Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice

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Wang, Xingqi; Ouyang, Zijun; You, Qian; He, Shuai; Meng, Qianqian; Hu, Chunhui; Wu, Xudong; Shen, Yan; Sun, Yang, E-mail: yangsun@nju.edu.cn; Wu, Xuefeng, E-mail: wuxf@nju.edu.cn; Xu, Qiang, E-mail: molpharm@163.com

2016-07-15

Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23 days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. - Highlights: • Obaculactone ameliorates bleomycin-induced pulmonary fibrosis in mice. • Obaculactone mitigates bleomycin-induced inflammatory response in lungs. • Obaculactone exerts inhibitory effects on TGF-β1 signaling and TGF-β1-induced EMT progress.

Obaculactone protects against bleomycin-induced pulmonary fibrosis in mice

International Nuclear Information System (INIS)

Wang, Xingqi; Ouyang, Zijun; You, Qian; He, Shuai; Meng, Qianqian; Hu, Chunhui; Wu, Xudong; Shen, Yan; Sun, Yang; Wu, Xuefeng; Xu, Qiang

2016-01-01

Idiopathic pulmonary fibrosis is a progressive, degenerative and almost irreversible disease. There is hardly an effective cure for lung damage due to pulmonary fibrosis. The purpose of this study was to evaluate the role of obaculactone in an already-assessed model of idiopathic pulmonary fibrosis induced by bleomycin administration. Mice were subjected to intratracheal instillation of bleomycin, and obaculactone was given orally after bleomycin instillation daily for 23 days. Treatment with obaculactone ameliorated body weight loss, lung histopathology abnormalities and pulmonary collagen deposition, with a decrease of the inflammatory cell number and the cytokine level in bronchoalveolar lavage fluid. Moreover, obaculactone inhibited the expression of icam1, vcam1, inos and cox2, and attenuated oxidative stress in bleomycin-treated lungs. Importantly, the production of collagen I and α-SMA in lung tissues as well as the levels of TGF-β1, ALK5, p-Smad2 and p-Smad3 in lung homogenates was also reduced after obaculactone treatment. Finally, the TGF-β1-induced epithelial-mesenchymal transition via Smad-dependent and Smad-independent pathways was reversed by obaculactone. Collectively, these data suggest that obaculactone may be a promising drug candidate for the treatment of idiopathic pulmonary fibrosis. - Highlights: • Obaculactone ameliorates bleomycin-induced pulmonary fibrosis in mice. • Obaculactone mitigates bleomycin-induced inflammatory response in lungs. • Obaculactone exerts inhibitory effects on TGF-β1 signaling and TGF-β1-induced EMT progress.

Bleomycin induced pulmonary to cytotoxicity in patients with germ cell tumours

International Nuclear Information System (INIS)

Usman, M.; Faruqui, Z.S.; Din, N.U.

2010-01-01

Background: Bleomycin is a cytotoxic drug used in treatment of Germ Cell Tumours (GCTs) and is associated with pulmonary toxicity. Bleomycin pulmonary toxicity (BPT) manifests predominantly as pulmonary fibrosis, organising pneumonia (OP) or Nonspecific Interstitial Pneumonitis (NSIP). Our objectives were to determine the incidence of BPT, describe the common HRCT patterns of pulmonary toxicity and to find out the correlation of variables (cumulative dose of bleomycin, age and glomerular filtration rate) with pulmonary toxicity. Methods: The study included the data of 96 patients from March 2006 to September 2008. All patients had histologically proven GCT and received bleomycin containing regimes. Variables age, GFR at the time of initial presentation along with cumulative dose of bleomycin at completion of chemotherapy or at the time of BPT were recorded. The High resolution CT chest (HRCT) of these patients was independently reviewed by two radiologists. Bleomycin toxicity was reported on the radiologic features of pulmonary fibrosis, OP or NSIP. Results : Fourteen patients (14.6%) developed BPT. Common patterns of BPT were, pulmonary fibrosis (5.2%), OP (5.2%) and NSIP (4.2%). Using the Univariate regression analysis there was significant relationship between BPT and age, cumulative bleomycin dose an d initial GFR at the beginning of treatment. Conclusions: Because BPT can be progressive and fatal, early recognition is important. The diagnosis of pulmonary toxicity should be considered in any patient with new or progressive respiratory complaints. BPT can be difficult to diagnose; therefore, knowledge and understanding of radiologic manifestations of toxicity caused by Bleomycin are necessary for institution of appropriate treatment. There is increasing incidence of BPT with increasing age, cumulative dose and decreasing GFR. (author)

Molecular interactions of the combined effects of bleomycin and x-rays on mammalian cell survival

International Nuclear Information System (INIS)

Byfield, J.E.; Lee, Y.C.; Tu, L.; Kulhanian, F.

