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Common preclinical models for testing anticancer treatment include cultured human tumor cell lines in monolayer, and xenografts derived from these cell lines in immunodeficient mice. Our goal was to determine how similar the xenografts are compared with their original cell line and to determine whether it is possible to predict the stability of a xenograft model beforehand. We studied a selection of 89 protein markers of interest in 14 human cell cultures and respective subcutaneous xenografts using the reverse-phase protein array technology. We specifically focused on proteins and posttranslational modifications involved in DNA repair, PI3K pathway, apoptosis, tyrosine kinase signaling, stress, cell cycle, MAPK/ERK signaling, SAPK/JNK signaling, NFκB signaling, and adhesion/cytoskeleton. Using hierarchical clustering, most cell culture-xenograft pairs cluster together, suggesting a global conservation of protein signature. Particularly, Akt, NFkB, EGFR, and Vimentin showed very stable protein expression and phosphorylation levels highlighting that 4 of 10 pathways were highly correlated whatever the model. Other proteins were heterogeneously conserved depending on the cell line. Finally, cell line models with low Akt pathway activation and low levels of Vimentin gave rise to more reliable xenograft models. These results may be useful for the extrapolation of cell culture experiments to in vivo models in novel targeted drug discovery., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to evaluate the impact of the time interval (TI) between surgery and adjuvant radiotherapy (RT) in soft tissue sarcoma (STS)., Methods and Materials: Data from 1131 patients treated between 1990 and 2014 were retrospectively reviewed. Inclusion criteria were: limb or superficial trunk wall STS (R0 or R1 resection) and adjuvant RT. The impact of TI on 10-year local relapse-free survival (LRFS) and 10-year overall survival (OS) was analyzed using a Log-rank test and then Cox Model., Results: The median TI was 82days (range, 18-346). With a median follow-up of 235months (range, 2-296months), the 10-year LRFS was 57.5% (±2%) and the 10-year OS was 64.2% (±2%). With a TI of 19-39days, 40-79days, 80-119days, and ⩾120days, 10-year LRFSs were 65.3%, 55.5%, 56.9% and 61.2% (p=0.465), and 10-year OSs were 72.8%, 60.7%, 66.4% and 62.1% (p=0.347), respectively. After adjustment for the factors significantly (p⩽0.05) associated with LRFS and OS, TI did not alter LRFS (p=0.182) either OS (p=0.335)., Conclusions: In this retrospective STS database study, the TI between surgery and start of adjuvant RT did not seem to affect outcomes., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Benign tumors of the skull base are a challenge when delivering radiotherapy. An appropriate choice of radiation technique may significantly improve the patient's outcomes. Our study aimed to compare the dosimetric results of fractionated stereotactic radiotherapy between non-coplanar dynamic arcs and coplanar volumetric modulated arctherapy (Rapidarc®)., Methods: Thirteen patients treated with Novalis TX® were analysed: six vestibular schwannomas, four pituitary adenomas and three meningioma. Two treatment plans were created for each case: dynamic arcs (4-5 non coplanar arcs) and Rapidarc® (2 coplanar arcs). All tumors were >3 cm and accessible to both techniques. Patients had a stereotactic facemask (Brainlab) and were daily repositioned by Exactrac®. GTV and CTV were contoured according to tumor type. A 1-mm margin was added to the CTV to obtain PTV. Radiation doses were 52.2-54 Gy, using 1.8 Gy per fraction. Treatment time was faster with Rapidarc®., Results: The mean PTV V95 % was 98.8 for Rapidarc® and 95.9 % for DA (p = 0.09). Homogeneity index was better with Rapidarc®: 0.06 vs. 0.09 (p = 0.01). Higher conformity index values were obtained with Rapidarc®: 75.2 vs. 67.9 % (p = 0.04). The volume of healthy brain that received a high dose (V90 %) was 0.7 % using Rapidarc® vs. 1.4 % with dynamic arcs (p = 0.05). Rapidarc® and dynamic arcs gave, respectively, a mean D40 % of 10.5 vs. 18.1 Gy (p = 0.005) for the hippocampus and a Dmean of 25.4 vs. 35.3 Gy (p = 0.008) for the ipsilateral cochlea. Low-dose delivery with Rapidarc® and dynamic arcs were, respectively, 184 vs. 166 cm(3) for V20 Gy (p = 0.14) and 1265 vs. 1056 cm(3) for V5 Gy (p = 0.67)., Conclusions: Fractionated stereotactic radiotherapy using Rapidarc® for large benign tumors of the skull base provided target volume coverage that was at least equal to that of dynamics arcs, with better conformity and homogeneity and faster treatment time. Rapidarc® also offered better sparing of the ipsilateral cochlea and hippocampus. Low-dose delivery were similar between both techniques.

