Basis of Cell Kill Following Clinical Radiotherapy

Faulhaber, Oliver; Bristow, Robert G.

doi:10.1007/1-4020-3302-8_13

Cited by 13 publications

(15 citation statements)

References 135 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3C) and supports a previous finding that NH 2 -terminal phosphorylation of p53 by DNA damage is conformation dependent (54,55).…”

Section: Expression Of Wtp53 or P53supporting

confidence: 90%

“…Treating the extracts with E-phosphatase eliminated the upper band, suggesting that the shift to 32jC causes some latent conformationdependent phosphorylation (data not shown). This phenomenon was further investigated using a limited panel of NH 2 No temperaturedependent changes in the phosphorylation levels at these particular sites were observed (data not shown), suggesting that the WTp53-specific phosphorylation site(s) are not detected with the panel of antibodies used in this study. These data suggest that the observed induction of p21 WAF1 and other p53-inducible genes could occur independently of DNA damage -induced NH 2 -terminal phosphorylation (56) and that there are other crucial latent phosphorylation sites that are WTp53 specific.…”

Section: Expression Of Wtp53 or P53mentioning

confidence: 82%

“…The DNA damage imparted by radiotherapy and chemotherapy can elicit apoptosis, mitotic catastrophe, and permanent growth arrest (e.g., tumor cell senescence) in solid tumor cells (2). Radiation and cDDP are used in combination along with other chemotherapies in the treatment of lung cancer.…”

Section: Expression Of Wtp53 or P53mentioning

confidence: 99%

See 2 more Smart Citations

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

Cuddihy

Jalali

Coackley

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

New molecular cancer treatment strategies aim to reconstitute wild-type p53 (WTp53) function in mutant p53 (MTp53) -expressing tumors as a means of resensitizing cells to chemotherapy or radiotherapy. The success of this approach may depend on whether MTp53 proteins are acting in a dominant-negative or independent gain-offunction mode. Herein, we describe an isogenic, temperature-sensitive p53 model (p53 A138V

show abstract

“…3C) and supports a previous finding that NH 2 -terminal phosphorylation of p53 by DNA damage is conformation dependent (54,55).…”

Section: Expression Of Wtp53 or P53supporting

confidence: 90%

Section: Expression Of Wtp53 or P53mentioning

confidence: 82%

See 1 more Smart Citation

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

Cuddihy

Jalali

Coackley

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…As such, we conclude that time from surgery to first fraction of radiotherapy treatment is not a significant confounding factor for cytokine expression in this treatment cohort. We also compared the baseline cytokine expression in the definitive IMRT group (intact prostate, n = 22) versus the postprostatectomy group (prostate removed, n = 20) to ascertain whether a (6) T 2a (2) T 2b (1) T 2b (1) T 3c (1) T 2c (4) unique prostate-specific cytokine signature could be identified (i.e. cytokines that are elevated in the definitive IMRT group only; Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Longitudinal Cytokine Expression during IMRT for Prostate Cancer and Acute Treatment Toxicity

Christensen

Pintilie

Evans

et al. 2009

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Proteomic profiling of patients undergoing intensity-modulated radiotherapy (IMRT) for prostate cancer can identify unique biomarkers that reflect acute toxicity in normal tissues. Our objectives were to measure inflammatory cytokine proteins during IMRT and assess the variability of individual proteomic signatures. Experimental Design: Forty-two patients with intermediate-risk prostate cancer were recruited as follows: group 1, definitive IMRT (78 Gy in 39 fractions, n = 22), and group 2, IMRT postprostatectomy (66 Gy in 33 fractions, n = 20). Blood/urine samples were collected at baseline and weekly during IMRT. Acute toxicity was graded weekly during radiotherapy using CTC-AE v3.0 criteria. Multiplexed immunoassays were used to quantify cytokines including granulocyte macrophage colony-stimulating factor, IFN-γ, tumor necrosis factor-α, interleukin (IL)-1α, IL-2, IL6, IL-8, IL-10, and IL-12p70. Results: We observed positive correlations between cytokine expression between serum and plasma, but not between serum/plasma and urine. The Mann-Whitney test showed a significant increase in IFN-γ and IL-6 during IMRT (P = 0.0077, 0.0035). Increasing IL-2 and IL-1 expression were associated with increased probability of acute gastrointestinal and genitourinary toxicity, respectively. Conclusions: Determination of radiation-response signatures is feasible using multiplexed immunoassays and is a promising predictive early biomarker of toxicity outcomes. (Clin Cancer Res 2009;15(17):5576-83) Cellular damage caused by ionizing radiation induces specific proteins involved in DNA repair, cell death, inflammation, and other pathophysiologic responses (1). The majority of biomarker studies in radiation oncology have focused on predicting tumor response and survival (2). Clinically, the acute toxicity of prostate cancer radiotherapy manifest as gastrointestinal and genitourinary symptoms based on validated scoring criteria, [e.g., Common Terminology Criteria for Adverse Events (CTC-AE); ref. 3]. Radiotherapy dose escalation using intensity-modulated radiotherapy (IMRT) is associated with improved biochemical tumor control, yet still has radiation-induced toxicity. Dose-dependent markers of acute normal toxicity could help predict individuals at increased risk of radiotherapy-related injury and help to maximize the therapeutic ratio for individual patients.Rubin and colleagues were among the first to describe the role of cytokines (small glycoproteins involved in intercellular signaling) in mediating radiation toxicity (4). They showed in preclinical and clinical lung studies that levels of interleukin (IL)-1, transforming growth factor (TGF)-β, and tumor necrosis factor (TNF)-α were increased immediately after radiation exposure, and that chronically elevated TGF-β levels were associated with increased risk of pulmonary fibrosis. The link between radiation toxicity and cytokine expression is supported by studies showing that prolonged cytokine expression postradiotherapy is correlated to specific lung radi...

