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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 32646

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Prof. Dr. Luitpold Valentin R. Distel

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Guest Editor

Radiation Oncology Erlangen, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen, 91054 Erlangen, Germany
Interests: cell biology; immunology; cancer research; cancer biology; radiation biology
Special Issues, Collections and Topics in MDPI journals

Dr. Tina Jost

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Radiation Oncology Erlangen, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen, 91054 Erlangen, Germany
Interests: cell culture; cell biology; cancer research; cancer biology; radiation biology; kinase inhibitors; immunology; head and neck cancer

Laura Hildebrand

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Guest Editor Assistant

Radiation Oncology Erlangen, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen, 91054 Erlangen, Germany
Interests: cell biology; cancer research; cancer biology; radiation biology; kinase inhibitors

Special Issue Information

Dear Colleagues,

In the last decades, we gained better knowledge of processes and mechanisms in cancer cells, and therapies were developed according to these findings. Chemotherapy and radiation therapy are two of the most important strategies for the treatment of patients with cancerous malignancies. The improvement of systemic chemotherapy led to innovations such as targeted therapy and immunotherapy by counteracting cancer cells with antibodies and small molecules. Furthermore, modern adjuvant radiotherapy improves local control and reduces cancer-specific mortality. To further progress in cancer therapy, the combination of several different therapies is becoming more and more crucial, especially in the context of personalized medicine. In this Special Issue, we want to have a closer look at prospective and promising combinations based on radiotherapy and drugs targeting cancer-related pathways and their potential to affect each other. We are still lacking full knowledge about the interactions of, e.g., kinase inhibitors and radiotherapy.

This Special Issue of Cells invites contributions (original research articles, reviews, and other relevant contributions) that highlight our enhanced understanding of the radiation biology of cancer cells and the combination with novel therapeutic strategies that may show us new directions in cancer therapy.

Prof. Dr. Luitpold Valentin R. Distel
Dr. Tina Jost
Guest Editors
Laura Hildebrand
Guest Editor Assistant

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Keywords

radiobiology
targeted therapy
radiosensitivity
combination therapy
radiotherapy

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Published Papers (11 papers)

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Research

16 pages, 4273 KiB

Open AccessFeature PaperArticle

Prospective Evaluation of CD45RA+/CCR7- Effector Memory T (T_EMRA) Cell Subsets in Patients with Primary and Secondary Brain Tumors during Radiotherapy of the Brain within the Scope of the Prospective Glio-CMV-01 Clinical Trial

by Ilka Scheer, Ina Becker, Charlotte Schmitter, Sabine Semrau, Rainer Fietkau, Udo S. Gaipl, Benjamin Frey and Anna-Jasmina Donaubauer

Cells 2023, 12(4), 516; https://doi.org/10.3390/cells12040516 - 4 Feb 2023

Cited by 3 | Viewed by 2584

Abstract

Radiotherapy (RT) of the brain is a common treatment for patients with high-grade gliomas and brain metastases. It has previously been shown that reactivation of cytomegalovirus (CMV) frequently occurs during RT of the brain. This causes neurological decline, demands antiviral treatment, and is associated with a worse prognosis. CMV-specific T cells are characterized by a differentiated effector memory phenotype and CD45RA+ CCR7- effector memory T (T_EMRA) cells were shown to be enriched in CMV seropositive individuals. In this study, we investigated the distribution of T_EMRA cells and their subsets in the peripheral blood of healthy donors and, for the first time, prospectively within the scope of the prospective Glio-CMV-01 clinical trial of patients with high-grade glioma and brain metastases during radiation therapy as a potential predictive marker. First, we developed a multicolor flow cytometry-based assay to monitor the frequency and distribution of T_EMRA cells in a longitudinal manner. The CMV serostatus and age were considered as influencing factors. We revealed that patients who had a reactivation of CMV have significantly higher amounts of CD8+ T_EMRA cells. Further, the distribution of the subsets of T_EMRA cells based on the expression of CD27, CD28, and CD57 is highly dependent on the CMV serostatus. We conclude that the percentage of CD8+ T_EMRA cells out of all CD8+ T cells has the potential to serve as a biomarker for predicting the risk of CMV reactivation during RT of the brain. Furthermore, this study highlights the importance of taking the CMV serostatus into account when analyzing T_EMRA cells and their subsets. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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15 pages, 1901 KiB

