Low-dose X-ray irradiation combined with FAK inhibitors improves the immune microenvironment and confers sensitivity to radiotherapy in pancreatic cancer.

Radiation therapy offers limited clinical benefits for patients with pancreatic cancer, partly as a result of the predominantly immunosuppressive microenvironment characteristic of this specific type of cancer. A large number of abnormal blood vessels and high-density fibrous matrices in pancreatic cancer will lead to hypoxia within tumor tissue and hinder immune cell infiltration. We used low-dose X-ray irradiation, also known as low-dose radiation therapy (LDRT), to normalize the blood vessels in pancreatic cancer, while simultaneously administering an inhibitor of focal adhesion kinase (FAK) to reduce pancreatic cancer fibrosis. We found that this treatment successfully reduced pancreatic cancer hypoxia, increased immune cell infiltration, and increased sensitivity to radiation therapy for pancreatic cancer.

Low-dose X-ray therapy for COVID-19: lessons from the past.

Coronavirus disease 19 (Covid-19) poses a huge threat to health systems and economies worldwide. So far, there has been no proven effective treatment for SARS-CoV-2 infection. Various potential therapies, viz., immunomodulatory agents, antiviral therapy, and plasma transfusion, are undergoing clinical trials. An intensive search of the medical corpora revealed that low dose X-ray radiation therapy has been used in the past to treat interstitial pneumonia. In this article we explore a historical background of low-dose X-rays for the treatment of pneumonia and how it could be a promising therapy in treating patients with COVID-19.

Computational evaluation of dose distribution for BNCT treatment combined with X-ray therapy or proton beam therapy.

In this study, we performed Monte Carlo simulations to accurately reflect the beam delivery systems including patient-specific irradiation devices of X-ray and proton beam therapies. The dose distributions obtained from the simulations for X-rays or proton beams were successfully combined to the dose distribution of boron neutron capture therapy (BNCT), which was calculated by a treatment planning system called Tsukuba Plan. The results demonstrate the feasibility of dose evaluation for BNCT combined with other radiotherapy modalities using the Tsukuba Plan.

Single X-ray irradiation modulates proteoglycan expression in brain tissue: investigation using mouse model.

Radiotherapy is an integral part of glioblastoma treatment affecting both cancer cells and tumour microenvironment, where proteoglycans (PGs) are key extracellular components. However, the molecular effects of radiotherapy on PGs expression and functional activity in brain tissue are poorly understood. Here, we aimed to study the short-term effects of X-ray irradiation on PGs expression in normal brain tissue in mouse model in vivo. Two-month-old male CBL/6Bl mice (n = 54) were used in this study, animals' brains were irradiated using either research synchrotron VEPP-4 or clinical linear accelerator ElektaAxesse. Control (n = 18) and irradiated (n = 36) brain tissues were analysed at 24 h, 48 h and 72 h after irradiation. Morphology of the cortex and hippocampus was accessed by H&E staining, and expression of PGs (syndecan-1, glypican-1, HSPG2/perlecan, versican, brevican, neurocan, NG2/CSPG4, CD44, decorin, biglycan) was determined by RT-PCR. Single irradiation of mouse brain with a 7 Gy dose did not affect tissue morphology and mRNA levels of most highly-expressed PGs decorin and neurocan, although resulted in significant downregulation of brevican (3-10-fold) and NG2/CSPG4 (8-9-fold) expression both in cerebral cortex and subcortex. Research synchrotron and clinical linear accelerators demonstrated minor variability in their effects. Single X-ray irradiation with a 7 Gy dose does not significantly affect the mouse brain tissue morphology but selectively decreases expression levels of some PGs. The downregulation of brevican and NG2/CSPG4 but not decorin and neurocan reflects alteration of extracellular matrix in irradiated brain tissue, which might contribute to the formation of a permissive microenvironment for glioblastoma relapse development.

DNA Strand Break Properties of Protoporphyrin IX by X-Ray Irradiation against Melanoma.

