ABSTRACT
This paper deals with the dynamic modeling and simulation of cell damage heterogeneity and associated mutant cell phenotypes in the therapeutic responses of cancer cell populations submitted to a radiotherapy session during in vitro assays. Each cell is described by a finite number of phenotypic states with possible transitions between them. The population dynamics is then given by an age-dependent multi-type branching process. From this representation, we obtain formulas for the average size of the global survival population as well as the one of subpopulations associated with 10 mutation phenotypes. The proposed model has been implemented into Matlab© and the numerical results corroborate the ability of the model to reproduce four major types of cell responses: delayed growth, anti-proliferative, cytostatic and cytotoxic.
Subject(s)
DNA Damage/radiation effects , Models, Biological , Mutation/radiation effects , Radiotherapy/adverse effects , Tumor Cells, Cultured/radiation effects , HumansABSTRACT
PURPOSE: Free doxorubicin (DXR) is not currently used to treat brain tumors because (i) the blood-brain barrier limits the drug deposition into the brain (ii) lethal toxic effects occur when combined with radiation therapy. Since encapsulation of DXR within liposomal carriers could overcome these drawbacks, the present study aimed at evaluating the radiosensitizing properties of non-pegylated (NPL-DXR) and pegylated (PL-DXR) liposomal doxorubicin on orthotopic high-grade glioma xenografts (U87). METHODS: DXR accumulation in brain tissues was assessed by a high-performance liquid chromatography method and antitumor efficacy was evaluated by mice survival determination. RESULTS: We showed that encapsulation of DXR ensured a preferential deposition of DXR in tumoral tissue in comparison with normal brain tissue: the best AUC tumor tissue/AUC normal tissue ratio depended greatly on the schedule. Overall, thanks to the optimization of the delivery schedule, we demonstrated a radiosensitizing effect for both liposomal DXR without toxicity of this combination on the U87 human malignant glioma orthotopic xenografts. CONCLUSION: This study shows that the use of nanocarriers, allowing targeting of intracerebral tumor, renders relevant the combination of anthracyclin with radiation therapy to treat brain tumors, opening a new field of therapeutic applications. However, our results point out that, for each new delivery system, the administration schedules need to be rigorously optimized.
Subject(s)
Brain Neoplasms/radiotherapy , Doxorubicin/analogs & derivatives , Glioma/radiotherapy , Radiation-Sensitizing Agents/therapeutic use , Animals , Brain Neoplasms/drug therapy , Brain Neoplasms/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Doxorubicin/therapeutic use , Doxorubicin/toxicity , Drug Administration Schedule , Female , Glioma/drug therapy , Glioma/metabolism , Humans , Mice, Nude , Neoplasm Grading , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Polyethylene Glycols/therapeutic use , Polyethylene Glycols/toxicity , Radiation-Sensitizing Agents/administration & dosage , Radiation-Sensitizing Agents/pharmacokinetics , Radiation-Sensitizing Agents/toxicity , Tissue Distribution , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Over the last few years, taking advantage of the linear kinetics of the tumor growth during the steady-state phase, tumor diameter-based rather than tumor volume-based models have been developed for the phenomenological modeling of tumor growth. In this study, we propose a new tumor diameter growth model characterizing early, late and steady-state treatment effects. Model parameters consist of growth rhythms, growth delays and time constants and are meaningful for biologists. Biological experiments provide in vivo longitudinal data. The latter are analyzed using a mixed effects model based on the new diameter growth function, to take into account inter-mouse variability and treatment factors. The relevance of the tumor growth mixed model is firstly assessed by analyzing the effects of three therapeutic strategies for cancer treatment (radiotherapy, concomitant radiochemotherapy and photodynamic therapy) administered on mice. Then, effects of the radiochemotherapy treatment duration are estimated within the mixed model. The results highlight the model suitability for analyzing therapeutic efficiency, comparing treatment responses and optimizing, when used in combination with optimal experiment design, anti-cancer treatment modalities.
Subject(s)
Models, Biological , Neoplasms/pathology , Animals , Cell Proliferation , Humans , Kinetics , Mice , Neoplasms/drug therapy , Neoplasms/radiotherapyABSTRACT
Aurora kinases (A, B and C) are proteins expressed only in cells which divide actively and their increase is a factor of bad prognosis in cancer. They regulate the maturation of centrosomes, the separation and the condensation of chromosomes, mitotic checkpoint and cytokinesis. The inhibition of aurora kinases, by powerful and selective inhibitors, is due to the formation of abnormal cells which are eliminated by apoptosis. The purpose of this article is to present the role, the antitumor activity and the tolerability of these inhibitors. They can be administered orally or intravenously, on weekly or monthly schedules. In our knowledge, twelve molecules are evaluated at the present time and will be discussed only the most advanced namely: VX-680, ZM 447439, MLN 8054, AZD 1152, PHA 739358, SU 6668 and AT 9283. The main indications are breast, colon, lung, pancreas and bladder cancers as well as hematologic tumors such as leukemia (ALL, AML, CML) and lymphoma. These inhibitors can be associated with other chemotherapies. They seem well tolerated; the reported side effects are digestive disorders (diarrhea), fever, asthenia, alopecia, slumber, neutropenia, myelosuppression and disturbance of the biological markers.