Open AccessArticle

Preoperative Radiochemotherapy in Rectal Cancer: Is There an Impact of Oxaliplatin on Pathologic Complete Response and Survival Rates under “Real World“ Conditions?

by Alexander Grabenbauer, Thomas Aigner, Holger Göbel, Bernhard J. Leibl, Christof Lamberti, Gerhard G. Grabenbauer and Luitpold V. Distel

Cells 2023, 12(3), 399; https://doi.org/10.3390/cells12030399 - 22 Jan 2023

Cited by 2 | Viewed by 2083

Abstract

This study aimed to evaluate the benefit of additional administration of oxaliplatin during fluorouracil-based neoadjuvant radiochemotherapy (nRCT) in terms of pathologic complete remission (pCR), disease-free survival (DFS), and overall survival (OS) in patients with advanced rectal cancer. Between 2006 and 2021, 669 patients (pts) were diagnosed with locally advanced rectal cancer, of whom a total of 414 pts with nRCT were identified and included in the study. A total of 283 pts were treated by nRCT using concurrent chemotherapy with fluorouracil or capecitabine; 131 pts were treated using a combination of fluorouracil or capecitabine and oxaliplatin. Propensity score matching analyses (PSM) with 114 pts in each group were used to balance the patients’ characteristics. OS, DFS, pCR-rate, and potential prognostic factors were compared between the two groups. The median follow-up time was 59.5 weeks in the fluorouracil-group and 43 weeks in the fluorouracil/oxaliplatin group (p = 0.003). After PSM, the pCR-rate (including sustained clinical complete remission) was 27% (31/114 pts) in the fluorouracil/oxaliplatin group and 16% (18/114 pts) in the fluorouracil-group (p = 0.033). There was no difference between these two groups for both 10-year OS and DFS neither before nor after PSM, respectively (OS: 72.6% vs. 55.4%, p = 0.066, and 67.8% vs. 55.1%, p = 0.703, and DFS: 44.8% vs. 46.8%, p = 0.134, and 44.7% vs. 42.3%, p = 0.184). Multivariate analysis identified regression grading according to Dworak grade 4 (HR: 0.659; CI: 0.471–0.921; p = 0.015) and age over 60 years (HR: 2.231; CI: 1.245–4.001; p = 0.007) as independent predictors for OS. In conclusion, the addition of oxaliplatin to fluorouracil during nRCT significantly improved pCR-rate without having an impact on survival. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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12 pages, 2113 KiB

Open AccessArticle

Comparison of Radiation Response between 2D and 3D Cell Culture Models of Different Human Cancer Cell Lines

by Julia Raitanen, Bernadette Barta, Marcus Hacker, Dietmar Georg, Theresa Balber and Markus Mitterhauser

Cells 2023, 12(3), 360; https://doi.org/10.3390/cells12030360 - 18 Jan 2023

Cited by 14 | Viewed by 4230

Abstract

Radiation therapy is one of the most effective tools in cancer therapy. However, success varies individually, necessitating improved understanding of radiobiology. Three-dimensional (3D) tumor spheroids are increasingly gaining attention, being a superior in vitro cancer model compared to 2D cell cultures. This in vitro study aimed at comparing radiation responses in 2D and 3D cell culture models of different human cancer cell lines (PC-3, LNCaP and T-47D) irradiated with varying doses (1, 2, 4, 6, 8 or 20 Gy) of X-ray beams. Radiation response was analyzed by growth analysis, various cell viability assays (e.g., clonogenic assay, resazurin assay) and amount of DNA damage (γH2AX Western Blot). Results showed decreasing cell proliferation with the increase of radiation doses for all cell lines in monolayers and spheroids of LNCaP and T-47D. However, significantly lower radiosensitivity was detected in spheroids, most pronounced in PC-3, evincing radiation resistance of PC-3 spheroids up to 8 Gy and significant growth inhibition only by a dose escalation of 20 Gy. Cell line comparison showed highest radiosensitivity in LNCaP, followed by T-47D and PC-3 in 2D, whereas, in 3D, T-47D showed highest sensitivity. The results substantiate the significant differences in radiobiological response to X-rays between 2D and 3D cell culture models. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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20 pages, 4240 KiB