Recent reports have suggested that 5-aminolevulinic acid (5-ALA), which is a precursor to protoporphyrin IX (PpIX), leads to selective accumulation of PpIX in tumor cells and acts as a radiation sensitizer in vitro and in vivo in mouse models of melanoma, glioma, and colon cancer. In this study, we investigated the effect of PpIX under X-ray irradiation through ROS generation and DNA damage. ROS generation by the interaction between PpIX and X-ray was evaluated by two kinds of probes, 3'-(p-aminophenyl) fluorescein (APF) for hydroxyl radical (•OH) detection and dihydroethidium (DHE) for superoxide (O2•-). •OH showed an increase, regardless of the dissolved oxygen. Meanwhile, the increase in O2•- was proportional to the dissolved oxygen. Strand breaks (SBs) of DNA molecule were evaluated by gel electrophoresis, and the enhancement of SBs was observed by PpIX treatment. We also studied the effect of PpIX for DNA damage in cells by X-ray irradiation using a B16 melanoma culture. X-ray irradiation induced γH2AX, DNA double-strand breaks (DSBs) in the context of chromatin, and affected cell survival. Since PpIX can enhance ROS generation even in a hypoxic state and induce DNA damage, combined radiotherapy treatment with 5-ALA is expected to improve therapeutic efficacy for radioresistant tumors.

Technical advances in x-ray microbeam radiation therapy.

In the last 25 years microbeam radiation therapy (MRT) has emerged as a promising alternative to conventional radiation therapy at large, third generation synchrotrons. In MRT, a multi-slit collimator modulates a kilovoltage x-ray beam on a micrometer scale, creating peak dose areas with unconventionally high doses of several hundred Grays separated by low dose valley regions, where the dose remains well below the tissue tolerance level. Pre-clinical evidence demonstrates that such beam geometries lead to substantially reduced damage to normal tissue at equal tumour control rates and hence drastically increase the therapeutic window. Although the mechanisms behind MRT are still to be elucidated, previous studies indicate that immune response, tumour microenvironment, and the microvasculature may play a crucial role. Beyond tumour therapy, MRT has also been suggested as a microsurgical tool in neurological disorders and as a primer for drug delivery. The physical properties of MRT demand innovative medical physics and engineering solutions for safe treatment delivery. This article reviews technical developments in MRT and discusses existing solutions for dosimetric validation, reliable treatment planning and safety. Instrumentation at synchrotron facilities, including beam production, collimators and patient positioning systems, is also discussed. Specific solutions reviewed in this article include: dosimetry techniques that can cope with high spatial resolution, low photon energies and extremely high dose rates of up to 15 000 Gy s-1, dose calculation algorithms-apart from pure Monte Carlo Simulations-to overcome the challenge of small voxel sizes and a wide dynamic dose-range, and the use of dose-enhancing nanoparticles to combat the limited penetrability of a kilovoltage energy spectrum. Finally, concepts for alternative compact microbeam sources are presented, such as inverse Compton scattering set-ups and carbon nanotube x-ray tubes, that may facilitate the transfer of MRT into a hospital-based clinical environment. Intensive research in recent years has resulted in practical solutions to most of the technical challenges in MRT. Treatment planning, dosimetry and patient safety systems at synchrotrons have matured to a point that first veterinary and clinical studies in MRT are within reach. Should these studies confirm the promising results of pre-clinical studies, the authors are confident that MRT will become an effective new radiotherapy option for certain patients.

RESULTS OF CZECH NATIONAL STUDY OF RADIATION EXPOSURE FROM RADIOTHERAPY OF NON-MALIGNANT DISEASES, IN PARTICULAR OF HEEL SPURS.

About 26 000 patients are treated per year with radiotherapy for non-malignant diseases in the Czech Republic. Approximately 75% of them are treated on X-ray therapy units and most of these patients undergo radiotherapy of heel spurs. The evaluation of radiation exposure of these patients was based on measured organ doses and on data from clinical practice. Collective effective doses for particular diagnoses were calculated in order to compare doses resulting from different diagnoses treated on X-ray therapy units. The collective effective dose from radiotherapy of heel spurs in the Czech Republic in 2013 was evaluated to 77 manSv. It represents 25.6% of the total collective effective dose for all diagnoses of radiotherapy for non-malignant diseases treated on X-ray therapy units.