The ability of cancer cells to recognize damage and initiate DNA repair is an important mechanism for therapeutic resistance. The use of inhibitors of DNA damage repair or signaling pathways appears to provide a unique opportunity for targeting genetic differences between tumor and normal cells. In this review, we firstly describe the main DNA lesions induced by the different treatments and the pathways involved in their repair. Then we review the mechanism of action and applications of an innovative DNA repair inhibitor: Dbait (and its clinical form DT01). Dbait/DT01 consists of 32 bp deoxyribonucleotides forming an intramolecular DNA double helix that mimics DNA lesions. They act as a bait for DNA damage signaling enzymes, the polyadenyl-ribose polymerase (PARP), and the DNA-dependent kinase (DNA-PK), inducing a "false" DNA damage signal and ultimately inhibiting recruitment at the damage site of many proteins involved in double-strand break and single-strand break repair pathways. Preclinical studies have demonstrated the capacity of Dbait/DT01 to improve the efficiency of (i) chemotherapy in colorectal cancer or hepatocellular carcinoma models, (ii) radiofrequency ablative in colorectal cancer liver metastases models, and (iii) radiotherapy in xenografted mice with head & neck squamous cell carcinoma, glioblastoma and melanoma. Following this good preclinical results, we performed a first-in-human phase 1-2a study evaluating the safety and efficacy of the combination of DT01 with radiotherapy for the treatment of skin metastases of melanoma. Twenty-three patients were included. No dose-limiting toxicity was observed. An objective response was observed in 59% lesions, including 30% complete responses. This first promising clinical efficacy provides future potential interesting clinical development of Dbait/DT01 with various anticancer treatments., (Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Malignant gliomas are the most common primary brain tumors. Grade III and IV gliomas harboring wild-type IDH1/2 are the most aggressive. In addition to surgery and radiotherapy, concomitant and adjuvant chemotherapy with temozolomide (TMZ) significantly improves overall survival (OS). The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) promoter is predictive of TMZ response and a prognostic marker of cancer outcome. However, the promoter regions the methylation of which correlates best with survival in aggressive glioma and whether the promoter methylation status predictive value could be refined or improved by other MGMT-associated molecular markers are not precisely known. In a cohort of 87 malignant gliomas treated with radiotherapy and TMZ-based chemotherapy, we retrospectively determined the MGMT promoter methylation status, genotyped single nucleotide polymorphisms (SNPs) in the promoter region and quantified MGMT mRNA expression level. Each of these variables was correlated with each other and with the patients' OS. We found that methylation of the CpG sites within MGMT exon 1 best correlated with OS and MGMT expression levels, and confirmed MGMT methylation as a stronger independent prognostic factor compared to MGMT transcription levels. Our main finding is that the presence of only the A allele at the rs34180180 SNP in the tumor was significantly associated with shorter OS, independently of the MGMT methylation status. In conclusion, in the clinic, rs34180180 SNP genotyping could improve the prognostic value of the MGMT promoter methylation assay in patients with aggressive glioma treated with TMZ., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Radiotherapy is an essential component of glioma standard treatment. Glioblastomas (GBM), however, display an important radioresistance leading to tumor recurrence. To improve patient prognosis, there is a need to radiosensitize GBM cells and to circumvent the mechanisms of resistance caused by interactions between tumor cells and their microenvironment. STAT3 has been identified as a therapeutic target in glioma because of its involvement in mechanisms sustaining tumor escape to both standard treatment and immune control. Here, we studied the role of STAT3 activation on tyrosine 705 (Y705) and serine 727 (S727) in glioma radioresistance. This study explored STAT3 phosphorylation on Y705 (pSTAT3-Y705) and S727 (pSTAT3-S727) in glioma cell lines and in clinical samples. Radiosensitizing effect of STAT3 activation down-modulation by Gö6976 was explored. In a panel of 15 human glioma cell lines, we found that the level of pSTAT3-S727 was correlated to intrinsic radioresistance. Moreover, treating GBM cells with Gö6976 resulted in a highly significant radiosensitization associated to a concomitant pSTAT3-S727 down-modulation only in GBM cell lines that exhibited no or weak pSTAT3-Y705. We report the constitutive activation of STAT3-S727 in all GBM clinical samples. Targeting pSTAT3-S727 mainly in pSTAT3-Y705-negative GBM could be a relevant approach to improve radiation therapy., (© 2015 International Society of Neuropathology.)