Open AccessArticle

SESN2 Knockdown Increases Betulinic Acid-Induced Radiosensitivity of Hypoxic Breast Cancer Cells

by Antje Güttler, Claus Weinholdt, Elisabeth Ruff, Judith Reidt, Elisa Darnstaedt, Alicia Wildemann, Marina Petrenko, Jacqueline Keßler, Matthias Kappler, Ivo Grosse, Dirk Vordermark and Matthias Bache

Cells 2023, 12(1), 177; https://doi.org/10.3390/cells12010177 - 31 Dec 2022

Cited by 3 | Viewed by 2650

Abstract

Betulinic acid (BA) is a natural compound well known for its anti-inflammatory, anti-viral, anti-bacterial, anti-malarial effects and anti-tumor properties. Its enhanced cytotoxicity in tumor cells and induction of cell death in various cancer entities qualifies BA as an interesting candidate for novel treatment concepts. Our analyses showed enhanced cytotoxicity and radiosensitization under hypoxic conditions in human breast cancer cells. So far, the underlying mechanisms are unknown. Therefore, we investigated the BA-treated human breast cancer cell lines MDA-MB-231 and MCF-7 under normoxic and hypoxic conditions based on microarray technology. Hypoxia and BA regulated a variety of genes in both breast cancer cell lines. KEGG pathway analysis identified an enrichment of the p53 pathway in MCF-7 cells (wtp53) under hypoxia. In MDA-MB-231 cells (mtp53) an additional BA incubation was required to activate the p53 signaling pathway. Fourteen down-regulated and up-regulated genes of the p53 pathway were selected for further validation via qRT-PCR in a panel of five breast cancer cell lines. The stress-induced gene Sestrin-2 (SESN2) was identified as one of the most strongly up-regulated genes after BA treatment. Knockdown of SESN2 enhanced BA-induced ROS production, DNA damage, radiosensitivity and reduced autophagy in breast cancer cells. Our results identified SESN2 as an important target to enhance the radiobiological and anti-tumor effects of BA on breast cancer cells. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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13 pages, 3022 KiB

Open AccessArticle

Cell-In-Cell Structures in Early Breast Cancer Are Prognostically Valuable

by Mareike F. Bauer, Laura S. Hildebrand, Marie-Charlotte Rosahl, Ramona Erber, Sören Schnellhardt, Maike Büttner-Herold, Florian Putz, Oliver J. Ott, Carolin C. Hack, Rainer Fietkau and Luitpold Distel

Cells 2023, 12(1), 81; https://doi.org/10.3390/cells12010081 - 24 Dec 2022

Cited by 9 | Viewed by 2286

Abstract

Cell-in-cell (CIC) structures in breast cancer have so far been studied in a small inhomogeneous patient population, suggesting the prognostic importance of CIC. In the present study, we focused on CIC in early hormone-sensitive breast cancer. With in vitro co-culture experiments, we compared the homotypic phagocytic capacity of two breast cancer cell lines to that of primary human fibroblasts. Afterward, we studied 601 tissue specimens from 147 patients participating in an institutional accelerated partial breast irradiation (APBI) phase II trial. Both breast cancer cell lines performed non-professional phagocytosis at a higher rate than primary human fibroblasts. In this study cohort, 93.2% of the patients had T1 tumours, and 6.8% had T2 tumours. CIC was found in 61.2% of the patients, with a CIC rate ranging from <1/mm² to 556.5/mm² with a mean of 30.9/mm² ± 68.4/mm². CIC structures were prognostically favourable for local recurrence-free survival and disease-free survival. Regarding metastasis-free survival, CIC-positive patients had an unfavourable prognosis. Subgroup analysis indicated a correlation between a high proliferation index and high CIC rates. CIC had the highest prognostic value in young breast cancer patients (p = 0.004). With this study, we provide further evidence of CIC as a prognostic marker in breast cancer. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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25 pages, 2239 KiB