LOW DOSE BATH FROM IMPT VS. IMXT FOR THE PELVIC AREA WHEN TREATING ADVANCED PROSTATE CANCER.

Twenty (10 intensity-modulated proton therapy (IMPT) and 10 intensity-modulated x-ray therapy (IMXT) treatment plans for patients with advanced prostate carcinoma were compared in this study. All chosen patients were indicated for prostate and pelvic lymph nodes irradiation using simultaneous integrated boost technique. These patients represent typical specimen for this diagnose. IMPT irradiates just half of the tissue volume with a low dose (up to 10 cobalt gray equivalent) compared to IMXT without compromise in target volumes coverage and in this way reduces the risk of secondary cancer development or other possible complications.

Targeting the Hedgehog pathway in combination with X­ray or carbon ion radiation decreases migration of MCF­7 breast cancer cells.

The use of carbon ion therapy for cancer treatment is becoming more widespread due to the advantages of carbon ions compared with X­rays. Breast cancer patients may benefit from these advantages, as the surrounding healthy tissues receive a lower dose, and the increased biological effectiveness of carbon ions can better control radioresistant cancer cells. Accumulating evidence indicates that the Hedgehog (Hh) pathway is linked to the development and progression of breast cancer, as well as to resistance to X­irradiation and the migratory capacity of cancer cells. Hence, there is an increasing interest in targeting the Hh pathway in combination with radiotherapy. Several studies have already investigated this treatment strategy with conventional radiotherapy. However, to the best of our knowledge, the combination of Hh inhibitors with particle therapy has not yet been explored. The aim of the present study was to investigate the potential of the Hh inhibitor GANT61 as an effective modulator of radiosensitivity and migration potential in MCF­7 breast cancer cells, and compare potential differences between carbon ion irradiation and X­ray exposure. Although Hh targeting was not able to radiosensitise cells to any radiation type used, the combination of GANT61 with X­rays or carbon ions (energy: 95 MeV/n; linear energy transfer: 73 keV/µm) was more effective in decreasing MCF­7 cell migration compared with either radiation type alone. Gene expression of the Hh pathway was affected to different degrees in response to X­ray and carbon ion irradiation, as well as in response to the combination of GANT61 with irradiation. In conclusion, combining Hh inhibition with radiation (X­rays or carbon ions) more effectively decreased breast cancer cell migration compared with radiation treatment alone.

Data for the dosimetry of low- and medium-energy kV x rays.

Following the publication of the ICRU Report 90 (2016) on key data for measurement standards in radiation dosimetry, where ionometric air-kerma standards for kilovoltage (kV) x-ray beams are estimated to change by up to about 0.5%, an update of the backscatter factors and water/air ratios of mass energy-absorption coefficients in kV dosimetry protocols was deemed necessary for consistency through the entire dosimetry chain. In addition, numerical methods and Monte Carlo (MC) systems that did not exist at the time when air-kerma protocols were developed, are currently available. Calculations of the chamber-independent quantities required for the dosimetry of low- and medium-energy kV x rays were carried out using a consistent set of key data throughout the complete process. The quantities were based on MC calculations of a database for a dense grid of monoenergetic photons for different beam diameters and source-to-surface distances, followed by an averaging procedure to compute water/air energy-absorption coefficient ratios and backscatter factors for 342 experimental and calculated kV spectra. It was found that for a given HVL and field size the variation of backscatter factors for different kVs can be up to about 5%, a trend confirmed with independent calculations that shows the limitation of using only the HVL for the beam quality specification of kV x rays. Extensive tables as a function of beam quality in terms of kV and HVL were developed for configurations that might be encountered in clinical practice; the data are also available in the form of a GUI web app at http://52.233.195.208. Results were compared with data used at PTB for deriving low-energy [Formula: see text] ion chamber calibration coefficients, finding agreement within about [Formula: see text]0.5%, and with independent full MC kerma calculations that agreed within better than about 1%. Compared with the data in the AAPM TG-61 protocol (Ma et al 2001 Med. Phys. 28 868-93) there was in general good agreement for the ratios of mass energy-absorption coefficients, although differences of up to 1.5% resulted when both kV and HVL were taken into account; more significant discrepancies, within about 2%-6%, were obtained for backscatter factors, the present values being generally higher.

