Distribution and Radiosensitizing Effect of Cholesterol-Coupled Dbait Molecule in Rat Model of Glioblastoma

Coquery, Nicolas; Pannetier, Nicolas; Farion, Régine; Herbette, Aurélie; Azurmendi, Leire; Clarençon, Didier; Baugé, Stéphane; Josserand, Véronique; Rome, Claire; Coll, Jean‐Luc; Sun, Jian‐Sheng; Barbier, Emmanuel; Dutreix, Marie; Rémy, Chantal

doi:10.1371/journal.pone.0040567

Cited by 20 publications

(21 citation statements)

References 39 publications

(55 reference statements)

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“…In addition, an important challenge on the horizon will be to identify better methods of limiting side-effects, and avoidance of over-treatment in patients with radiation-insensitive tumours. Appropriate patient selection is essential and novel strategies for identifying radio-sensitive tumours and directly targeting radioresistance mechanisms are currently the focus of investigation in a series of clinical and pre-clinical trials [65-67]. These strategies will help enhance the oncological benefit conferred by IORT in more precisely stratified patient groups.…”

Section: Discussionmentioning

confidence: 99%

Intraoperative radiotherapy in colorectal cancer: Systematic review and meta-analysis of techniques, long-term outcomes, and complications

et al. 2013

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Background The precise contribution of IORT to the management of locally advanced and recurrent colorectal cancer (CRC) remains uncertain. We performed a systematic review and meta-analysis to assess the value of IORT in this setting. Methods Studies published between 1965 and 2011 that reported outcomes after IORT for advanced or recurrent CRC were identified by an electronic literature search. Studies were assessed for methodological quality and design, and evaluated for technique of IORT delivery, oncological outcomes, and complications following IORT. Outcomes were analysed with fixed-effect and random-effect model meta-analyses and heterogeneity and publication bias examined. Results 29 studies comprising 14 prospective and 15 retrospective studies met the inclusion criteria and were assessed, yielding a total of 3003 patients. The indication for IORT was locally advanced disease in 1792 patients and locally recurrent disease in 1211 patients. Despite heterogeneity in methodology and reporting practice, IORT is principally applied for the treatment of close or positive margins. When comparative studies were evaluated, a significant effect favouring improved local control (OR 0.22; 95% CI=0.05-0.86; p=0.03), disease free survival (HR 0.51; 95% CI=0.31-0.85; p=0.009), and overall survival (HR 0.33; 95% CI=0.2-0.54; p=0.001) was noted with no increase in total (OR 1.13; 95% CI=0.77-1.65; p=0.57), urologic (OR 1.35; 95% CI=0.84-2.82; p=0.47), or anastomotic complications (OR 0.94; 95% CI=0.42-2.1; p=0.98). Increased wound complications were noted after IORT (OR 1.86; 95% CI=1.03-3.38; p=0.049). Conclusions Despite methodological weaknesses in the studies evaluated, our results suggest that IORT may improve oncological outcomes in advanced and recurrent CRC.

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Section: Discussionmentioning

confidence: 99%

Intraoperative radiotherapy in colorectal cancer: Systematic review and meta-analysis of techniques, long-term outcomes, and complications

et al. 2013

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“…15 Briefly, 5 mL of tumor cell suspension in serum-free alpha-minimum essential medium were inoculated under anesthesia: 5% isoflurane for induction and 2.5% for maintenance in air. Bupivacaine (8 mg/kg; Centravet) was subcutaneously injected before incision to prevent postoperative pain.…”

Section: Animal Modelmentioning

confidence: 99%

Microvascular MRI and Unsupervised Clustering Yields Histology-Resembling Images in Two Rat Models of Glioma