Open AccessArticle

Divergent Molecular and Cellular Responses to Low and High-Dose Ionizing Radiation

by Bharath Sampadi, Sylvia Vermeulen, Branislav Mišovic, Jan J. Boei, Tanveer S. Batth, Jer-Gung Chang, Michelle T. Paulsen, Brian Magnuson, Joost Schimmel, Hanneke Kool, Cyriel S. Olie, Bart Everts, Alfred C. O. Vertegaal, Jesper V. Olsen, Mats Ljungman, Penny A. Jeggo, Leon H. F. Mullenders and Harry Vrieling

Cells 2022, 11(23), 3794; https://doi.org/10.3390/cells11233794 - 27 Nov 2022

Cited by 8 | Viewed by 3088

Abstract

Cancer risk after ionizing radiation (IR) is assumed to be linear with the dose; however, for low doses, definite evidence is lacking. Here, using temporal multi-omic systems analyses after a low (LD; 0.1 Gy) or a high (HD; 1 Gy) dose of X-rays, we show that, although the DNA damage response (DDR) displayed dose proportionality, many other molecular and cellular responses did not. Phosphoproteomics uncovered a novel mode of phospho-signaling via S12-PPP1R7, and large-scale dephosphorylation events that regulate mitotic exit control in undamaged cells and the G2/M checkpoint upon IR in a dose-dependent manner. The phosphoproteomics of irradiated DNA double-strand breaks (DSBs) repair-deficient cells unveiled extended phospho-signaling duration in either a dose-dependent (DDR signaling) or independent (mTOR-ERK-MAPK signaling) manner without affecting signal magnitude. Nascent transcriptomics revealed the transcriptional activation of genes involved in NRF2-regulated antioxidant defense, redox-sensitive ERK-MAPK signaling, glycolysis and mitochondrial function after LD, suggesting a prominent role for reactive oxygen species (ROS) in molecular and cellular responses to LD exposure, whereas DDR genes were prominently activated after HD. However, how and to what extent the observed dose-dependent differences in molecular and cellular responses may impact cancer development remain unclear, as the induction of chromosomal damage was found to be dose-proportional (10–200 mGy). Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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18 pages, 4415 KiB

Open AccessArticle

MYH9 Facilitates Cell Invasion and Radioresistance in Head and Neck Cancer via Modulation of Cellular ROS Levels by Activating the MAPK-Nrf2-GCLC Pathway

by Guo-Rung You, Joseph T. Chang, Yan-Liang Li, Chi-Wei Huang, Yu-Liang Tsai, Kang-Hsing Fan, Chung-Jan Kang, Shiang-Fu Huang, Po-Hung Chang and Ann-Joy Cheng