A Novel Radiotherapy Approach for Keloids with Intrabeam.

BACKGROUND: Keloids are hard nodules or plaques formed by excessive proliferation of connective tissue. Radiotherapy, widely used in various benign and malignant skin diseases, is an effective treatment for keloids. This work evaluates Intrabeam photon radiotherapy in the management of keloids. METHODS: Fourteen patients who have undergone Intrabeam radiotherapy for a total of 15 sites of keloids were followed up. Twelve cases were first onset and the other two had recurrent diseases. Thirteen patients underwent surgical resection of keloids before radiotherapy. One relapsing patient received only 2 rounds of radiation therapy as she could not be reoperated. Radiotherapy was divided into 2 sessions on days 0 and 3 after surgery. The dose was 4 or 5 Gy each time for 3 min 14 s to 12 min 1 s. In addition, we compared our data to the recurrence of keloids in fourteen patients who had previously been exposed to electron beam using conventional accelerators. RESULTS: We analyzed the treatment for adverse reactions and recurrence. In the Intrabeam group, one patient developed superficial skin ulcers a month after treatment. No one experienced wound rupture, bleeding, infection, skin contractures, or obvious hyperpigmentation. None of the fourteen cases showed any recurrence so far after on median 22.5 months of follow-up. Five patients in the electron beam group relapsed 3 to 10 months after treatment. CONCLUSION: Here, Intrabeam photon radiotherapy was shown to be an effective treatment for keloid scars and it is therefore recommended for management of this disease.

Bcl2-Expressing Quiescent Type B Neural Stem Cells in the Ventricular-Subventricular Zone Are Resistant to Concurrent Temozolomide/X-Irradiation.

The ventricular-subventricular zone (V-SVZ) of the mammalian brain is a site of adult neurogenesis. Within the V-SVZ reside type B neural stem cells (NSCs) and type A neuroblasts. The V-SVZ is also a primary site for very aggressive glioblastoma (GBM). Standard-of-care therapy for GBM consists of safe maximum resection, concurrent temozolomide (TMZ), and X-irradiation (XRT), followed by adjuvant TMZ therapy. The question of how this therapy impacts neurogenesis is not well understood and is of fundamental importance as normal tissue tolerance is a limiting factor. Here, we studied the effects of concurrent TMZ/XRT followed by adjuvant TMZ on type B stem cells and type A neuroblasts of the V-SVZ in C57BL/6 mice. We found that chemoradiation induced an apoptotic response in type A neuroblasts, as marked by cleavage of caspase 3, but not in NSCs, and that A cells within the V-SVZ were repopulated given sufficient recovery time. 53BP1 foci formation and resolution was used to assess the repair of DNA double-strand breaks. Remarkably, the repair was the same in type B and type A cells. While Bax expression was the same for type A or B cells, antiapoptotic Bcl2 and Mcl1 expression was significantly greater in NSCs. Thus, the resistance of type B NSCs to TMZ/XRT appears to be due, in part, to high basal expression of antiapoptotic proteins compared with type A cells. This preclinical research, demonstrating that murine NSCs residing in the V-SVZ are tolerant of standard chemoradiation therapy, supports a dose escalation strategy for treatment of GBM. Stem Cells 2019;37:1629-1639.

X-ray Magnetic Circular Dichroism Spectroscopy Applied to Nitrogenase and Related Models: Experimental Evidence for a Spin-Coupled Molybdenum(III) Center.

