Abstract
Tumor vasculature is known to be poorly organized leading to increased leakage of molecules to the extravascular space. This process can potentially increase interstitial fluid pressure impairing intra-tumoral blood flow and oxygen supply, and can affect drug uptake. Anti-angiogenic therapies are believed to reduce vascular permeability, potentially reducing interstitial fluid pressure and improving the extravasation of small molecule-based chemotherapeutics. Here we show that pretreatment of human ovarian carcinoma tumors with sub-optimal doses of the VEGFR targeting tyrosine kinase inhibitor axitinib, but not the EGFR targeting kinase inhibitor erlotinib, induces a transient period of increased tumor oxygenation. Doxorubicin administered within this window was found to enter the extravascular tumor space more rapidly compared to doxorubicin when applied alone or outside this time window. Treatment with the chemotherapeutics, doxorubicin and RAPTA-C, as well as applying photodynamic therapy during this period of elevated oxygenation led to enhanced tumor growth inhibition. Improvement of therapy was not observed when applied outside the window of increased oxygenation. Taken together, these findings further confirm the hypothesis of angiostasis-induced vascular normalization and also help to understand the interactions between anti-angiogenesis and other anti-cancer strategies.
Highlights
Tumor vasculature is known to be poorly organized leading to increased leakage of molecules to the extravascular space
We determined the window during which a transient increase of intra-tumoral oxygenation, referred to as the normalization window, takes place following treatment with targeted angiostatic tyrosine kinase inhibitors (TKIs) in A2780 human ovarian carcinoma xenografts implanted on the chicken chorioallantoic membrane (CAM) model
Oxygenation of human A2780 ovarian carcinoma tumors, that are negative for EGFR, xenografted onto the chorioallantoic membrane of chicken embryos was studied following treatment with the anti-angiogenic tyrosine kinase inhibitors (TKIs) axitinib, sunitinib or erlotinib (Fig. 1A)
Summary
Tumor vasculature is known to be poorly organized leading to increased leakage of molecules to the extravascular space. The presence of excessive pro-angiogenic growth factors, results in a phenotypically aberrant tumor vasculature characterized by dilatation, tortuosity and increased permeability Such leakiness leads to protein extravasation and blood clotting, which impairs blood flow and induces high interstitial fluid pressure (IFP) in the tumor[4,5]. Several approaches have been developed to enhance intra-tumoral drug delivery, e.g. low-dose PDT10, the application of a type I collagenase inhibitor[11] and the use of various anti-angiogenic agents[12,13,14] These treatments result in a transient period where the morphology of the tumor vasculature appears more normal enabling improved drug delivery. Intra-tumoral blood flow may increase giving rise to enhanced tumor oxygenation This anti-angiogenesis induced transient window of tumor blood vasculature normalization has been exploited to apply other chemotherapeutics, at the appropriate time and dose, leading www.nature.com/scientificreports to improved treatment outcomes[22,23]. In all the combination therapies evaluated, improved anti-tumor efficacy was observed when the treatment was performed during the axitinib-induced normalization window, compared to tumors treated with the same compounds without an axitinib pretreatment or when applied outside the normalization window
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