Cells 2022, 11(18), 2855; https://doi.org/10.3390/cells11182855 - 13 Sep 2022

Cited by 21 | Viewed by 3260

Abstract

The MYH9 (Myosin heavy chain 9), an architecture component of the actomyosin cytoskeleton, has been reported to be dysregulated in several types of cancers. However, how this molecule contributes to cancer development is still obscure. This study deciphered the molecular function of MYH9 in head and neck cancer (HNC). Cellular methods included clonogenic survival, wound-healing migration, and Matrigel invasion assays. Molecular techniques included RT-qPCR, western blot, luciferase reporter assays, and flow cytometry. Clinical association studies were undertaken by TCGA data mining, Spearman correlation, and Kaplan-Meier survival analysis. We found that MYH9 was overexpressed in tumors and associated with poor prognosis in HNC patients. MYH9 promoted cell motility along with the modulation of the extracellular matrix (fibronectin, ITGA6, fascin, vimentin, MMPs). Also, MYH9 contributed to radioresistance and was related to the expression of anti-apoptotic and DNA repairing molecules (XIAP, MCL1, BCL2L1, ATM, RAD50, and NBN). Mechanically, MYH9 suppressed cellular ROS levels, which were achieved by activating the pan-MAPK signaling molecules (Erk, p38, and JNK), the induction of Nrf2 transcriptional activity, and the up-regulation of antioxidant enzymes (GCLC, GCLM, GPX2). The antioxidant enzyme GCLC was further demonstrated to facilitate cell invasion and radioresistance in HNC cells. Thus, MYH9 exerts malignant functions in HNC by regulating cellular ROS levels via activating the MAPK-Nrf2-GCLC signaling pathway. As MYH9 contributes to radioresistance and metastasis, this molecule may serve as a prognostic biomarker for clinical application. Furthermore, an in vivo study is emergent to support the therapeutic potential of targeting MYH9 to better manage refractory cancers. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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14 pages, 3230 KiB

Open AccessArticle

Targeting of p21-Activated Kinase 4 Radiosensitizes Glioblastoma Cells via Impaired DNA Repair

by Leon J. Blankenstein, Nils Cordes, Leoni A. Kunz-Schughart and Anne Vehlow

Cells 2022, 11(14), 2133; https://doi.org/10.3390/cells11142133 - 6 Jul 2022

Cited by 2 | Viewed by 2700

Abstract

Glioblastoma is a devastating malignant disease with poor patient overall survival. Strong invasiveness and resistance to radiochemotherapy have challenged the identification of molecular targets that can finally improve treatment outcomes. This study evaluates the influence of all six known p21-activated kinase (PAK) protein family members on the invasion capacity and radio-response of glioblastoma cells by employing a siRNA-based screen. In a panel of human glioblastoma cell models, we identified PAK4 as the main PAK isoform regulating invasion and clonogenic survival upon irradiation and demonstrated the radiosensitizing potential of PAK4 inhibition. Mechanistically, we show that PAK4 depletion and pharmacological inhibition enhanced the number of irradiation-induced DNA double-strand breaks and reduced the expression levels of various DNA repair proteins. In conclusion, our data suggest PAK4 as a putative target for radiosensitization and impairing DNA repair in glioblastoma, deserving further scrutiny in extended combinatorial treatment testing. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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14 pages, 5429 KiB

Open AccessArticle

The Prognostic and Predictive Significance of Tumor-Infiltrating Memory T Cells Is Reversed in High-Risk HNSCC

by Rebekka Hartan, Sören Schnellhardt, Maike Büttner-Herold, Christoph Daniel, Arndt Hartmann, Rainer Fietkau and Luitpold Distel

Cells 2022, 11(12), 1960; https://doi.org/10.3390/cells11121960 - 17 Jun 2022

Cited by 4 | Viewed by 2214

Abstract

Tumor-infiltrating CD45RO+ memory T cells have unanimously been described as a positive prognostic factor in head and neck squamous cell carcinomas (HNSCCs). Here, we investigated the long-term prognostic relevance of CD45RO+ memory T cells in HNSCC with special regard to the influence of clinical characteristics. Pre-treatment biopsy samples from 306 patients with predominantly advanced HNSCC were analyzed. Immunohistochemistry was used to stain tissue microarrays for CD45RO+ memory T cells. CD45RO cell densities were semi-automatically registered and used for survival analysis. High CD45RO+ cell densities were clearly associated with prolonged overall survival (OS) and recurrence-free survival as well as no evidence of disease status after 10 years (p < 0.05). In contrast, the prognostic significance of tumor-infiltrating memory T cells was completely reversed in high-risk groups: in poorly differentiated tumors (G3, G4) and in cases with lymph node involvement (N+), high memory T cell densities correlated with reduced 10-year OS (p < 0.05). In conclusion, an increased density of tumor-infiltrating CD45RO+ cells in HNSCC can be a positive as well as a negative prognostic factor, depending on disease stage and histological grade. Therefore, if CD45RO+ cell density is to be used as a prognostic biomarker, further clinical characteristics must be considered. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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14 pages, 2092 KiB