Nitrogenase enzymes catalyze the reduction of atmospheric dinitrogen to ammonia utilizing a Mo-7Fe-9S-C active site, the so-called FeMoco cluster. FeMoco and an analogous small-molecule (Et4 N)[(Tp)MoFe3 S4 Cl3 ] cubane have both been proposed to contain unusual spin-coupled MoIII sites with an S(Mo)=1/2 non-Hund configuration at the Mo atom. Herein, we present Fe and Mo L3 -edge X-ray magnetic circular dichroism (XMCD) spectroscopy of the (Et4 N)[(Tp)MoFe3 S4 Cl3 ] cubane and Fe L2,3 -edge XMCD spectroscopy of the MoFe protein (containing both FeMoco and the 8Fe-7S P-cluster active sites). As the P-clusters of MoFe protein have an S=0 total spin, these are effectively XMCD-silent at low temperature and high magnetic field, allowing for FeMoco to be selectively probed by Fe L2,3 -edge XMCD within the intact MoFe protein. Further, Mo L3 -edge XMCD spectroscopy of the cubane model has provided experimental support for a local S(Mo)=1/2 configuration, demonstrating the power and selectivity of XMCD.

ROS Reduction Does Not Decrease the Anticancer Efficacy of X-Ray in Two Breast Cancer Cell Lines.

Radiotherapy is effective on a large number of cancer types and is one of the most frequently administrated treatments for cancer patients. The anticancer efficacy of X-ray radiotherapy has been frequently correlated with reactive oxygen species (ROS) elevation, which is also a limiting factor for its toxicity on normal tissues. Here, we found that although 4-10 Gy X-rays could significantly reduce cell numbers in both MDA-MB-231 and MCF-7 breast cancer cells, the ROS level changes are less in MCF-7 cells than in MDA-MB-231 cells. Moreover, although both the ROS scavenger N-acetyl-L-cysteine (NAC) and 1 T static magnetic field (SMF) could reduce X-ray-induced ROS elevation, they did not prevent X-ray-induced cell number reduction or cell death increase, which is significantly different from cisplatin. These results demonstrate that although the anticancer efficacy of cisplatin on two breast cancer cell lines is dependent on ROS, the anticancer efficacy of X-ray is not. Moreover, by testing 19 different cell lines, we found that 1 T SMF could effectively reduce ROS levels in multiple cell lines by 10-20%, which encourages further studies to investigate whether SMF could be used as a potential "physical antioxidant" in the future.

Improved neuropsychological outcomes following proton therapy relative to X-ray therapy for pediatric brain tumor patients.

BACKGROUND: Survivors of pediatric brain tumors are at risk for impaired development in multiple neuropsychological domains. The purpose of this study was to compare neuropsychological outcomes of pediatric brain tumor patients who underwent X-ray radiotherapy (XRT) versus proton radiotherapy (PRT). METHODS: Pediatric patients who underwent either XRT or PRT and received posttreatment age-appropriate neuropsychological evaluation-including measures of intelligence (IQ), attention, memory, visuographic skills, academic skills, and parent-reported adaptive functioning-were identified. Multivariate analyses were performed to assess differences in neuropsychological outcomes and included tests for interaction between treatment cohort and follow-up time. RESULTS: Between 1998 and 2017, 125 patients with tumors located in the supratentorial (17.6%), midline (28.8%), or posterior fossa (53.6%) compartments received radiation and had posttreatment neuropsychological evaluation. Median age at treatment was 7.4 years. The PRT patient cohort had higher estimated SES and shorter median time from radiotherapy completion to last neuropsychological evaluation (6.7 vs 2.6 y, P < 0.001). On multivariable analysis, PRT was associated with higher full-scale IQ (ß = 10.6, P = 0.048) and processing speed (ß = 14.4, P = 0.007) relative to XRT, with trend toward higher verbal IQ (ß = 9.9, P = 0.06) and general adaptive functioning (ß = 11.4, P = 0.07). Planned sensitivity analyses truncating follow-up interval in the XRT cohort re-demonstrated higher verbal IQ (P = 0.01) and IQ (P = 0.04) following PRT, with trend toward improved processing speed (P = 0.09). CONCLUSIONS: PRT is associated with favorable outcomes for intelligence and processing speed. Combined with other strategies for treatment de-intensification, PRT may further reduce neuropsychological morbidity of brain tumor treatment.

