scholarly journals Quantification of Differential Response of Tumour and Normal Cells to Microbeam Radiation in the Absence of FLASH Effects

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3238
Author(s):  
Harriet Steel ◽  
Sarah C. Brüningk ◽  
Carol Box ◽  
Uwe Oelfke ◽  
Stefan H. Bartzsch
Keyword(s):  
Cell Lines ◽  
Tumour Cell ◽  
Differential Response ◽  
Therapeutic Window ◽  
High Dose ◽  
Linear Quadratic ◽  
Normal Cells ◽  
Dose Rates ◽  
Mixed Beam

Microbeam radiotherapy (MRT) is a preclinical method of delivering spatially-fractionated radiotherapy aiming to improve the therapeutic window between normal tissue complication and tumour control. Previously, MRT was limited to ultra-high dose rate synchrotron facilities. The aim of this study was to investigate in vitro effects of MRT on tumour and normal cells at conventional dose rates produced by a bench-top X-ray source. Two normal and two tumour cell lines were exposed to homogeneous broad beam (BB) radiation, MRT, or were separately irradiated with peak or valley doses before being mixed. Clonogenic survival was assessed and compared to BB-estimated surviving fractions calculated by the linear-quadratic (LQ)-model. All cell lines showed similar BB sensitivity. BB LQ-model predictions exceeded the survival of cell lines following MRT or mixed beam irradiation. This effect was stronger in tumour compared to normal cell lines. Dose mixing experiments could reproduce MRT survival. We observed a differential response of tumour and normal cells to spatially fractionated irradiations in vitro, indicating increased tumour cell sensitivity. Importantly, this was observed at dose rates precluding the presence of FLASH effects. The LQ-model did not predict cell survival when the cell population received split irradiation doses, indicating that factors other than local dose influenced survival after irradiation.

scholarly journals The FLASH effect depends on oxygen concentration

2020 ◽  
Vol 93 (1106) ◽  
pp. 20190702 ◽  
Author(s):  
Gabriel Adrian ◽  
Elise Konradsson ◽  
Michael Lempart ◽  
Sven Bäck ◽  
Crister Ceberg ◽  
...  
Keyword(s):  
Oxygen Concentration ◽  
Underlying Mechanism ◽  
Oxygen Depletion ◽  
Therapeutic Window ◽  
High Dose ◽  
Dose Rates ◽  
Conventional Dose ◽  
Oxygen Concentrations

Objective: Recent in vivo results have shown prominent tissue sparing effect of radiotherapy with ultra-high dose rates (FLASH) compared to conventional dose rates (CONV). Oxygen depletion has been proposed as the underlying mechanism, but in vitro data to support this have been lacking. The aim of the current study was to compare FLASH to CONV irradiation under different oxygen concentrations in vitro. Methods: Prostate cancer cells were irradiated at different oxygen concentrations (relative partial pressure ranging between 1.6 and 20%) with a 10 MeV electron beam at a dose rate of either 600 Gy/s (FLASH) or 14 Gy/min (CONV), using a modified clinical linear accelerator. We evaluated the surviving fraction of cells using clonogenic assays after irradiation with doses ranging from 0 to 25 Gy. Results: Under normoxic conditions, no differences between FLASH and CONV irradiation were found. For hypoxic cells (1.6%), the radiation response was similar up to a dose of about 5–10 Gy, above which increased survival was shown for FLASH compared to CONV irradiation. The increased survival was shown to be significant at 18 Gy, and the effect was shown to depend on oxygen concentration. Conclusion: The in vitro FLASH effect depends on oxygen concentration. Further studies to characterize and optimize the use of FLASH in order to widen the therapeutic window are indicated. Advances in knowledge: This paper shows in vitro evidence for the role of oxygen concentration underlying the difference between FLASH and CONV irradiation.

TAT-Apoptin Mediated Induction of Apoptosis in Leukaemic Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1900-1900
Author(s):  
Joop Gaken ◽  
Louisa Pericleous ◽  
Farzin Farzaneh ◽  
Ghulam J. Mufti ◽  
Mahvash Tavassoli
Keyword(s):  
Epithelial Cells ◽  
Cancer Cells ◽  
Cell Lines ◽  
Tumour Cell ◽  
Solid Tumour ◽  
Tumour Cells ◽  
Normal Cells ◽  
Leukaemic Cells ◽  
Tumour Cell Lines

