A phase II trial of low-dose total body irradiation and subcutaneous Interleukin-2 in metastatic melanoma

Safwat, Akmal; Schmidt, Henrik; Bastholt, Lars; Fode, Kirsten; Larsen, Stine Rosenkilde; Aggerholm, Ninna; Maase, Hans von der

doi:10.1016/j.radonc.2005.09.008

Cited by 21 publications

(11 citation statements)

References 15 publications

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“…Similar results have been obtained for acute myeloid leukemia and transplanted solid tumors in mice (15,16). Low-dose totalbody irradiation (TBI) has also been used in the treatment of some cancer patients with varying degrees of success (17,18). The anti-tumor effects of low-dose TBI could be explained at least partly by immune enhancement, induction of apoptosis in premalignant cells, and intrinsic hypersensitivity of certain cancer cell genotypes to low-dose radiation (19,20).…”

Section: Introductionmentioning

confidence: 99%

Low-Dose Total-Body γ Irradiation Modulates Immune Response to Acute Proton Radiation

et al. 2012

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Health risks due to exposure to low-dose/low-dose-rate radiation alone or when combined with acute irradiation are not yet clearly defined. This study quantified the effects of protracted exposure to low-dose/low-dose-rate γ rays with and without acute exposure to protons on the response of immune and other cell populations. C57BL/6 mice were irradiated with ⁵⁷Co (0.05 Gy at 0.025 cGy/h); subsets were subsequently exposed to high-dose/high-dose-rate proton radiation (250 MeV; 2 or 3 Gy at 0.5 Gy/min). Analyses were performed at 4 and 17 days postexposure. Spleen and thymus masses relative to body mass were decreased on day 4 after proton irradiation with or without pre-exposure to γ rays; by day 17, however, the decrease was attenuated by the priming dose. Proton dose-dependent decreases, either with or without pre-exposure to γ rays, occurred in white blood cell, lymphocyte and granulocyte counts in blood but not in spleen. A similar pattern was found for lymphocyte subpopulations, including CD3+ T, CD19+ B, CD4+ T, CD8+ T and NK1.1+ natural killer (NK) cells. Spontaneous DNA synthesis by leukocytes after proton irradiation was high in blood on day 4 and high in spleen on day 17; priming with γ radiation attenuated the effect of 3 Gy in both body compartments. Some differences were also noted among groups in erythrocyte and thrombocyte characteristics. Analysis of splenocytes activated with anti-CD3/anti-CD28 antibodies showed changes in T-helper 1 (Th1) and Th2 cytokines. Overall, the data demonstrate that pre-exposure of an intact mammal to low-dose/low-dose-rate γ rays can attenuate the response to acute exposure to proton radiation with respect to at least some cell populations.

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Section: Introductionmentioning

confidence: 99%

Low-Dose Total-Body γ Irradiation Modulates Immune Response to Acute Proton Radiation

et al. 2012

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“…Based on this and our previous studies, we can conclude that LDR stimulates cell proliferation in several normal tissues, including hematopoietic progenitor cell proliferation and peripheral mobilization, and does not induce the same stimulating effect in tumor cells. Up to 75 mGy of X-rays as LDR can stimulate bone marrow stem cells [32] and is also a tolerable dose for patients [33]. Therefore, the findings of the current study may have a great potential for clinical application in cancer radiotherapy.…”

Section: Discussionmentioning

confidence: 93%

Different responses of tumor and normal cells to low-dose radiation

Yu¹,

Liu²,

Wang³

et al. 2013

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Aim of the studyWe demonstrated stimulation of both erythrocyte immune function and superoxide dismutase activity in tumor-bearing mice in response to whole-body 75 mGy X-rays. In addition, we enhanced the chemotherapeutic effect by exposing tumor-bearing mice to low-dose radiation (LDR). This study aims to investigate the different responses of tumor cells and normal cells to LDR.Material and methodsSurvival fraction, micronucleus frequency, and cell cycle of Lewis cells and primary human fibroblast AG01522 cells were measured. S180 sarcoma cells were implanted in mice, and tumor sizes were measured in vivo.ResultsIn response to LDR exposure in vitro, a stimulating effect was observed in AG01522 cells but not in Lewis cells. Low-dose radiation did not cause an adaptive response in the Lewis cell cycle. Lack of an LDR-induced radioadaptive response in tumor cells was observed in tumor-bearing mouse models. Furthermore, a higher apoptotic effect and lower expression of the anti-apoptosis gene Bcl-2 were found in tumor cells of tumor-bearing mice exposed to D1 + D2 than those in tumor cells of tumor-bearing mice exposed to D2 alone.ConclusionsDifferent responses of tumor cells and normal cells to LDR were found. Low-dose radiation was found to stimulate the growth of normal cells but not of tumor cells in vitro and in vivo, which is a very important and clinically relevant phenomenon.