Merging Orthovoltage X-Ray Minibeams spare the proximal tissues while producing a solid beam at the target.

Conventional radiation therapy of brain tumors often produces cognitive deficits, particularly in children. We investigated the potential efficacy of merging Orthovoltage X-ray Minibeams (OXM). It segments the beam into an array of parallel, thin (~0.3 mm), planar beams, called minibeams, which are known from synchrotron x-ray experiments to spare tissues. Furthermore, the slight divergence of the OXM array make the individual minibeams gradually broaden, thus merging with their neighbors at a given tissue depth to produce a solid beam. In this way the proximal tissues, including the cerebral cortex, can be spared. Here we present experimental results with radiochromic films to characterize the method's dosimetry. Furthermore, we present our Monte Carlo simulation results for physical absorbed dose, and a first-order biologic model to predict tissue tolerance. In particular, a 220-kVp orthovoltage beam provides a 5-fold sharper lateral penumbra than a 6-MV x-ray beam. The method can be implemented in arc-scan, which may include volumetric-modulated arc therapy (VMAT). Finally, OXM's low beam energy makes it ideal for tumor-dose enhancement with contrast agents such as iodine or gold nanoparticles, and its low cost, portability, and small room-shielding requirements make it ideal for use in the low-and-middle-income countries.

Fast optimized Monte Carlo phase-space generation and dose prediction for low energy x-ray intra-operative radiation therapy.

Low energy x-ray intra-operative radiation therapy (IORT) is used mostly for breast cancer treatment with spherical applicators. X-ray IORT treatment delivered during surgery (ex: INTRABEAM®, Carl Zeiss) can benefit from accurate and fast dose prediction in a patient 3D volume. However, full Monte Carlo (MC) simulations are time-consuming and no commercial treatment planning system (TPS) was available for this treatment delivery technique. Therefore, the aim of this work is to develop a dose computation tool based on MC phase space information, which computes fast and accurate dose distributions for spherical and needle INTRABEAM® applicators. First, a database of monoenergetic phase-space (PHSP) files and depth dose profiles (DDPs) in water for each applicator is generated at factory and stored for on-site use. During commissioning of a given INTRABEAM® unit, the proposed fast and optimized phase-space (FOPS) generation process creates a phase-space at the exit of the applicator considered, by fitting the energy spectrum of the source to a combination of the monoenergetic precomputed phase-spaces, by means of a genetic algorithm, with simple experimental data of DDPs in water provided by the user. An in-house hybrid MC (HMC) algorithm which takes into account condensed history simulations of photoelectric, Rayleigh and Compton interactions for x-rays up to 1 MeV computes the dose from the optimized phase-space file. The whole process has been validated against radiochromic films in water as well as reference MC simulations performed with penEasy in heterogeneous phantoms. From the pre-computed monoenergetic PHSP files and DDPs, building the PHSP file optimized to a particular depth-dose curve in water only takes a few minutes in a single core (i7@2.5 GHz), for all the applicators considered in this work, and this needs to be done only when the x-ray source (XRS) is replaced. Once the phase-space file is ready, the HMC code is able to compute dose distributions within 10 min. For all the applicators, more than 95% of voxels from dose distributions computed with the FOPS+hybrid code agreed within 7%-0.5 mm with both reference MC simulations and measurements. The method proposed has been fully validated and it is now implemented into radiance (GMV SA, Spain), the first commercial IORT TPS.

X-ray irradiation induced Disabled-2 gene promoter de-methylation enhances radiosensitivity of non-small-cell lung carcinoma cells.