Head and neck cancers have been widely studied concerning their sensitivity to radiation therapy. Several parameters affect tumour response to radiation therapy. Some parameters are linked to the tumour. Large or invasive tumours, localization, such as oral cavity or adenopathy, are factors of radioresistance. Others parameters are linked to the patients themselves. Tobacco intoxication during radiotherapy and a low hemoglobin level contribute to radioresistance. More recently, a positive human papilloma virus (HPV) status has been reported to positively affect radiosensitivity. Finally, other parameters are related to tumour biology. Hypoxia, intrinsic radiosensitivity of tumour cells, tumour differentiation and repopulation (provided by Ki-67 index or EGFR level) are components of radiosensitivity. Currently, concurrent chemoradiotherapy is one of the gold standard treatments to overcome clinical outcome of locally advanced head and neck cancer. This combination increases locoregional control and survival. Taxane-based induction chemotherapy can also be an alternative. Another validated approach is the association of radiotherapy with cetuximab (EGFR targeting) but only one randomized study has been published. Fractionation modifications, especially hyperfractionation, have given positive results on both tumour control and survival. Strategies targeting hypoxia improve locoregional control but have less clinical impact., (Copyright © 2015 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The incidence of glioblastoma increases with age, with a median age, at diagnosis, of 65 years. Indeed, the optimization of standard of care of elderly glioblastoma patients in an aging population in Western countries becomes crucial. The age remains the main prognostic factor of glioblastoma. Survival among elderly patients is significantly less than among younger patients. The median survival of elderly glioblastoma patients is generally inferior to 6 months. More aggressive tumor behavior, less aggressive treatments, increased toxicity of therapies and more unfavorable clinical factors and comorbidities could explain a higher severity of the disease in the elderly. The balance between treatment efficacy and quality of life is a major focus because of the shorter life expectancy of patients. The standard of care of glioblastoma in elderly patients remains controversial. Large optimal resection, when achievable, should be preferred to biopsy. Survival is longer after adjuvant radiotherapy, either normofractionated over 6-weeks course or hypofractionated over 3-weeks course, for patients with good clinical status. Hypofractionation is often preferred because of shorter procedure. Chemotherapy alone with temozolomide can be proposed to patients with methylated MGMT promoter. A phase III randomized study, testing short-course adjuvant radiotherapy with or without temozolomide in elderly patients with good clinical status, is ongoing., (Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of "palliative" RT (10 × 3 Gy) or "radical" RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the "palliative" protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67 days] or the "radical" protocol (TGD by 3.2-fold; median survival: 221 vs 109 days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial).

