Low dose hypersensitivity in the T98G human glioblastoma cell line

Short, Christie

doi:10.1080/095530099139908

Cited by 87 publications

(22 citation statements)

References 7 publications

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“…The rationale for introducing these compounds into breast cancer treatment regimens is based on studies reporting overexpression of Notch receptors in breast cancers [3,19,25] and a central role for the Notch signaling pathway in the self-renewal process of breast cancer stem cells [6]. Furthermore, preclinical use of γ-secretase inhibitors reduced the number of breast cancer stem cells [20,24,25] and partially prevented radiation-induced reprogramming of non-tumorigenic breast cancer cells into breast cancer stem cells [16]. …”

Section: Discussionmentioning

confidence: 99%

“…Mouse studies suggest that Notch receptor and ligand expression and Notch activation are highly dynamic [25] and part of the general cellular response to oxidative stress [21,24]. Therefore, knowledge of the exact temporal expression pattern of the Notch receptor and ligand family members appears to be crucial for the design of effective treatment schedules.…”

Section: Discussionmentioning

confidence: 99%

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Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

Lagadec

Vlashi

Alhiyari

et al. 2013

International Journal of Radiation Oncology*Biology*Physics

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Purpose Breast cancers are thought to be organized hierarchically with a small number of breast cancer stem cells able to self-renew and to regrow the entire tumor. Importantly, breast cancer stem cells are resistant to established chemotherapeutic agents and relatively resistant to radiation. Self-renewal of breast cancer stem cells is under control of the Notch signaling pathway, which suggests that targeting this pathway could be a novel way of eliminating breast cancer stem cells. The γ-secretase complex controls the final intramembranous cleavage step that activates Notch receptors upon binding of its ligands and specific inhibitors of γ-secretase, which prevent Notch activation, are currently clinically tested against solid cancers in combination with radiotherapy. Radiation activates Notch signaling and therefore, we sought to explore patterns of Notch receptor and ligand expression in response to radiation that could be crucial in defining optimal dosing schemes for γ-secretase inhibitors if combined with radiation. Methods and Materials Using MCF-7 and T47D breast cancer cell lines we used realtime RT-PCR to study the Notch pathway in response to radiation. Results We show that Notch receptor and ligand expression during the first 48 hours after irradiation followed a complex radiation dose-dependent pattern and was most pronounced in mammospheres, enriched for breast cancer stem cells. Additionally, radiation activated the Notch pathway. Treatment with a γ-secretase inhibitor prevented radiation-induced Notch family gene expression and led to a significant reduction in the size of the breast cancer stem cell pool. Conclusions Our results indicate that, if combined with radiation, γ-secretase inhibitors may prevent up-regulation of Notch receptor and ligand family members and thus reduce the number of surviving breast cancer stem cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

Lagadec

Vlashi

Alhiyari

et al. 2013

International Journal of Radiation Oncology*Biology*Physics

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“…Survival data sets for each of the three cell lines tested for the presence of low-dose HRS were fitted to the basic two-parameter linear-quadratic (LQ) model (Kellerer and Rossi, 1972) as well as to the four-parameter induced-repair (IR) model (Joiner et al 1993); for the explicit equation and interpretation of IR model parameters see Short et al (1999). The LQ or IR model best-fit parameters in Table 1 were obtained using Sigma-Plot software, version 6.10 (SystatSoftware, Inc. San Jose, CA, U.S.A.) and, independently, using JPM ® SAS software (Cary, NC, U.S.A.) (data not shown).…”

Section: Methodsmentioning

confidence: 99%

“…This successful strategy for the delivery of upper abdominal radiation has been based on experimental data demonstrating the low dose radiation hypersensitivity (HRS) phenomenon i.e. a statistically significant disagreement between predictions of the linear-quadratic model and measurements of cell survival after radiation doses of less 1 Gy (Marples and Joiner, 1993; Short and Joiner, 1998; Short et al 1999; Joiner et al 2001). According to these reports, the linear-quadratic model (Kellerer and Rossi, 1972) overestimates survival in the low dose range (Joiner et al 1993).…”

Section: Introductionmentioning

confidence: 99%

The Effect of Docetaxel (Taxotere®) on Human Gastric Cancer Cells Exhibiting Low-Dose Radiation Hypersensitivity

