Study of Modern Control Methodologies Applied to Tumor Growth under Angiogenic Inhibition

Cancer treatment is one of the most important research fields of modern medicine. In the last decades, targeted molecular therapies showed pr osperous results. These treatments achieve tumor regression with limited side-effects. Mathem atical models were posed which describe the dynamics of tumor regression under the applied control. The current paper investigates antiangiogenic therapy, which inhibits the t umor to grow its own endothelial capillaries and thus inhibits tumor to grow over a certain si ze. Many different control approaches were elaborated and published since the model formulation w as posed. The aim of this paper is to give an overview of these methods and results, and to rev iew the work carried out by the authors

Parameter optimization of H∞ controller designed for tumor growth in the light of physiological aspects

According to the fact that cancer diseases are leading causes of death all around the world, development of cancer fighting therapies is necessary. Beside the medical knowledge, there is an extra need for engineering approach to solve this complex problem. The aim of this paper is to design controller for tumor growth under angiogenic inhibition, which on the one hand minimizes the input signal as far as possible (in order to have less side effects and greater cost-effectiveness) and on the other hand results in appropriately low tumor volume. Since the model contains uncertainties and measurement noise, the controller was designed using modern robust control methodology. Choosing of the ideal system and the weighting functions were done in the light of physiological aspects

Model-based Angiogenic Inhibition of Tumor Growth using Adaptive Fuzzy Techniques

Fighting tumors is one of the most important problems of medical research. In this paper, antiangiogenic cancer therapy is investigated through its mathematical model.This tumor treatment method targets the endothelium of a growing tumor and belongs to the targeted molecular therapies.The aim of the therapy is not to eliminate the entire tumor,but to decrease the tumor to a minimal volume. An advantage of applying antiangiogenic treatment is that tumor cells show lower tendency of becoming resistant to the applied drugs.Adaptive fuzzy control is implemented for a simplified model to elaborate a control technique which is able to handle the effects of parameter perturbations and uncertainties while keeping the daily and total inhibitor inlet under a given limit

Magnetic Resonance imaging Assessment of Tumor Microvessels and Response to Antiangiogenesis Therapy

Magnetic resonance Imaging (MRI) is a diagnostic modality with high inherent contrast resolution and multiplanar imaging capability. Advances in MR technology and image processing have increased the utility and availability of this technique in the past two decades. MRI has become one of the leading modalities in current diagnostic imaging, combining soft tissue contrast with high anatomic and temporal resolution. MRI is now a widely employed diagnostic method for the clinical evaluation of tumors. One of the most recent applications of MRI is the investigation of angiogenesis using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI represents the acquisition of serial MR images before, during, and after the administration of an intravenous contrast agent. The use of contrast enhancement in conjunction with magnetic resonance imaging provides a means to evaluate tissue function, as well as morphology. Tissue blood volume, blood flow, perfusion and capillary permeability represent indicators of the status of the vasculature that can be investigated with DCE-MRI. Use of such quantitation potentially allows tumors to be characterized in terms of pathophysiology and to be monitored over time, during the course of therapeutic interventions. The understanding of the angiogenesis process and the evaluation of new drugs that inhibit or stimulate angiogenesis are directly related to the development of an imaging assay of angiogenic activity. This method should provide functionally relevant and quantitative images, should be high in spatial resolution, should sample the entire tumor and could be repeated at frequent intervals. DCE-MRI has grown in importance with the development of antiangiogenic and neoadjuvant strategies for tumor therapy. Dedicated software makes it possible to interpret imaging pharmacokinetics and aid the assessment of physiological parameters such as capillary permeability and tissue perfusion. For instance, the permeability of functional tumor microvessels can be assessed noninvasively by dynamic MRI of contrast agent uptake in the tumor tissue (1-4). The analysis of contrast kinetics can be applied to differentiate between a malignant and a benign lesion and to determine whether a tumor is responding to treatment (5). It has been demonstrated that the permeability of blood vessels correlates with the ability of the tumor to metastasize, and with its response to treatment (6, 7). Thus, information concerning the status of vascular permeability might help assessing the metastatic potential of tumors and predict the sensitivity to chemotherapy or to antiangiogenic treatment

Radionuclide carriers for targeting of cancer

This review describes strategies for the delivery of therapeutic radionuclides to tumor sites. Therapeutic approaches are summarized in terms of tumor location in the body, and tumor morphology. These determine the radionuclides of choice for suggested targeting ligands, and the type of delivery carriers. This review is not exhaustive in examples of radionuclide carriers for targeted cancer therapy. Our purpose is two-fold: to give an integrated picture of the general strategies and molecular constructs currently explored for the delivery of therapeutic radionuclides, and to identify challenges that need to be addressed. Internal radiotherapies for targeting of cancer are at a very exciting and creative stage. It is expected that the current emphasis on multidisciplinary approaches for exploring such therapeutic directions should enable internal radiotherapy to reach its full potential

Novel anti-endothelial therapeutic strategies in malignant melanoma : the metronomic approach.

Treatment strategies for advanced malignancy remain limited in their success, despite major advances in the understanding of cancer aetiology and molecular biology. The incidence of many cancers, including melanoma, continues to rise, with a huge demand for therapies even if treatment goals are purely cytostatic. One particular therapeutic strategy is the metronomic (continuous and low) dosing of conventional chemotherapy. There is evidence to suggest that tumour vasculature is the main target of this dosing schedule resulting in an overall ‘non specific’ anti-angiogenic effect. It is now being studied in clinical trials alone and in combination with specific antiangiogenic agents.This thesis had two main aims: firstly to investigate the additive or synergistic antiendothelial effects of a number of conventional cytotoxic agents (Temozolomide, Paclitaxel, Vinorelbine, Etoposide, Carboplatin) in vitro given in a metronomic schedule in combination with a specific anti-angiogenic compound (Sorafenib) and a non-specific sompound (Combretastatin). The anti-proliferative, cytotoxic activities of the metronomic combinatorial schedules were assessed on microvascular endothelial cells and cancer cells using an MTT proliferation assay. Results confirmed significant (