Numerous studies have shown that intensity-modulated radiation therapy is the standard technique for the radiation treatment of head and neck cancers. Intensity-modulated radiation therapy reduces side effects (xerostomia, dysphagia, fibrosis, etc.) and improves the results for cancer localizations with highly complex shapes such as the cavum or nasal cavity. Intensity-modulated radiation therapy is also a costly technique that necessitates a numerous staff, highly trained, with regular practice. If this technique cannot be available (understaffing, overwork, etc.) the choice between entrusting the patient to a colleague and treating the patient with a less sophisticated technique such as 3-dimensional conformal radiation therapy depends on different objective and ethical criteria., (Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The aim of this article is to present the determination and delineation of nodal target volumes for head and neck cancers treated with intensity-modulated radiotherapy. The delineation on computerized tomography scanner (CT scan) requires a precise methodology. Different elements are necessary: clinical examination, diagram of the initially involved lymph nodes, surgical and pathological reports and medical imagings (CT scan, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography). The different clinical target volumes are approached and the concept of selectivity of neck nodal targets is specified according to current literature., (Copyright © 2014 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

Purpose: Social media and mobile technology are transforming the way in which young physicians are learning and practicing medicine. The true impact of such technologies has yet to be evaluated., Methods and Materials: We performed a nationwide cross-sectional survey to better assess how young radiation oncologists used these technologies. An online survey was sent out between April 24, 2013, and June 1, 2013. All residents attending the 2013 radiation oncology French summer course were invited to complete the survey. Logistic regressions were performed to assess predictors of use of these tools in the hospital on various clinical endpoints., Results: In all, 131 of 140 (93.6%) French young radiation oncologists answered the survey. Of these individuals, 93% owned a smartphone and 32.8% owned a tablet. The majority (78.6%) of the residents owning a smartphone used it to work in their department. A total of 33.5% had more than 5 medical applications installed. Only 60.3% of the residents verified the validity of the apps that they used. In all, 82.9% of the residents had a social network account., Conclusions: Most of the residents in radiation oncology use their smartphone to work in their department for a wide variety of tasks. However, the residents do not consistently check the validity of the apps that they use. Residents also use social networks, with only a limited impact on their relationship with their patients. Overall, this study highlights the irruption and the risks of new technologies in the clinical practice and raises the question of a possible regulation of their use in the hospital., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gathering evidence has revealed that Akt signaling pathway plays an important role in glioma progression and aggressiveness. Among Akt kinases the most studied, Akt1, has been involved in many cellular processes that are in favor of cell malignancy. More recently, the actions of the two other isoforms, Akt2 and Akt3 have emerged in glioma. After a description of Akt pathway activation, we will explore the role of each isoform in malignant glioma that strengthens the current preclinical and clinical studies evaluating the impact of Akt pathway targeting in glioblastomas.

Purpose: To assess the usefulness of combining hyperthermia with a DNA repair inhibitor (double-strand break bait [Dbait]) and its potential application to radiofrequency ablation (RFA) in a preclinical model of human colorectal cancer., Materials and Methods: The local ethics committee of animal experimentation approved all investigations. First, the relevance was assessed by studying the survival of four human colorectal adenocarcinoma cell cultures after 1 hour of hyperthermia at 41°C or 43°C with or without Dbait. Human colon adenocarcinoma cells (HT-29) were grafted subcutaneously into nude mice (n = 111). When tumors reached approximately 500 mm(3), mice were treated with Dbait alone (n = 20), sublethal RFA (n = 21), three different Dbait schemes and sublethal RFA (n = 52), or a sham treatment (n = 18). RFA was performed to ablate the tumor center alone. To elucidate antitumor mechanisms, 39 mice were sacrificed for blinded pathologic analysis, including assessment of DNA damage, cell proliferation, and tumor necrosis. Others were monitored for tumor growth and survival. Analyses of variance and log-rank tests were used to evaluate differences., Results: When associated with mild hyperthermia, Dbait induced cytotoxicity in all tested colon cancer cell lines. Sublethal RFA or Dbait treatment alone moderately improved survival (median, 40 days vs 28 days for control; P = .0005) but combination treatment significantly improved survival (median, 84 days vs 40 days for RFA alone, P = .0004), with approximately half of the animals showing complete tumor responses. Pathologic studies showed that the Dbait and RFA combination strongly enhances DNA damage and coagulation areas in tumors., Conclusion: Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy., (RSNA, 2013)

