISO SUV did not change after dovitinib-WoO treatment compared to vehicle-WoO (0.54 vs. 0.6) treatment in Panc215, but it decreased significantly in Panc286 (0.58 vs. 1.18; P < 0.05). In parallel, 10-KDa perivascular dextran extravasation was not reduced with dovitinib or vehicle-WoO treatment in Panc215, but it was reduced in Panc286. Whereas the addition of dovitinib to gemcitabine was indifferent in Panc215, it increased TGI in Panc286 (TGI switched from -59% to +49%). [F-18]-FMISO SUV changes were accompanied by an almost 100% increase in interstitial gemcitabine delivery (665-1260 ng/mL). The results were validated in the PyMT model. Conclusions: [F-18]-FMISO accurately monitored vascular re-normalization and improved interstitial chemotherapy delivery. (C) 2015 The Authors. Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.

keywords

  • antiangiogenics; vascular normalization; biomarker; f-18-misonidazole-pet; pancreatic cancer; breast cancer; cell lung cancer; positron emission tomography; metastatic breast cancer; tumor angiogenesis; neck cancer; hepatocellular carcinoma; drug development; ovarian cancer; mouse models; bevacizumab