BACKGROUND: Disabled-2 (Dab2) is known as a tumor suppressor as well as a Wnt pathway inhibitor. We previously reported that Dab2 was down-regulated due to gene promoter hypermethylation in lung cancer. Here, we aim to study if X-ray irradiation can induce de-methylation of the Dab2 gene and subsequently up-regulate its expression, and also to attempt to suppress the malignant biological behavior of and enhance the radiosensitivity in lung cancer cells with hypermethylation of the Dab2 gene. METHODS: Immunostaining was performed to investigate the relationship between Dab2 expression and lung cancer clinicopathological characteristics. Bisulfite sequencing PCR (BSP) was used to evaluate the methylation status of lung cancer cells with or without X-ray treatment. Real-time PCR and western Blot were performed to investigate the expression of Dab2, Wnt pathway factors, DNMTs and methyl CpG binding protein 2 (MeCP2). Colony Formation, matrigel invasion and xenograft experiment were performed to evaluate the malignant biological behavior of lung cancer cells with irradiation. RESULTS: The result of immunostaining of Dab2 in lung cancer tissues showed that decreased Dab2 expression was positively correlated with poor differentiation, lymph node metastasis, advanced TNM stage and poor prognosis. X-ray treatment significantly up-regulated Dab2 expression and inhibited Wnt factors in LK2 cells (with hypermethylation of the Dab2 gene promoter, P < 0.05), but not in SPC-A-1 cells (with hypomethylation of the Dab2 gene promoter); however, the effect could be reversed by Dab2 or Axin knockdown (P < 0.05). Decreased expression of DNMT1, DNMT3b and MeCP2 could be detected in both LK2 and SPC-A-1 cells compared to non-irradiated cells (P < 0.05). Both in vitro studies and in vivo xenograft tumor growth demonstrated that X-ray could significantly inhibit the proliferation and invasion of LK2 but not SPC-A-1 cells (P < 0.05). CONCLUSION: In general, X-ray-induced up-regulation of Dab2 and inhibition of the Wnt pathway may be mediated by de-methylation of a hypermethylated Dab2 gene promoter. X-ray treatment significantly inhibits proliferation and invasion of lung cancer cells with hypermethylation of the Dab2 gene promoter, but is less effective in lung cancer cells with hypomethylation of the Dab2 gene promoter. These results indicate that the methylation status of the Dab2 gene promoter might be a potential predictor of the radiosensitivity of lung cancer cells.

Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations.

INTRODUCTION: Li-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterised by a remarkably high incidence of multiple primary cancers (MPCs), and the key role of p53 in response to DNA damage questions the contribution of anticancer treatments to MPCs development. MATERIALS AND METHODS: We first evaluated genotoxicity of X-rays and different classes of conventional chemotherapies, thanks to genotoxicity assays, based on the measurement of transcriptional response to DNA damage and performed in murine splenocytes, either exposed ex vivo or extracted from exposed mice. We then exposed a total of 208 Trp53Δ/Δ, wt/Δ or wt/wt mice to clinical doses of X-rays or genotoxic or non-genotoxic chemotherapies. Tumour development was monitored using whole-body magnetic resonance imaging and pathological examination at death. RESULTS: X-rays and conventional chemotherapies, except mitotic spindle poisons, were found to be genotoxic in both p53 genotoxicity assays. Exposition to X-rays and the topoisomerase inhibitor etoposide, analysed as genotoxic anticancer treatment, drastically increase the tumour development risk in Trp53Δ/Δ and wt/Δ mice (hazard ration [HR] = 4.4, 95% confidence interval [CI] [2.2-8.8], p < 0.001*** and HR = 4.7, 95% CI [2.4-9.3], p < 0.001***, respectively). In contrast, exposure to the non-genotoxic mitotic spindle poison, docetaxel, had no impact on tumour development. CONCLUSIONS: This study shows that radiotherapy and genotoxic chemotherapies significantly increase the risk of tumour development in a LFS mice model. These results strongly support the contribution of genotoxic anticancer treatments to MPC development in LFS patients. Therefore, to reduce the risk of MPCs in germline TP53 mutation carriers, radiotherapy should be avoided whenever possible, surgical treatment prioritised, and non-genotoxic treatments considered.