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1. Towards Predicting the Response of a Solid Tumour to Chemotherapy and Radiotherapy Treatments: Clinical Insights from a Computational Model.

Author

Powathil, Gibin G., Adamson, Douglas J. A., and Chaplain, Mark A. J.

Subjects
TUMORS, CANCER chemotherapy, CELL cycle, RADIOTHERAPY, RADIATION-sensitizing agents, MATHEMATICAL models, THERAPEUTICS
Abstract

In this paper we use a hybrid multiscale mathematical model that incorporates both individual cell behaviour through the cell-cycle and the effects of the changing microenvironment through oxygen dynamics to study the multiple effects of radiation therapy. The oxygenation status of the cells is considered as one of the important prognostic markers for determining radiation therapy, as hypoxic cells are less radiosensitive. Another factor that critically affects radiation sensitivity is cell-cycle regulation. The effects of radiation therapy are included in the model using a modified linear quadratic model for the radiation damage, incorporating the effects of hypoxia and cell-cycle in determining the cell-cycle phase-specific radiosensitivity. Furthermore, after irradiation, an individual cell's cell-cycle dynamics are intrinsically modified through the activation of pathways responsible for repair mechanisms, often resulting in a delay/arrest in the cell-cycle. The model is then used to study various combinations of multiple doses of cell-cycle dependent chemotherapies and radiation therapy, as radiation may work better by the partial synchronisation of cells in the most radiosensitive phase of the cell-cycle. Moreover, using this multi-scale model, we investigate the optimum sequencing and scheduling of these multi-modality treatments, and the impact of internal and external heterogeneity on the spatio-temporal patterning of the distribution of tumour cells and their response to different treatment schedules. [ABSTRACT FROM AUTHOR]

Published
2013
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2. Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy

Author

Defne Yιlmaz, Mehmet Burcin Unlu, Mohammad Kohandel, Colin Phipps, and Sirin Yonucu

Subjects
0301 basic medicine, Angiogenesis, Physiology, Cancer Treatment, Pharmacology, Cardiovascular Physiology, Neovascularization, 0302 clinical medicine, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, Medicine and Health Sciences, Nanotechnology, lcsh:QH301-705.5, Chemotherapeutic Agents, Ecology, Neovascularization, Pathologic, Pharmaceutics, Drugs, Combination chemotherapy, 3. Good health, Drug Therapy, Computer-Assisted, Tumor Burden, Treatment Outcome, Computational Theory and Mathematics, Oncology, 030220 oncology & carcinogenesis, Modeling and Simulation, Drug delivery, Engineering and Technology, Oncology Agents, medicine.symptom, Cellular Structures and Organelles, Research Article, Clinical Oncology, Drug Extravasation, Models, Biological, 03 medical and health sciences, Cellular and Molecular Neuroscience, Cancer Chemotherapy, Drug Therapy, Genetics, medicine, Adjuvant therapy, Humans, Chemotherapy, Computer Simulation, Vesicles, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Tumor microenvironment, Dose-Response Relationship, Drug, business.industry, Biology and Life Sciences, Cell Biology, 030104 developmental biology, Targeted drug delivery, lcsh:Biology (General), Liposomes, Nanoparticles, Clinical Medicine, business, Drug Delivery, Combination Chemotherapy, Developmental Biology
Abstract

Tumor-induced angiogenesis leads to the development of leaky tumor vessels devoid of structural and morphological integrity. Due to angiogenesis, elevated interstitial fluid pressure (IFP) and low blood perfusion emerge as common properties of the tumor microenvironment that act as barriers for drug delivery. In order to overcome these barriers, normalization of vasculature is considered to be a viable option. However, insight is needed into the phenomenon of normalization and in which conditions it can realize its promise. In order to explore the effect of microenvironmental conditions and drug scheduling on normalization benefit, we build a mathematical model that incorporates tumor growth, angiogenesis and IFP. We administer various theoretical combinations of antiangiogenic agents and cytotoxic nanoparticles through heterogeneous vasculature that displays a similar morphology to tumor vasculature. We observe differences in drug extravasation that depend on the scheduling of combined therapy; for concurrent therapy, total drug extravasation is increased but in adjuvant therapy, drugs can penetrate into deeper regions of tumor., Author summary Tumor vessels being very different from their normal counterparts are leaky and lack organization that sustains blood circulation. As a result, insufficient blood supply and high fluid pressure begin to appear inside the tumor which leads to a reduced delivery of drugs within the tumor, especially in tumor center. A treatment strategy that utilizes anti-vascular drugs is observed to revert these alterations in tumor vessels, making them more normal. This approach is suggested to improve drug delivery by enhancing physical transport of drugs. In this paper, we build a mathematical model to simulate tumor and vessel growth as well as fluid pressure inside the tumor. This framework enables us to simulate drug treatment scenarios on tumors. We use this model to find whether the delivery of the chemotherapy drugs is enhanced by application of anti-vascular drugs by making vessels more normal. Our simulations show that anti-vascular drug not only enhances the amount of drugs that is released into tumor tissue, but also enhances drug distribution enabling drug release in the central regions of tumor.

Published
2017