Abstract We have studied the specific targeting of leukaemic cells using the Chicken Anaemia Virus (CAV)-derived protein VP3 (Apoptin) linked to the protein transduction domain (PTD) from HIV TAT with the aim of using this strategy for in vitro purging. Apoptin is a 13.6 kDa protein which induces apoptosis specifically in cancer cells whilst leaving normal cells unaffected. Expression of Apoptin in normal cells results in its cytoplasmic localisation. In tumour cells Apoptin resides initially in the cytoplasm and subsequently translocates to the nucleus and induces apoptosis. Apoptin is phosphorylated both in vitro and in vivo in tumour cells but negligibly in normal cells at threonine 108. A gain-of-function point mutation (T108E) results in accumulation of Apoptin in the nucleus and the killing of normal cells, implying that phosphorylation is a key factor of the tumour-specific properties of Apoptin. We have demonstrated that Apoptin induces apoptosis in a variety of human solid tumour cell lines, but not in normal fibroblast and epithelial cells. Apoptin induced apoptosis in HSC3 head and neck cancer cells acts through the mitochondrial pathway and was blocked (>75%) by shRNA against PUMA, a BH3 Only protein which induces Bax and BAK resulting in loss of mitochondrial membrane potential and release of cytochrome C. Furthermore, activation of the p53 family member, p73, substantially increased (5–10 fold for p73 β and γ) sensitivity of Saos2 tumour cells to Apoptin-induced killing. For efficient protein delivery, Apoptin was fused to a TAT PTD and addition of this protein to normal and tumour cells resulted in the selective killing of tumour cells. To increase the stability and solubility of TAT-Apoptin we have fused it to the maltose binding protein (MBP), this modification significantly increases both yield and the solubility of Apoptin while retaining its biological function. Apoptin tumour specific toxicity was assessed in a range of leukaemic and solid tumour cell lines. Addition of MBP-TAT-Apoptin protein to HL60, K562 and Jurkat cells resulted in 50%, 55% and 75% cell death by apoptosis as judged by PARP cleavage, respectively, at day 4 as compared to MBP-TAT control whilst normal B cells, fibroblasts and epithelial cells are unaffected. Fluorescent microscopy demonstrated that MBP-TAT-Apoptin was rapidly internalised in almost 100% of cells within 24hrs in all cell types tested. Direct injection of Apoptin expressing Ad vectors also showed clear regression of established tumours in mice. The cancer specific toxicity of Apoptin has potential value for a range of therapeutic applications such as purging of autologous bone marrow as used for the treatment of multiple myeloma and possibly direct treatment of leukaemias either alone or linked to antibodies for targeting of specific types of leukaemias.

scholarly journals Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity

Molecules ◽  
2021 ◽  
Vol 26 (7) ◽  
pp. 1838
Author(s):  
Naglaa M. Ahmed ◽  
Mahmoud M. Youns ◽  
Moustafa K. Soltan ◽  
Ahmed M. Said
Keyword(s):  
Molecular Modeling ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Antitumor Agents ◽  
Cancer Cell Lines ◽  
Normal Cells

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1–4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 μM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53–79 %) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

scholarly journals Translational Research in FLASH Radiotherapy—From Radiobiological Mechanisms to In Vivo Results

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 181
Author(s):  
Loredana G. Marcu ◽  
Eva Bezak ◽  
Dylan D. Peukert ◽  
Puthenparampil Wilson
Keyword(s):  
Dose Rate ◽  
High Dose Rate ◽  
Current Status ◽  
Therapeutic Window ◽  
High Dose ◽  
Linear Accelerators ◽  
Radiation Delivery ◽  
Tissue Sparing

FLASH radiotherapy, or the administration of ultra-high dose rate radiotherapy, is a new radiation delivery method that aims to widen the therapeutic window in radiotherapy. Thus far, most in vitro and in vivo results show a real potential of FLASH to offer superior normal tissue sparing compared to conventionally delivered radiation. While there are several postulations behind the differential behaviour among normal and cancer cells under FLASH, the full spectra of radiobiological mechanisms are yet to be clarified. Currently the number of devices delivering FLASH dose rate is few and is mainly limited to experimental and modified linear accelerators. Nevertheless, FLASH research is increasing with new developments in all the main areas: radiobiology, technology and clinical research. This paper presents the current status of FLASH radiotherapy with the aforementioned aspects in mind, but also to highlight the existing challenges and future prospects to overcome them.

scholarly journals Synthesis and Antitumour activity of some aryl semicarbazones

2000 ◽  
Vol 68 (4) ◽  
pp. 369-377 ◽  
Author(s):  
S.N. Pandeya ◽  
P. Yogeeswari ◽  
E.A. Sausville ◽  
A.B. Mauger ◽  
V.L. Narayanan
Keyword(s):  
Breast Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Tumour Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Significant Activity

Various 4-substituted phenyl semicarbazone derivatives were synthesized and evaluated in vitro by NCI in the 3-cell line, one dose primary anticancer assay. Three compounds showed significant activity against breast MCF7 cell line and were further evaluated for potential anticancer activity in an in vitro human disease-oriented tumour cell line screening panel that consisted of 60 human tumour cell lines arranged in nine subpanels, representing diverse histologies. Leukemia, colon, ovarian and breast cancer cell lines were relatively more sensitive to these compounds than the other cell lines. The 4-carboxy substituted p-nitrobenzylidene phenyl semicarbazone (1c) emerged as the most active compound with average GI50 value (the molar drug concentration required for the 50% growth inhibition) of 28.6µM. This compound showed greater activity than methotrexate against NCI-H226(Lung), BT-549 and T-47D(Breast) cancer cell lines.