Balcer‐Kubiczek

Attarpour

Wang

et al. 2008

Clinical medicine. Oncology

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Low-dose radiation hypersensitivity (HRS) describes a phenomenon of excessive sensitivity to X ray doses <0.5 Gy. Docetaxel is a taxane shown to arrest cells in the G2/M phase of the cell cycle. Some previous studies suggested that HRS might result from the abrogation of the early G2 checkpoint arrest. First we tested whether HRS occurs in gastric cancer—derived cells, and whether pre-treatment of cells with low docetaxel concentrations can enhance the magnitude of HRS in gastric cancer cells. The results demonstrated HRS at ~0.3 Gy and the synergy between 0.3 Gy and docetaxel (3 nM for 24 h), and the additivity of other drug/dose combinations. The synergistic effect was associated with a significant docetaxel-induced G2 accumulation. Next, we evaluated in time-course experiments ATM kinase activity and proteins associated with the induction and maintenance of the early G2 checkpoint. The results of multi-immunoblot analysis demonstrate that HRS does not correlate with the ATM-dependent early G2 checkpoint arrest. We speculate that G2 checkpoint adaptation, a phenomenon associated with a prolonged cell cycle arrest, might be involved in HRS. Our results also suggest a new approach for the improvement the effectiveness of docetaxel-based radiotherapy using low doses per fraction.

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“…For this reason, Short et al . investigated the affect of low-dose irradiation on five human GBM cell lines (T98G, A7, U87MG, U138, and HGL21) and one anaplastic astrocytoma-derived cell line (U373) [15,16]. Survival time was calculated using the DMIPS method for T98G, A7, and U373, whereas the FC method (as modified by Wouters et al .)…”

Section: Experimental Studiesmentioning

confidence: 99%

Three-Times Daily Ultrafractionated Radiation Therapy, A Novel and Promising Regimen for Glioblastoma Patients

Beauchesne

2013

Cancers

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Glioblastomas are considered to be one of the most radio resistant tumors. Despite new therapies, the prognosis of this disease remains dismal. Also, the mechanisms of radiation resistance in mammalian cells are more complex than once believed. Experimental studies have indicated that some human cell lines are sensitive to low radiation doses of <1 Gy. This phenomenon has been termed low-dose hyper-radio-sensitivity (HRS), and is more apparent in radio resistant cell lines, such as glioblastoma cells. Sensitivity may result from the inability of low dose radiation to efficiently induce repair mechanisms, whereas higher doses cause enough damage to trigger repair responses for radio resistance. In vitro studies have demonstrated this phenomenon using various human malignant glioma cell lines: (1) daily repeated irradiation of cells with low doses compared to irradiation using a single biologically equivalent dose resulted in significantly higher cell killing; (2) experiments conducted on glioma xenografts demonstrated that repeated irradiation with low doses was more effective for inhibiting tumor growth than a single dose. In order to confirm and validate these promising studies on HRS, a few phase II trials were developed. For translating the experimental observations into the clinic, ultra fractionation protocols (with three daily doses) were tested in glioblastoma patients. Tolerance and toxicity were the primary endpoints, with overall survival as a secondary endpoint. These protocols were initiated before concomitant radio chemotherapy became the standard of care. For these trials, patients with an unfavorable clinical prognostic factor of newly unresectable GBM were included. When comparing the results of these trials with international literature using multivariate analysis for both progression free survival and overall survival, ultra fractionated irradiation showed superiority over radiotherapy alone. In addition, it was found to be equivalent to treatment using radiotherapy and temozolomide. Therefore, ultra fractionated protocols may prolong survival of glioblastoma patients. In this review, we describe the main experimental data regarding low-dose hypersensitivity as well as the findings of clinical trials that have investigated this new radiotherapy regimen.

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Low dose hypersensitivity in the T98G human glioblastoma cell line

Abstract: T98G glioblastoma cells demonstrate marked HRS, which is a characteristic of the whole population rather than being due to the influence of a small subpopulation of hyper-radiosensitive cells within a particular phase of the cell cycle.

Cited by 87 publications

References 7 publications

Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

Radiation-Induced Notch Signaling in Breast Cancer Stem Cells

The Effect of Docetaxel (Taxotere®) on Human Gastric Cancer Cells Exhibiting Low-Dose Radiation Hypersensitivity

Three-Times Daily Ultrafractionated Radiation Therapy, A Novel and Promising Regimen for Glioblastoma Patients

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