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“…A typical treatment schedule consists of 0.1- to 0.25-Gy fractions given several times a week until a cumulative dose of approximately 1.5–2 Gy is reached. Despite no recommendation to metastatic melanoma patients due to its poor clinical efficacy (Safwat et al 2005), LTBI is successful in inducing long-term remissions and has been shown to be as effective as the chemotherapy to which it has been compared in lymphoma (Safwat 2000a). However, the mechanism of this effect is unknown.…”

Section: Discussionmentioning

confidence: 99%

Different radiosensitivity of CD4⁺CD25⁺regulatory T cells and effector T cells to low dose gamma irradiation in vitro

Cao

Cabrera

et al. 2010

International Journal of Radiation Biology

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Purpose To determine the radiosensitivity difference of human Cluster of Differentiation (CD)4+CD25+ regulatory T cells (Treg) and effector T cells to low dose gamma ray and elucidate the underlying mechanisms in vitro. Materials and methods Blood samples were collected from five health subjects and five patients with advanced hepatocellular carcinoma (HCC). Treg and CD4+CD25− T cells were selected using magnetic microbeads. The proliferative profiles, cytokine secretion, and differential expressions of apoptosis-related proteins in Treg and CD4+CD25− T cells were compared using [3H]-thymidine incorporation, Luminex assay and flow cytometry when treated with various low doses of γ-ray. Results A dose-dependent reduction of proliferation in response to irradiation which paralleled the induction of apoptosis existed in Treg and CD4+CD25− T cells. Treg were more radiosensitive to low-dose irradiation (0.94 Gray [Gy]) than effector T cells. The interferon-γ (IFNγ) was significantly upregulated and interleukin 10 (IL-10) was significantly downregulated in irradiated Treg. An enhanced immune response to low dose gamma ray existed in the peripheral blood in patients with advanced HCC. Higher levels of active caspase-3, CD95, B cell lymphoma 2 (Bcl-2)-associated X protein (Bax) expression were observed in Treg compared to CD4+CD25− T cells. In addition, gamma irradiation activated CD4+CD25−T cells to express CD25. Conclusions These studies revealed that Treg were more radiosensitive than CD4+CD25− T cells to low dose irradiation. Higher expressions of apoptosis-related proteins such as caspase-3, CD95 and Bax were observed in Treg when compared to CD4+CD25− T cells. Our results suggest that treatment with low doses of gamma irradiation may be a viable strategy to enhance immune response in patients with advanced HCC.

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A phase II trial of low-dose total body irradiation and subcutaneous Interleukin-2 in metastatic melanoma

Cited by 21 publications

References 15 publications

Low-Dose Total-Body γ Irradiation Modulates Immune Response to Acute Proton Radiation

Low-Dose Total-Body γ Irradiation Modulates Immune Response to Acute Proton Radiation

Different responses of tumor and normal cells to low-dose radiation

Different radiosensitivity of CD4⁺CD25⁺regulatory T cells and effector T cells to low dose gamma irradiation in vitro

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A phase II trial of low-dose total body irradiation and subcutaneous Interleukin-2 in metastatic melanoma

Cited by 21 publications

References 15 publications

Low-Dose Total-Body γ Irradiation Modulates Immune Response to Acute Proton Radiation

Low-Dose Total-Body γ Irradiation Modulates Immune Response to Acute Proton Radiation

Different responses of tumor and normal cells to low-dose radiation

Different radiosensitivity of CD4+CD25+regulatory T cells and effector T cells to low dose gamma irradiation in vitro

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Different radiosensitivity of CD4⁺CD25⁺regulatory T cells and effector T cells to low dose gamma irradiation in vitro