Robert-Alain Toillon

The in vivo performance of ferrocenyl tamoxifen lipid nanocapsules in xenografted triple negative breast cancer

Triple-negative breast cancers (TNBC) represent the most aggressive form of breast cancers and their treatment are challenging due to the tumor heterogeneity. The high death rate and the limited systemic treatment options for TNBC necessitate the search for alternative chemotherapeutics. We previously found that FcOHTAM, an organometallic derivative of hydroxytamoxifen, showed in vitro a strong antiproliferative effect on various breast cancer cell lines, including MDA-MB-231 cells, the archetype of TNBC. In this study, we developed stealth FcOHTAM loaded lipid nanocapsules (LNCs) to further evaluate this novel drug on a TNBC xenografted model. Cell cycle analysis of MDA-MB-231 cells confirmed the preservation of the drug activity through LNCs causing a cycle arrest in phase S after 48 h exposure at the IC50 concentration (2 μm). Two intraperitoneal injections of FcOHTAM loaded LNCs (20 mg/kg) administered to luciferase-transfected MDA-MB-231 tumors bearing mice led to a marked delay in tumor growth. As a consequence, a significantly lower tumor volume was obtained at the end of the experiment with a difference of 36% at day 38 compared to the untreated group. These results represent the first evidence of an in vivo effect of FcOHTAM and ferrocenyl derivatives in general on xenografted breast tumors.

Different clinical impact of estradiol receptor determination according to the analytical method: a study on 1940 breast cancer patients over a period of 16 consecutive years.

SummaryThe knowledge of estrogen receptor (ER) status is important in the management of breast cancer patients. More precisely, analytical methods for ER determination have changed over the last two decades from ligand binding assay (LBA) dextran-coated charcoal (DCC) to enzyme immuno-assay (EIA) and more recently immunohistochemistry (IHC). We examined the respective clinical impact of ER determination according to these 3 methods over the period 1983–1999 within a group of 1940 patients, all operated and followed in the single institution Centre Antoine Lacassagne. Validated cut off values were 10 and 15xa0fmol/mg protein for both LBA-DCC and EIA, respectively and 10% of stained cells for IHC. During the years it was noted that the initial size of the tumor decreased and that the proportion of positive axillary nodes and negative ER tumors was different according to the ER method. ER negativity was 20, 13 and 10% in LBA-DCC, EIA, IHC, respectively. ER was a strong predictor of overall survival in the whole population (Mantel-Cox, p<0.00001); however when stratifying the analysis on ER method groups, ER was still a prognostic indicator in the EIA, LBA-DCC group but not in the IHC group (the follow-up was too short). It is important to keep these data in mind when conducting large retrospective studies evaluating prognostic markers in breast cancer patients.

Facteurs de radiorésistance des cellules souches cancéreuses et perspectives de radiosensibilisation : l’exemple du glioblastomeCancer stem cells, cornerstone of radioresistance and perspectives for radiosensitization: glioblastoma as an example

Cancer stem cells are a subject of increasing interest in oncology. In particular, several data suggest that cancer stem cells are involved in the mechanisms of tumor radioresistance, and may explain the therapeutic failures after radiotherapy. Because of its poor prognosis and high recurrence rate after irradiation, glioblastoma model is often studied in the search for new radiosensitizers. There are several preclinical data suggesting that cancer stem cells could be a potential therapeutic target for improving the biological effectiveness of radiation therapy. Through the example of glioblastoma, we review the main signaling pathways involved in the mechanisms of radiation resistance of cancer stem cells and for which pharmacological targeting could potentially enhance tumor radiosensitivity.

La radiothérapie induit-elle une agressivité accrue des cellules tumorales du glioblastome ? Radiation-induces increased tumor cell aggressiveness of tumors of the glioblastomas?

Glioblastoma multiform is the most common and aggressive brain tumor with a worse prognostic. Ionizing radiation is a cornerstone in the treatment of glioblastome with chemo-radiation association being the actual standard. As a paradoxal effect, it has been suggested that radiotherapy could have a deleterious effect on local recurrence of cancer. In vivo studies have studied the effect of radiotherapy on biological modification and pathogenous effect of cancer cells. It seems that ionizing radiations with photon could activate oncogenic pathways in glioblastoma cell lines. We realized a review of the literature of photon-enhanced effect on invasion and migration of glioblastoma cells by radiotherapy.

La radiothérapie induit-elle une agressivité accrue des cellules tumorales du glioblastome?

Glioblastoma multiform is the most common and aggressive brain tumor with a worse prognostic. Ionizing radiation is a cornerstone in the treatment of glioblastome with chemo-radiation association being the actual standard. As a paradoxal effect, it has been suggested that radiotherapy could have a deleterious effect on local recurrence of cancer. In vivo studies have studied the effect of radiotherapy on biological modification and pathogenous effect of cancer cells. It seems that ionizing radiations with photon could activate oncogenic pathways in glioblastoma cell lines. We realized a review of the literature of photon-enhanced effect on invasion and migration of glioblastoma cells by radiotherapy.

Ciblage du récepteur aux facteurs de croissance épithéliaux (REGF) par les inhibiteurs de tyrosine kinase et applications dans les cancers colorectaux

Résumé:La détermination du niveau d’expression du REGF présentenun intérêt de premier ordre dans les cancers colorectauxnpuisqu’elle est à la fois synonyme de valeur pronostique parnelle-même, qu’elle permet une meilleure orientation dentraitement, et qu’elle offre de plus la possibilité d’unntraitement ciblé hautement spécifique anti-REGF.nIn vitro, pour les cancersncolorectaux, l’association d’inhibiteurs de tyrosine kinasen(ITK) spécifique du REGF à un traitement conventionneln(5-fluorouracile, capecitabine, radiation ionisante) estnsupra-additive et les changements moléculaires induits par lesnITK permettent d’en fournir des explications mécanistiquesnplausibles. Sur ces bases, des futurs essais thérapeutiques sontnà mettre en œuvre en pathologie digestive.Abstract:EGF receptor is moderately overexpressed in colorectalncancer and it is globally associated to poor prognosis outcome.nThus determination of EGFR level represents a major interest innorder to orientate a targeted therapy and to redefine a newnprognostic biological marker to treat colorectal cancernpatients. In vitro studiesnconduced with tyrosine kinase inhibitors in colorectal cancerncell lines have demonstrated additive effects with conventionalntreatment and molecular biology could explained these positiveninteractions. Basis on these preclinical studies, future largenclinical trials could create a real hope for all patientsnpresenting a colorectal cancer.