A correlation between radiation sensitivity and initial chromatid breaks in cancer cell lines revealed by Calyculin A-induced premature condensation

2006 ◽  
Vol 1 (3) ◽  
pp. 451-462 ◽  
Author(s):  
Jianshe Yang ◽  
Xigang Jing ◽  
Zhuanzi Wang ◽  
Wenjian Li
Keyword(s):  
Cell Lines ◽  
Radiation Sensitivity ◽  
Calyculin A ◽  
Linear Quadratic ◽  
Technique Survival ◽  
Positive Linear Correlation ◽  
Radiation Induced ◽  
Clinical Radiotherapy

AbstractThree human malignancy cell lines were irradiated with 60Co γ-rays. Initial chromatid breaks were measured by using the chemically induced premature chromosome condensation technique. Survival curves of cells exposed to gamma rays was linear-quadratic while the efficiency of Calyculin A in inducing PCC of G2 PCC was about five times more than G1 PCC. A dose-dependent increase in radiation-induced chromatid/isochromatid breaks was observed in G1 and G2 phase PCC and a nearly positive linear correlation was found between cell survival and chromatin breaks. This study implies that low LET radiation-induced chromatid/isochromatid breaks can potentially be used to predict the radiosensitivity of tumor cells either in in vitro experimentation or in in vivo clinical radiotherapy.

Immunophenotype of Mammary Tumour Cell Lines for In-Vitro Analysis Using Three Different Techniques

2020 ◽  
Vol 174 ◽  
pp. 184
Author(s):  
F. Torrigiani ◽  
A. Sammarco ◽  
M.E. Gelain ◽  
F. Bonsembiante ◽  
R. Zanetti ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tumour Cell ◽  
Mammary Tumour ◽  
Tumour Cell Lines ◽  
Vitro Analysis ◽  
In Vitro Analysis

scholarly journals Iron Causes Lipid Oxidation and Inhibits Proteasome Function in Multiple Myeloma Cells: A Proof of Concept for Novel Combination Therapies

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 970 ◽  
Author(s):  
Jessica Bordini ◽  
Federica Morisi ◽  
Fulvia Cerruti ◽  
Paolo Cascio ◽  
Clara Camaschella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Iron Toxicity ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Ferric Carboxymaltose ◽  
High Dose ◽  
Iron Loading

Adaptation to import iron for proliferation makes cancer cells potentially sensitive to iron toxicity. Iron loading impairs multiple myeloma (MM) cell proliferation and increases the efficacy of the proteasome inhibitor bortezomib. Here, we defined the mechanisms of iron toxicity in MM.1S, U266, H929, and OPM-2 MM cell lines, and validated this strategy in preclinical studies using Vk*MYC mice as MM model. High-dose ferric ammonium citrate triggered cell death in all cell lines tested, increasing malondialdehyde levels, the by-product of lipid peroxidation and index of ferroptosis. In addition, iron exposure caused dose-dependent accumulation of polyubiquitinated proteins in highly iron-sensitive MM.1S and H929 cells, suggesting that proteasome workload contributes to iron sensitivity. Accordingly, high iron concentrations inhibited the proteasomal chymotrypsin-like activity of 26S particles and of MM cellular extracts in vitro. In all MM cells, bortezomib-iron combination induced persistent lipid damage, exacerbated bortezomib-induced polyubiquitinated proteins accumulation, and triggered cell death more efficiently than individual treatments. In Vk*MYC mice, addition of iron dextran or ferric carboxymaltose to the bortezomib-melphalan-prednisone (VMP) regimen increased the therapeutic response and prolonged remission without causing evident toxicity. We conclude that iron loading interferes both with redox and protein homeostasis, a property that can be exploited to design novel combination strategies including iron supplementation, to increase the efficacy of current MM therapies.

scholarly journals Novel O-methyl goniofufurone and 7-epi-goniofufurone derivatives: synthesis, in vitro cytotoxicity and SAR analysis

MedChemComm ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 2017-2027
Author(s):  
Jovana Francuz ◽  
Mirjana Popsavin ◽  
Sanja Djokić ◽  
Vesna Kojić ◽  
Tatjana Srdić-Rajić ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tumour Cell ◽  
Methoxy Group ◽  
Antitumour Activity ◽  
In Vitro Cytotoxicity ◽  
Human Tumour ◽  
Tumour Cell Lines ◽  
Sar Analysis ◽  
Human Tumour Cell Lines

Novel goniofufurone (1) and 7-epi-goniofufurone (2) derivatives bearing a methoxy group at the C-5 and/or C-7 positions were prepared and their in vitro antitumour activity against some human tumour cell lines was evaluated.

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