Coquery

Ochsenbein

Lemasson

et al. 2014

J Cereb Blood Flow Metab

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Imaging heterogeneous cancer lesions is a real challenge. For diagnosis, histology often remains the reference, but it is widely acknowledged that biopsies are not reliable. There is thus a strong interest in establishing a link between clinical in vivo imaging and the biologic properties of tissues. In this study, we propose to construct histology-resembling images based on tissue microvascularization, a magnetic resonance imaging (MRI) accessible source of contrast. To integrate the large amount of information collected with microvascular MRI, we combined a manual delineation of a spatial region of interest with an unsupervised, model-based cluster analysis (Mclust). This approach was applied to two rat models of glioma (C6 and F98). Six MRI parameters were mapped: apparent diffusion coefficient, vessel wall permeability, cerebral blood volume fraction, cerebral blood flow, tissular oxygen saturation, and cerebral metabolic rate of oxygen. Five clusters, defined by their MRI features, were found to correspond to specific histologic features, and revealed intratumoral spatial structures. These results suggest that the presence of a cluster within a tumor can be used to assess the presence of a tissue type. In addition, the cluster composition, i.e., a signature of the intratumoral structure, could be used to characterize tumor models as histology does.

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“…We previously showed Dbait to be effective in combination with radiotherapy on several radio-resistant tumors, both in vitro and in vivo (8,(11)(12)(13). Furthermore, studies on an intestinal tumor rodent model revealed that oral administration of Dbait, in association with the chemotherapy agents 5-fluorouracil and camptothecin leads to increased chemosensitization of intestinal tumors and to a low systemic exposure (14).…”

Section: Introductionmentioning

confidence: 99%

The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis

Herath

Devun

Lienafa

et al. 2016

Molecular Cancer Therapeutics

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Metastatic liver disease from colorectal cancer is a significant clinical problem. This is mainly attributed to nonresectable metastases that frequently display low sensitivities to available chemotherapies and develop drug resistance partly via hyperactivation of some DNA repair functions. Combined therapies have shown some disease control; however, there is still a need for more efficient chemotherapies to achieve eradication of colorectal cancer liver metastasis. We investigated the tolerance and efficacy of a novel class of DNA repair inhibitors, Dbait, in association with conventional chemotherapy. Dbait mimics double-strand breaks and activates damage signaling, consequently inhibiting single-and double-stranded DNA repair enzyme recruitment. In vitro, Dbait treatment increases sensitivity of HT29 and HCT116 colorectal cancer cell lines. In vivo, the pharmacokinetics, biodistribution and the efficacy of the cholesterol-conjugated clinical form of Dbait, DT01, were assessed. The chemosensitizing abilities of DT01 were evaluated in association with oxaliplatin and 5-fluorouracil in intrahepatic HT29 xenografted mice used as a model for colorectal cancer liver metastasis. The high uptake of DT01 indicates that the liver is a specific target. We demonstrate significant antitumor efficacy in a liver metastasis model with DT01 treatment in combination with oxaliplatin and 5-fluorouracil (mean: 501 vs. 872 mm 2 , P ¼ 0.02) compared to chemotherapy alone. The decrease in tumor volume is further associated with significant histologic changes in necrosis, proliferation, angiogenesis and apoptosis. Repeated cycles of DT01 do not increase chemotherapy toxicity. Combining DT01 with conventional chemotherapy may prove to be a safe and effective therapeutic strategy in the treatment of metastatic liver cancer. Mol Cancer Ther; 15(1); 15-22. Ó2015 AACR.

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Distribution and Radiosensitizing Effect of Cholesterol-Coupled Dbait Molecule in Rat Model of Glioblastoma

Cited by 20 publications

References 39 publications

Intraoperative radiotherapy in colorectal cancer: Systematic review and meta-analysis of techniques, long-term outcomes, and complications

Intraoperative radiotherapy in colorectal cancer: Systematic review and meta-analysis of techniques, long-term outcomes, and complications

Microvascular MRI and Unsupervised Clustering Yields Histology-Resembling Images in Two Rat Models of Glioma

The DNA Repair Inhibitor DT01 as a Novel Therapeutic Strategy for Chemosensitization of Colorectal Liver Metastasis

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