Open AccessArticle

cGAS Regulates the Radioresistance of Human Head and Neck Squamous Cell Carcinoma Cells

by Taichi Nyui, Hironori Yoshino, Tetsuya Nunota, Yoshiaki Sato and Eichi Tsuruga

Cells 2022, 11(9), 1434; https://doi.org/10.3390/cells11091434 - 23 Apr 2022

Cited by 2 | Viewed by 3162

Abstract

Cyclic GMP-AMP synthase (cGAS) plays an important role in biological responses to pathogens. The activation of the cGAS pathway in immune cells is known to induce antitumor effects, but the role of cGAS in cancer cells remains poorly understood. In silico analysis using public databases suggested that high cGAS expression in head and neck squamous cell carcinoma (HNSCC) is indicative of a poor prognosis for HNSCC patients. We therefore investigated the role of cGAS in malignancies and the cellular radiation response of human HNSCC cells (SAS and Ca9-22) in vitro, because radiotherapy is one of the treatments most commonly used for HNSCC. Although cGAS knockdown failed to suppress the proliferation of non-irradiated HNSCC cells, it enhanced the radiosensitivity of HNSCC cells. The administration of the cGAS agonist increased the radioresistance of HNSCC cells. cGAS knockdown increased radiation-induced mitotic catastrophe, apoptosis, or cellular senescence, depending on the cell line, and this cell line-dependent response might be due to different responses of p21 after irradiation. Collectively, our findings indicate that the cGAS pathway regulates the radioresistance of HNSCC cells. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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13 pages, 1575 KiB

Open AccessArticle

A Boronated Derivative of Temozolomide Showing Enhanced Efficacy in Boron Neutron Capture Therapy of Glioblastoma

by Jing Xiang, Lin Ma, Zheng Gu, Hongjun Jin, Hongbin Zhai, Jianfei Tong, Tianjiao Liang, Juan Li, Qiushi Ren and Qi Liu

Cells 2022, 11(7), 1173; https://doi.org/10.3390/cells11071173 - 31 Mar 2022

Cited by 7 | Viewed by 2955

Abstract

There is an incontestable need for improved treatment modality for glioblastoma due to its extraordinary resistance to traditional chemoradiation therapy. Boron neutron capture therapy (BNCT) may play a role in the future. We designed and synthesized a ¹⁰B-boronated derivative of temozolomide, TMZB. BNCT was carried out with a total neutron radiation fluence of 2.4 ± 0.3 × 10¹¹ n/cm². The effects of TMZB in BNCT were measured with a clonogenic cell survival assay in vitro and PET/CT imaging in vivo. Then, ¹⁰B-boronated phenylalanine (BPA) was tested in parallel with TMZB for comparison. The IC50 of TMZB for the cytotoxicity of clonogenic cells in HS683 was 0.208 mM, which is comparable to the IC50 of temozolomide at 0.213 mM. In BNCT treatment, 0.243 mM TMZB caused 91.2% ± 6.4% of clonogenic cell death, while 0.239 mM BPA eliminated 63.7% ± 6.3% of clonogenic cells. TMZB had a tumor-to-normal brain ratio of 2.9 ± 1.1 and a tumor-to-blood ratio of 3.8 ± 0.2 in a mouse glioblastoma model. BNCT with TMZB in this model caused 58.2% tumor shrinkage at 31 days after neutron irradiation, while the number for BPA was 35.2%. Therefore, by combining the effects of chemotherapy from temozolomide and radiotherapy with heavy charged particles from BNCT, TMZB-based BNCT exhibited promising potential for therapeutic applications in glioblastoma treatment. Full article

(This article belongs to the Special Issue Cancer and Radiation Therapy)

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