Cytokine profiles in patients receiving wide-field + prostate boost radiotherapy (xRT) for adenocarcinoma of the prostate

Kovacs, C. J.; Daly, Barbara; Evans, Mark J.; Johnke, Roberta M.; Lee, T.K.; Karlsson, Ulf; Allison, Ron R.; Eaves, Gregory S; Biggs, Lisa

doi:10.1016/s1043-4666(03)00185-6

Cited by 27 publications

(26 citation statements)

References 48 publications

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“…With regard to IL-1, we observed that its expression was associated with increased probability of genitourinary toxicity, although we were not able to establish a dose-response relationship as per Kovacs and colleagues (10). Previous work has shown that radiation induces IL-1, which acts as a radioprotectant of hematopoietic cells (24).…”

Section: Discussionmentioning

confidence: 54%

“…Allen and colleagues (9) found that longitudinal increases in IL-6, IL-8, vascular endothelial growth factor (VEGF), HGF, and GRO-1 during radiotherapy were significantly associated with decreased cause-specific survival in Head and Neck Squamous Cell Carcinoma (HNSCC). Similarly, Kovacs and colleagues (10) reported that expression patterns of IL-1α, M-CSF, and TGF-β follow cyclical waves in patients during conventional wide-field radiotherapy for prostate cancer, where waves of proinflammatory IL-1α and M-CSF preceded profibrotic TGF-β. In summary, although cytokine levels are up-regulated in response to radiation (8)(9)(10)(11), the temporal pattern of these changes during radiotherapy has not been closely studied.…”

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confidence: 89%

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

Christensen

Pintilie

Evans

et al. 2009

Clinical Cancer Research

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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...

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Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 89%

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

Christensen

Pintilie

Evans

et al. 2009

Clinical Cancer Research

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“…Studies have demonstrated that the levels of proinflammatory cytokines were increased in systemic circulation of patients diagnosed with prostate cancer [21][22][23]. We have previously demonstrated the The Prostate DOI 10.1002/pros Fig.…”

Section: Discussionmentioning

confidence: 89%

Molecular imaging of NF‐kappaB in prostate tissue after systemic administration of IL‐1β

et al. 2007

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BACKGROUND. Activation of nuclear-factor kappaB (NF-kB) influences the transcription of number of genes, many of which participate in inflammatory responses and tumor development. A wide range of human cancers and inflammatory disorders express inappropriate regulation of NF-kB. The role of NF-kB in intraprostatic inflammation has not been elucidated. METHODS. Using transgenic NF-kB-Luciferase Tag mice coupled to the luciferase reporter gene, we performed serial, noninvasive in vivo and ex vivo molecular imaging of NF-kB activation in the mouse body after systemic administration of mouse pro-inflammatory cytokines: TNF-a, IL-6, and IL-1b at 10 mg/kg body weights. In some experiments, pretreatment with dexamethasone (10 mg/kg) was used to modulate the cytokine-induced NF-kB-dependent luminescence in vivo. RESULTS. Treatment of NF-kB-Luc mice with cytokines increased luminescence in a time-and organ-specific manner. Highest levels of NF-kB-dependent luminescence were observed approximately 3-4 hr after IL-1b administration. An important finding was the cumulative effect of IL-1b to activate NF-kB in the prostate during chronic administration. CONCLUSIONS. The molecular imaging of NF-kB activity might be an attractive approach to distinguish the role of cytokine-induced NF-kB signaling in intraprostatic inflammation and prostate cancer development. Since dexamethasone, a known NF-kB inhibitor, could reduce the IL-1b-induced NF-kB-dependent luminescence in the prostate, NF-kB-Luc mice might be useful tool to screen potential candidate drugs for treatment of inflammation and tumor associated with aberrant NF-kB activity.

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“…A number of clinical studies have also shown that cytokines are elevated during and after Radiotherapy for a variety of malignancies. 10,[18][19] Using this as a feasibility study, we measured the cytokines protein levels of p53, PCNA and p21 in human breast skin cells after receiving post-mastectomy radiotherapy treatment regimens as biomarkers for radiation response. The radiation response of cytokines within a controlled population with the same dose but in different fraction size has never been studied before.…”

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

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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...

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Cytokine profiles in patients receiving wide-field + prostate boost radiotherapy (xRT) for adenocarcinoma of the prostate

Cited by 27 publications

References 48 publications

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

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

Molecular imaging of NF‐kappaB in prostate tissue after systemic administration of IL‐1β

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

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