Tumor vasculature remodeling by radiation therapy increases doxorubicin distribution and efficacy. (10th August 2019)

• Record Type: Journal Article
• Authors: Potiron, Vincent; Clément-Colmou, Karen; Jouglar, Emmanuel; Pietri, Manon; Chiavassa, Sophie; Delpon, Grégory; Paris, François; Supiot, Stéphane
• Is Part Of: Cancer letters. Volume 457(2019)
• Page Start: 1
• Page End: 9
• Publication Date: 2019-08-10
• Subjects: Radiotherapy -- Vascular normalization -- Drug distribution -- Chemotherapy -- Pericyte; Doxo doxorubicin -- MVD microvascular density -- RIVR radiation-induced vascular remodeling -- RT radiation therapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.05.005
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The tumor microenvironment regulates cancer initiation, progression and response to treatment. In particular, the immature tumor vasculature may impede drugs from reaching tumor cells at a lethal concentration. We and others have shown that radiation therapy (RT) induces pericyte recruitment, resembling vascular normalization. Here, we asked whether radiation-induced vascular remodeling translates into improved tissue distribution and efficacy of chemotherapy. First, RT induced vascular remodeling, accompanied by decreased hypoxia and/or increased Hoechst perfusion in prostate PC3 and LNCaP and Lewis lung carcinoma. These results were independent of the RT regimen, respectively 10 × 2 Gy and 2 × 12 Gy, suggesting a common effect. Next, using doxorubicin as a fluorescent reporter, we observed that RT improves intra-tumoral chemotherapy distribution. These effects were not hindered by anti-angiogenic sunitinib. Moreover, sub-optimal doses of doxorubicin had almost no effect alone, but significantly delayed tumor growth after RT. These data demonstrate that RT favors the efficacy of chemotherapy by improving tissue distribution, and could be an alternative chemosensitizing strategy. Highlights: Radiotherapy induces vascular remodeling in different models and schedules of RT. Radiotherapy increases intra-tumoral distribution of doxorubicin. Radiotherapy enhances anti-tumor efficacy of doxorubicin when delivered prior to doxorubicin. Radiotherapy is a robust strategy that favors small molecule distribution.