Objectives: A national survey was conducted among the radiation oncology residents about their clinical activities and responsibilities. The aim was to evaluate the clinical workload and to assess how medical tasks are delegated and supervised., Materials and Methods: A first questionnaire was administered to radiation oncology residents during a national course. A second questionnaire was mailed to 59 heads of departments., Results: The response rate was 62% for radiation oncology residents (99 questionnaires) and 51% for heads of department (30). Eighteen heads of department (64%) declared having written specifications describing the residents' clinical tasks and roles, while only 31 radiation oncology residents (34%) knew about such a document (P=0.009). A majority of residents were satisfied with the amount of medical tasks that were delegated to them. Older residents complained about insufficient exposure to new patient's consultation, treatment planning and portal images validation. The variations observed between departments may induce heterogeneous trainings and should be addressed specifically., Conclusion: National specifications are necessary to reduce heterogeneities in training, and to insure that the residents' training covers all the professional skills required to practice radiation oncology. A frame endorsed by academic and professional societies would also clarify the responsibilities of both residents and seniors., (Copyright © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The aim of this article is to present the determination and the delineation of target volumes for oral cavity and oropharyngeal carcinomas treated with intensity-modulated irradiation. The delineation on the computerized tomography scanner (CT scan) requires a precise method because of the complexity of the head-and-neck anatomy. Different elements are necessary: clinical examination, diagram of the initial tumor, surgical and pathological reports and medical imaging (CT scan, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography). The clinical target volumes, the planning target volumes, the organs at risk and the planning organs at risk volumes are discussed. The concept of selectivity of the potential subclinical disease near the primary tumour and the selection of neck nodal targets are specified according to the literature., (Copyright © 2013 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.)

The various image-guided radiotherapy techniques raise the question of how to achieve the control of patient positioning before irradiation session and sharing of tasks between radiation oncologists and radiotherapy technicians. We have put in place procedures and operating methods to make a partial delegation of tasks to radiotherapy technicians and secure the process in three situations: control by orthogonal kV imaging (kV-kV) of bony landmarks, control by kV-kV imaging of intraprostatic fiducial goldmarkers and control by cone beam CT (CBCT) imaging for prostate cancer. Significant medical overtime is required to control these three IGRT techniques. Because of their competence in imaging, these daily controls can be delegated to radiotherapy technicians. However, to secure the process, initial training and regular evaluation are essential. The analysis of the comparison of the use of kV/kV on bone structures allowed us to achieve a partial delegation of control to radiotherapy technicians. Controlling the positioning of the prostate through the use and automatic registration of fiducial goldmarkers allows better tracking of the prostate and can be easily delegated to radiotherapy technicians. The analysis of the use of daily cone beam CT for patients treated with intensity modulated irradiation is underway, and a comparison of practices between radiotherapy technicians and radiation oncologists is ongoing to know if a partial delegation of this control is possible., (Copyright © 2013. Published by Elsevier SAS.)

Hematology Oncology has a rich history including few crucial therapeutic innovations. These were possible because of the evolution of the cell and molecular biology allowing a better understanding of basic mechanisms of cancerogenesis. We propose here to summarize the most important therapeutic innovations since the beginning of Hematology/Oncology history. We also describe evolution of therapeutic strategies themselves. New insights and therapeutic perspectives for next future are also discussed.

