Dataset Information

External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase.

ABSTRACT: Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double-stranded viral DNA genomes as cellular dsDNA breaks. We hypothesise that combining adenovirus treatment with radiotherapy has the potential for enhancing tumour-specific cytotoxicity through inhibition of the DDR and augmentation of virus production. We show that EnAd, an Ad3/Ad11p chimeric oncolytic adenovirus currently being trialled in colorectal and other cancers, targets the DDR pathway at a number of junctures. Infection is associated with a decrease in irradiation-induced 53BP1 and Rad51 foci formation, and in total DNA ligase IV levels. We also demonstrate a radiation-associated increase in EnAd production in vitro and in a pilot in vivo experiment. Given the current limitations of in vitro techniques in assessing for synergy between these treatments, we adapted the plaque assay to allow monitoring of viral plaque size and growth and utilised the xCELLigence cell adhesion assay to measure cytotoxicity. Our study provides further evidence on the interaction between adenovirus and radiation in vitro and in vivo and suggests these have at least an additive, and possibly a synergistic, impact on cytotoxicity.

SUBMITTER: Pokrovska TD

PROVIDER: S-EPMC7226394 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase.

Pokrovska Tzveta D TD Jacobus Egon J EJ Puliyadi Rathi R Prevo Remko R Frost Sally S Dyer Arthur A Baugh Richard R Rodriguez-Berriguete Gonzalo G Fisher Kerry K Granata Giovanna G Herbert Katharine K Taverner William K WK Champion Brian R BR Higgins Geoff S GS Seymour Len W LW Lei-Rossmann Janet J

Cancers 20200326 4

Ionising radiation causes cell death through the induction of DNA damage, particularly double-stranded DNA (dsDNA) breaks. Evidence suggests that adenoviruses inhibit proteins involved in the DNA damage response (DDR) to prevent recognition of double-stranded viral DNA genomes as cellular dsDNA breaks. We hypothesise that combining adenovirus treatment with radiotherapy has the potential for enhancing tumour-specific cytotoxicity through inhibition of the DDR and augmentation of virus production ...[more]

PMID: 32224979

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Project description:PurposeBeam angle optimization is a critical issue for modern radiotherapy (RT) and is a challenging task, especially for large body sizes and noncoplanar designs. Noncoplanar RT techniques may have dosimetric advantages but increase the risk of mechanical collision. We propose a software solution to accurately predict colliding/noncolliding configurations for coplanar and noncoplanar beams.Materials and methodsIndividualized software models for two different linear accelerators were built to simulate noncolliding gantry orientations for phantom/patient subjects. The sizes and shapes of the accelerators were delineated based on their manuals and on-site measurements. The external surfaces of the subjects were automatically contoured based on computed tomography (CT) simulations. An Alderson Radiation Therapy phantom was used to predict the accuracy of spatial collision prediction by the software. A gantry collision problem encountered by one patient during initial setup was also used to test the validity of the software. Results: In the comparison between the software estimates and on-site measurements, the noncoplanar collision angles were all predicted within a 5-degree difference in gantry position. The confusion matrix was calculated for each of the two empty accelerator models, and the accuracies were 98.7% and 97.3%. The true positive rates were 97.7% and 96.9%, while the true negative rates were 99.8% and 97.9%, respectively. For the phantom study, the collision angles were predicted within a 5-degree difference. The software successfully predicted the collision problem encountered by the breast cancer patient in the initial setup position and generated shifted coordinates that were validated to correspond to a noncolliding geometry.ConclusionThe developed software effectively and accurately predicted collisions for accelerator-only, phantom, and patient setups. This software may help prevent collisions and expand the range of spatially applicable beam angles.

Project description:PurposeTo compare patient-reported disease-specific functional outcomes after external beam radiation therapy (EBRT) and EBRT combined with low-dose-rate brachytherapy prostate boost (EB-LDR) among men with localized prostate cancer.Methods and materialsThe prospective, population-based Comparative Effectiveness Analysis of Surgery and Radiation study enrolled men with localized prostate cancer in 2011 to 2012. The 26-item Expanded Prostate Cancer Index Composite measured patient-reported disease-specific function at baseline and at 6, 12, and 36 months. Higher domain scores indicate better function. Minimal clinically important difference was defined as 6 for urinary incontinence, 5 for urinary irritative function, 4 for bowel function, 12 for sexual function, and 4 for hormonal function. Multivariable linear and logistic regression models were fit to estimate the effect of treatment on patient-reported outcomes.ResultsFive-hundred seventy-eight men received EBRT and 109 received EB-LDR. Median patient age was 69 years, and 70% had intermediate- or high-risk disease. Men in the EB-LDR group were younger (P < .001) and less likely to receive androgen deprivation therapy (P < .001). Baseline urinary, bowel, sexual, and hormonal function was similar between treatment groups (P > .05). On multivariable analyses, men receiving EB-LDR reported worse urinary irritative function at 6 months (adjusted mean difference [AMD] -14.4, P < .001), 12 months (AMD -12.9, P < .001), and 36 months (AMD -4.7, P = .034) than men receiving EBRT. At 12 months, men receiving EB-LDR reported worse bowel function (AMD -5.8, P = .002), but these differences were not seen at 36 months. There were no significant differences in sexual or hormone function between treatment groups.ConclusionsMen treated with EB-LDR report worse bowel function at 1 year and worse urinary irritative function through 3 years compared with men treated with EBRT alone. These side effect profiles should be discussed with patients when considering EB-LDR versus EBRT treatment.

Dataset Information

External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase.

Publications

External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase.

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