BackgroundRadiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes.MethodsMouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred.ResultsGenistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group.ConclusionGenistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients.

Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation.

Exposure to ionising radiation induces male infertility, accompanied by increasing permeability of the blood-testis barrier. However, the effect on male fertility by low-dose-rate chronic radiation has not been investigated. In this study, the effects of low-dose-rate chronic radiation on male mice were investigated by measuring the levels of tight-junction-associated proteins (ZO-1 and occludin-1), Niemann-Pick disease type 2 protein (NPC-2) and antisperm antibody (AsAb) in serum. BALB/c mice were exposed to low-dose-rate radiation (3.49 mGy h(-1)) for total exposures of 0.02 (6 h), 0.17 (2 d) and 1.7 Gy (21 d). Based on histological examination, the diameter and epithelial depth of seminiferous tubules were significantly decreased in 1.7-Gy-irradiated mice. Compared with those of the non-irradiated group, 1.7-Gy-irradiated mice showed significantly decreased ZO-1, occludin-1 and NPC-2 protein levels, accompanied with increased serum AsAb levels. These results suggest potential blood-testis barrier injury and immune infertility in male mice exposed to low-dose-rate chronic radiation.

No abstract

Eosinophilic, polymorphic and pruritic eruption associated with radiotherapy (EPPER) can occur in cancer patients after irradiation. In this study, we characterized the clinical and histopathological features of pig skin that developed widespread polymorphic and pruritic skin lesions following localized 50 Gy gamma-irradiation. The pigs developed pruritus 5-7 weeks after irradiation, and infiltration of the dermis by eosinophils was detected 4-7 weeks after irradiation. The irradiated animals also showed transiently increased numbers of peripheral eosinophils 5-7 weeks after treatment. Irradiation induced desquamation after 2-4 weeks, which and the desquamation gradually resolved after 7 weeks. These pathological changes correspond to those seen in irradiated human skin, indicating that this model could be useful for elucidating the pathogenesis of EPPER and for developing therapeutic and prophylactic methods.

PurposePelvic irradiation for the treatment of cancer can affect normal cells, such as the rapidly proliferating spermatogenic cells of the testis, leading to infertility, a common post-irradiation problem. The present study investigated the radioprotective effect of rolipram, a specific phosphodiesterase type-IV inhibitor known to increase the expression and phosphorylation of the cyclic adenosine monophosphate response element-binding protein (CREB), a key factor for spermatogenesis, with the testicular system against pelvic irradiation.Materials and MethodsMale C57BL/6 mice were treated with pelvic irradiation (2 Gy) and rolipram, alone or in combination, and were sacrificed at 12 hours and 35 days after irradiation.ResultsRolipram protected germ cells from radiation-induced apoptosis at 12 hours after irradiation and significantly increased testis weight compared with irradiation controls at 35 days. Rolipram also ameliorated radiation-induced testicular morphological changes, such as changes in seminiferous tubular diameter and epithelial height. Additionally, seminiferous tubule repopulation and stem cell survival indices were higher in the rolipram-treated group than in the radiation group. Moreover, rolipram treatment counteracted the radiation-mediated decrease in the sperm count and mobility in the epididymis.ConclusionsThese protective effects of rolipram treatment prior to irradiation may be mediated by the increase in pCREB levels at 12 hours post-irradiation and the attenuated decrease in pCREB levels in the testis at 35 days post-irradiation in the rolipram-treated group. These findings suggest that activation of CREB signaling by rolipram treatment ameliorates the detrimental effects of acute irradiation on testicular dysfunction and the related male reproductive functions in mice.

Hypoxia is associated with resistance to anticancer therapies. Additionally, it is involved in the immune evasion of cancer cells by inducing an immunosuppressive microenvironment. However, the role of hypoxia in modulating the immunogenicity of cancer cells remains unknown. Hypoxia is known to induce endoplasmic reticulum (ER) stress, which serves a key role in inducing the cell surface exposure of calreticulin, a marker of immunogenic cell death. The present study investigated whether hypoxia influenced the immunogenicity of cancer cells using FACS, western blot analysis and syngenic mouse tumor model. The results revealed that hypoxia induced the cell surface exposure of calreticulin in human and mouse breast cancer cell lines depending on ER stress. Enhanced cell surface exposure of calreticulin induced by hypoxia resulted in an increase in anticancer immunity in a mouse model, which suggested that hypoxia induced immunogenic cell death. Notably, hypoxia did not significantly modulate the cell surface exposure of CD47, an antagonist of calreticulin function in cancer immunogenicity. These results suggest that hypoxia may enhance the immunogenicity of cancer cells themselves, in addition to its role in inducing an immunosuppressive cancer microenvironment.

Although granulocyte-colony stimulating factor (G-CSF) is commonly used to support recovery from radiation-induced side-effects, the precise effects of G-CSF on colon cancer under radiotherapy remain poorly understood. In the present study, to investigate the effects of tumor growth following radiotherapy and G-CSF administration in a murine xenograft model of colon cancer, female BALB/c mice were injected with cells of a colon carcinoma cell line (CT26) with irradiation and G-CSF, alone or in combination. Mice received 2 Gy of focal radiation daily for 5 days and intraperitoneal injection of G-CSF (100 µg/kg/day) after irradiation for 7 days. Changes in the levels of myeloperoxidase (MPO), vascular endothelial growth factor (VEGF), matrix metalloproteinase type 9 (MMP-9) and CD31 were assessed in the mouse cancer induced by injection of colon cancer cells. We observed that G-CSF increased the number of circulating neutrophils, but facilitated tumor growth. However, G-CSF treatment did not affect radiation-induced cytotoxicity and cell viability in CT26 cells in vitro. Increased levels of myeloperoxidase, a neutrophil marker and those of vascular endothelial growth factor were observed in tumors with G-CSF supplementation. In addition, we found that increased levels of CD31 and matrix metalloproteinase-9 were correlated with the enhanced tumor growth after G-CSF treatment. Therefore, these data suggest that G-CSF may contribute to tumor growth and decrease the antitumor effect of radiotherapy, possibly by promoting vascularization in cancer lesions.