show abstract

“…12 Cellular damage caused by ionizing radiation induces production and recruitment of specific proteins that have the potential to predict radiation induced toxicity in tissues within the irradiated volume. [15][16] Our interest in these proteins expression during Radiation Therapy is based in part on Rubin 17 and colleagues' description of a cytokine-linked continuum of early and late radiation responses. Rubin et al showed in murine and clinical lung models that radiation induced fibrosis is progressive after treatment and begins immediately following lung irradiation.…”

Section: Discussionmentioning

confidence: 99%

Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure

Wong

Chor

Moorthy

et al. 2013

Int J Cancer Ther Oncol

View full text Add to dashboard Cite

Purpose: Knowledge of the pathophysiology of the irradiated skin is important to understand the tolerance and cosmetic response of the human skin to radiation. There are limited studies on the effect of radiotherapy dosage and fraction size in inducing apoptotic cell death in human skin. The expression of apoptotic biomarkers within a controlled population in different fractionation schemes has also never been studied. This study aims to investigate radiation induced apoptotic cell death in human skin cells after fractionated radiation exposure and the expression of unique biomarkers that reflect cell death or biology using multiplexed immunoassays. Methods: Breast skin biopsies were obtained from a single individual and divided into small pieces. Each piece was irradiated under different radiotherapy treatment fractionation schedules to a total dose of 50Gy. The irradiated skin tissues were analysed using Tunnel, immunohistochemistry and Western blot assays for expression of apoptotic keratinocytes and biomarkers (p53, p21, and PCNA). Haematoxylin and eosin (H&E) immunostaining was performed to study the morphological changes in the skin cells. Results: Radiation is mostly absorbed by the epidermal layers and observed to damage the epidermal keratinocytes leading to the activation of apoptotic proteins. Apoptotic proteins (p53, p21 and PCNA) were confirmed to be up-regulated in radiation exposed skin cells as compared to normal skin cells with no radiation. There is strong correlation of apoptotic protein expressions with increased radiation dosage and dose fractionation. Statistical analysis with ANOVA revealed a significant increase of PCNA and p21 expression with increased radiation dosage and dose fractionation (p < 0.05). Immunohistochemically, 14 % (range 10.71% to 17.29%) of the keratinocytes were positive for PCNA and 22.5% (range 18.28% to 27.2%) for p21 after 2Gy of irradiation. The most widespread, intense and uniform staining for PCNA and p21 was observed in skin that had received 50Gy of irradiation. The maximum expression of p53 (range 37.09% to 50.91%) was reached at 10Gy. Conclusion: Findings from this study will assist clinicians in predicting radiation induced skin toxicity with the current changes in radiation fractionation protocols.Keywords: Apoptosis; Fractionated radiation therapy; Immunohistochemistry; Skin IntroductionRadiation therapy (RT) is a commonly utilized modality for the treatment of breast cancer. It is routinely employed in breast conservation therapy. Its role as adjuvant therapy in selected patients undergoing mastectomy for stages I and II disease is currently evolving, and has become an essential component of the combined modality approach for stage III disease. Postmastectomy Radiotherapy (PMRT) to the chest wall and to the regional lymphatics has shown to decrease locoregional recurrence and increase survival for women with large tumors and/or node-positive disease. 1-2 However, the risk of toxicity to skin and cosmesis must be weighed against local and regional...

show abstract

Basis of Cell Kill Following Clinical Radiotherapy

Cited by 13 publications

References 135 publications

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

WTp53 induction does not override MTp53 chemoresistance and radioresistance due to gain-of-function in lung cancer cells

Longitudinal Cytokine Expression during IMRT for Prostate Cancer and Acute Treatment Toxicity

Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure

Contact Info

Product

Resources

About