RT Journal Article
T1 Monitoring vascular normalization induced by antiangiogenic treatment with F-18-fluoromisonidazole-PET
A1 Hernandez Agudo, Elena
A1 Mondejar, Tamara
A1 Soto Montenegro, Mª Luisa
A1 Megias, Diego
A1 Mouron, Silvana
A1 Sanchez, Jesus
A1 Hidalgo, Manuel
A1 Lopez Casas, Pedro Pablo
A1 Mulero, Francisca
A1 Desco Menéndez, Manuel
A1 Quintela Fandino, Miguel
AB 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.
PB FEBS Press
SN 1878-0261
YR 2016
FD 2016-05
LK https://hdl.handle.net/10016/38724
UL https://hdl.handle.net/10016/38724
LA eng
NO This work was supported by the following sources: Fondo de Investigación Sanitaria (Ministry of Health, Spain; numbers FIS PI10/0288, FIS PI13/00430, FIS PI 11/00616, CPII14/00005 and FIS PI14/00860; the first two awarded to MQF and the last three to MD), and "Fondo Europeo de Desarrollo Regional (FEDER) - Una manera de hacer Europa". MQF is a recipient of a 2010 Beca-Retorno from the AECC Scientific Foundation. Rosae Foundation and AVON España S.A.U. contributed to this work with unrestricted donations. Dovitinib was kindly provided by Novartis.
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RD 17 jul. 2024