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Angiostatic treatment prior to chemo- or photodynamic therapy improves anti-tumor efficacy
Andrea Weiss1, Débora Bonvin2, Robert H Berndsen1
11] Institute of Chemical Sciences and Engineering, Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland [2] Angiogenesis Laboratory, Department of Medical Oncology, VU University Medical Center Amsterdam, The Netherlands.
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.
Insights
Sub-optimal doses of axitinib, a VEGFR inhibitor, transiently improve tumor oxygenation and drug delivery. This vascular normalization window enhances chemotherapy and photodynamic therapy efficacy in ovarian cancer models.
Area of Science:
- Oncology
- Vascular Biology
- Pharmacology
Background:
- Tumor vasculature is often disorganized, leading to increased vascular permeability and impaired drug delivery.
- Anti-angiogenic therapies aim to normalize tumor vasculature, potentially improving chemotherapy efficacy.
- Understanding the timing of anti-angiogenic treatment is crucial for optimizing therapeutic outcomes.
Purpose of the Study:
- To investigate the effect of VEGFR and EGFR inhibitors on tumor oxygenation and vascular permeability.
- To determine if a specific treatment window exists for enhanced chemotherapy delivery and efficacy.
- To evaluate the combined efficacy of anti-angiogenic therapy with chemotherapy and photodynamic therapy.
Main Methods:
- Treatment of human ovarian carcinoma tumors with axitinib (VEGFR inhibitor) or erlotinib (EGFR inhibitor).
- Assessment of tumor oxygenation levels and vascular permeability.
- Administration of doxorubicin and RAPTA-C chemotherapy, and photodynamic therapy within specific time windows relative to anti-angiogenic treatment.
- Evaluation of tumor growth inhibition.
Main Results:
- Axitinib, but not erlotinib, induced a transient period of increased tumor oxygenation.
- Doxorubicin showed more rapid extravascular tumor space entry when administered during this window.
- Combined treatment with chemotherapy (doxorubicin, RAPTA-C) or photodynamic therapy during the elevated oxygenation window resulted in enhanced tumor growth inhibition.
- Therapeutic improvements were not observed when treatments were applied outside this specific window.
Conclusions:
- Findings support the hypothesis of angiostasis-induced vascular normalization.
- A specific therapeutic window exists where anti-angiogenic pretreatment enhances the efficacy of chemotherapy and photodynamic therapy.
- This study provides insights into the synergistic interactions between anti-angiogenesis and other anti-cancer strategies.
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