Conference
Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation
| العنوان: | Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation |
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| المؤلفون: | Delahousse, Julia, Skarbek, Charles, Gauthier, Valentine, Desbois, Mélanie, Roger, Emilie, Pioche-Durieu, C., Rivard, M., Desmaële, Didier, Martens, T., Lecam, E., Benoit, Jean-Pierre, Couvreur, P., Chaput-Gras, Nathalie, Paci, Angelo |
| المساهمون: | Vectorologie et thérapeutiques anti-cancéreuses Villejuif (UMR 8203), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut Curie Paris -Institut National de la Santé et de la Recherche Médicale (INSERM), Cytune Pharma Nantes, Laboratoire d’Immunomonitoring en Oncologie (LIO), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut Galien Paris-Sud (IGPS), Université Paris-Sud - Paris 11 (UP11)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS), Pharmacologie, Département de biologie et pathologie médicales Gustave Roussy, Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Université Paris-Saclay |
| المصدر: | AACR Annual Meeting 2017 ; https://univ-angers.hal.science/hal-02615988 ; AACR Annual Meeting 2017, 2017, Washington, United States. ⟨10.1158/1538-7445.AM2017-2195⟩ ; http://cancerres.aacrjournals.org/content/77/13_Supplement/2195 |
| بيانات النشر: | HAL CCSD American Association for Cancer Research |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | [SDV]Life Sciences [q-bio] |
| جغرافية الموضوع: | Washington, United States |
| Time: | Washington, United States |
| الوصف: | Oxazaphosphorines (Oxaza) represented by cyclophosphamide (CPA) and ifosfamide (IFO) are still the corner stone of several polychemotherapy protocols as they are widely indicated in the treatment of numerous cancer from soft tissue sarcomas to lymphomas and immune-related diseases. However, Oxaza are prodrugs requiring cytochrome (CYP) P450 bioactivation responsible of limiting adverse effects. In the case of IFO, bioactivation leads to a low release of 4-OH-IFO (10%), which generates the active nitrogen mustard displaying DNA cross-links. Associated toxicities of IFO due to acrolein, (urotoxicity) and to chloroacetaldehyde (neuro and nephrotoxicity) have been described. Thus, increasing IFO therapeutic index could be of major interest. To circumvent these toxicities, our team has designed new pre-activated IFO analogs to avoid CYP bioactivation (Skarbek et al J Med Chem 2015). Among these analogues some have the ability to self-assemble as nanoassemblies (NAs), the others can be encapsulated within nano-lipid capsules (NLCs). These new drug delivery systems (DDS) can take advantage of passive targeting, as stealthiness of these DDS can be provided by PEGylation by using Cholesterol-polyethylene glycol or the use of surfactant. These DDS can also be functionalized by appropriate monoclonal antibodies leading to multi stage DDS with active targeting properties. Regarding CPA, it has been shown and described in literature that low doses of CPA enhance the immunity by promoting differentiation of CD4⁺ cell toward Th1. As IFO is isomeric form of CPA, it was assumed that IFO could also have such properties. Studies on immunocompetent MCA205 mouse model, an immunogenic fibrosarcoma mouse model, demonstrate a dose-dependent immunomodulation of IFO towards a modulation of the secretion of IFNy, IL-17A and IL-6 cytokines. The ongoing experiments on mouse model depleted in CD4⁺ T cells and CD8⁺ T cells show the antitumor efficacy of IFO 150mg/kg on these immune cells in tumor regression. Both strategies could lead to the ... |
| نوع الوثيقة: | conference object |
| اللغة: | English |
| Relation: | hal-02615988; https://univ-angers.hal.science/hal-02615988; OKINA: ua16164 |
| DOI: | 10.1158/1538-7445.AM2017-2195 |
| الاتاحة: | https://univ-angers.hal.science/hal-02615988 https://doi.org/10.1158/1538-7445.AM2017-2195 |
| رقم الانضمام: | edsbas.5D61BA6F |
| قاعدة البيانات: | BASE |
| DOI: | 10.1158/1538-7445.AM2017-2195 |
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