Purpose: When evaluating dosimetric parameters predictive of lung toxicity in lung cancer, the total lung volume can be defined to exclude the gross tumor volume (lung-GTV) or to exclude the planning target volume (lung-PTV). The purpose of the study was to evaluate the impact of these 2 types of delineation on the dosimetric parameters V20, V30, and mean lung dose (MLD)., Methods and Materials: We analyzed 69 patients with lung cancer treated with 3-dimensional radiation therapy. Normal lung volume was defined using 2 modalities of delineation: lung-GTV and lung-PTV. The lung volume inside the PTV, but outside the GTV, corresponded to the margins within the lung parenchyma applied to the GTV and the clinical target volume (CTV) to obtain the PTV. This volume (expressed in percentage of total lung volume) increases with the following: (1) the margins (GTV to CTV and CTV to PTV) increase within the lung parenchyma; (2) the GTV increases; and (3) the total lung volume decreases., Results: Mean reduction of lung volume was 5.1% (range, 1.4-10.0). With the delineation lung-PTV rather than lung-GTV, the mean reduction was 3.1% (P < 10(-7)), 3.3% (P < 10(-7)), and 2.1 Gy (P < 10(-7)) for V20, V30, and MLD, respectively. These reductions correlated strongly with reduction of lung volume (r(2) range, 0.89-0.96). For 25% of patients having greater reduction of lung volume (high margins, high tumor volume, small lung volume), reduction of V20 ranged from 4.5%-6.3%, reduction of V30 ranged from 4.6%-7.0%, and reduction of MLD ranged from 2.9 Gy-4 Gy., Conclusions: The dosimetric parameters V20, V30, and MLD are reduced with the delineation using lung-PTV rather than lung-GTV. These reductions correlate with lung volume in the PTV and can be significant., (Copyright © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Daily set up of patients with prostate cancer using orthogonal kV/kV imaging and weekly set up control require 1h to 1h30 of off line revision by a radio-oncologist per day and per accelerator. The aim of this study was to evaluate the possibility to delegate this control to radiation therapists., Material and Methods: The files of 33 patients (including 13 with prostate cancer) treated from November 2010 to February 2011 on a Varian™ Clinac IX accelerator with an OBI™ system were evaluated. Radiation therapists made the daily kV/kV imaging. Radiation therapists made the online control by kV/kV for patient repositioning and radio-oncologists made the offline reviews; the results were compared and analysed (seven radiation therapists and seven radio-oncologists). For an isocentre displacement of 5mm, the radiation therapist had to call the radio-oncologist to make a medical decision (treatment or patient displacement). The difference of measures and the concordance of decisions between radiation therapists and radio-oncologists were calculated., Results: Five hundred and fifty-six measures were made for 33 treatments, including 226 measures for prostate cancer treatment. The difference of measures between radiation therapists and radio-oncologists was 3mm or less in 93.7% for all treatments and 96.2% for prostate cancer treatment. The concordance of decision between radiation therapists and radio-oncologists for measures up to 4mm was 97% (CI95±2%) vs. 57% (CI95±10%) for measures equal to or higher than 5mm (P<0.0001)., Conclusion: Radiation therapists are able to do daily set up using kV/kV on the bony structures of patients with prostate cancer, with a risk of disagreement higher than 3mm less than 4%. The weekly set up controls (different primaries) can be delegated to the radiation therapists, subject to an accurate procedure using a medical alert for a given threshold. Training and competence certification are required to secure the process., (Copyright © 2013. Published by Elsevier SAS.)

Background: Dbait molecules are a new class of DNA repair inhibitors triggering false DNA damage signaling in cancer cells. Dbait has already been shown to be effective in combination with radiotherapy. The aim of this study was to assess the adjuvant impact of Dbait on chemotherapy in vitro and in mouse models of colorectal cancer., Methods: We assessed DNA repair efficiency over time, in vitro, in human colon adenocarcinoma HT-29 (wild-type KRAS) and HCT-116 (mutated KRAS) cell lines treated with Dbait in combination with 5-fluorouracil and/or camptothecin. Genetically engineered mice spontaneously developing colorectal tumors in the intestines were selected for the evaluation of treatment efficacy., Results: Dbait delayed the repair of DNA damage induced by chemotherapy in vitro. In APC (+/1638N) mutant mice, the combination of Dbait and chemotherapy decreased tumor size more effectively than chemotherapy alone (median size: 3.6 vs. 10.85 mm(2), P < 0.05). In APC (+/1638N)/KRAS ( V12G ) mutant mice, animals treated with a combination of Dbait and chemotherapy survived significantly longer than animals treated by chemotherapy alone (median survival: 210 vs. 194 days, P < 0.05). A quarter of all the animals treated by chemotherapy alone died as rapidly as untreated animals, whereas the first death was delayed by 29 days by the addition of Dbait. No increase in toxicity due to Dbait was observed in either mouse model., Conclusions: The use of Dbait to inhibit DNA repair may be an effective additional treatment for increasing the efficacy of chemotherapy in colon or rectal cancer, independently of KRAS status.