Role of vascular normalization in benefit from metronomic chemotherapy
| Autor: | Mpekris, F., Baish, J. W., Stylianopoulos, T., Jain, R. K. |
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| Přispěvatelé: | Stylianopoulos, T. [0000-0002-3093-1696] |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
cancer inhibition Pharmacology feedback system Thrombospondin 1 low drug dose regulatory T lymphocyte 0302 clinical medicine Theoretical Models Neoplasms Antineoplastic Combined Chemotherapy Protocols Tumor Microenvironment Medicine animal CD8+ T lymphocyte antineoplastic agent comparative study cancer cell clinical article Multidisciplinary Neovascularization Pathologic theoretical model gemcitabine cell hypoxia Biological Sciences Vascular normalization Cell Hypoxia Thrompospondin-1 3. Good health tumor growth priority journal thrombospondin 1 validation study 030220 oncology & carcinogenesis Administration Drug delivery Neoplastic Stem Cells Perfusion cancer stem cell Tumor perfusion immunocompetent cell cancer chemotherapy Article pancreas tumor 03 medical and health sciences Immune system tumor vascularization Humans tumor microenvironment Animals controlled study human drug screening Dosing Immune response Metronomic thrombospondin-1 Neovascularization Pathologic Tumor microenvironment business.industry metronomic drug administration neovascularization (pathology) Models Theoretical natural killer cell Xenograft Model Antitumor Assays Metronomic Chemotherapy tumor xenograft drug efficacy 030104 developmental biology Oxygenation tumor volume drug effects Administration Metronomic vascular tumor Cancer cell treatment outcome Cancer research cyclophosphamide pathology business metabolism mathematical model neoplasm |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Metronomic dosing of chemotherapy - defined as frequent administration at lower doses - has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy. © 2017, National Academy of Sciences. All rights reserved. 114 1994 1999 1994-1999 |
| Databáze: | OpenAIRE |
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