1976-01-01

The interactions between bleomycin and x-ray damage and repair have been examined in rat and human tumor cells. Bleomycin itself induces extensive DNA single-strand breaks but does not appear to inhibit the repair of x-ray-induced DNA single-strand breaks. Quantitative analysis of these interactions is complicated by the retention of active bleomycin within cells that remains capable of further DNA degradation even under the conditions of alkaline sucrose gradient cell lysis. DNA double-strand breaks and/or disruptions of DNA-lipid complexes also occur following bleomycin exposure. X-ray-induced excision repair replication is only minimally influenced by even high concentrations of bleomycin. A small amount of excision repair is demonstrable in nonirradiated cells treated with high concentrations of bleomycin consistent with repair of bleomycin-induced nucleotide damage in cellular DNA by a ''cut and patch'' repair mechanism. Repair of bleomycin-induced DNA single-strand breaks also occurs. The data indicate that bleomycin and x-ray damage are quite similar both in their induction and repair, but that lesions occur and are repaired independently. The enzymatic mechanisms appear similar in the two cell types despite substantial differences in their sensitivity to bleomycin

Current status of indium-111 labeled bleomycin for tumor detection

International Nuclear Information System (INIS)

Taylor, R.D.; Blahd, W.H.

1975-01-01

The advantages and disadvantages of 111 In-labeled bleomycin for tumor detection are briefly mentioned. Indium-111 labeled bleomycin does localize in human tumors. However, its role in tumor detection and staging as compared with 67 Ga is still somewhat controversial

Use of pharmacogenomics in predicting bleomycin-induced pulmonary toxicity in testicular cancer patients.

NARCIS (Netherlands)

Nuver, J; Van Zweeden, M; Holzik, ML; Meijer, C; Hoekstra, H; Suurmeijer, A; Hofstra, R; Groen, H; Sleijfer, D; Gietema, J

2004-01-01

4531 Background:Use of bleomycin, important for treatment efficacy in testicular cancer, is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BLH). An A1450G polymorphic site in the BLH gene results in an amino acid

Acute respiratory failure induced by bleomycin and hyperoxia

International Nuclear Information System (INIS)

Goad, M.E.P.

1985-01-01

Bleomycin, a chemotherapeutic agent, and oxygen at concentrations greater than 20%, induce acute pulmonary damage separately and when administered together. The interaction of 5 U/kg intratracheal bleomycin and 24 hours of exposure to 80% oxygen in hamsters produces delayed onset acute respiratory distress syndrome three days after treatment. As little as 12 hours of 80% O 2 exposure, after intratracheal bleomycin, induces severe pulmonary damage. Lung lesions are characterized as diffuse alveolar damage. Significantly pulmonary edema, measured by iodine-125-bovine serum albumin and technetium-99m-diethylenetriaminepentaacetate, occurs 72 hours after treatment. Lesions progress from focal mild alveolar interstitial and air-space macrophage and granulocyte infiltrates at 24 hours to marked infiltrates and severe interstitial and air space edema with hemorrhages and hyaline membranes at 96 hours. Significant changes measured by electron microscopy morphometry are increases in volume fractions of neutrophils, alveolar tissue and mononuclear leukocytes. Surfactant assay of bronchoalveolar lavage fluid shows a marked decrease in the lecithin/sphingomyelin ratio at 72 hours. Proposed mechanisms of bleomycin and hyperoxia synergism include enhanced production of superoxide radicals either directly or indirectly by increasing neutrophil activity or numbers, or by alteration of cell mediators. The pulmonary edema, without evidence of severe morphological changes, may be secondary to alterations of transalveolar transport mechanisms

Bleomycin treatment of brain tumors: an evaluation

DEFF Research Database (Denmark)

Linnert, Mette; Gehl, Julie

2009-01-01

Bleomycin has been used in the treatment of brain tumors for over 30 years. Currently, we are evaluating electrochemotherapy (the use of electric pulses to enhance uptake of bleomycin) for patients with secondary brain tumors. We, therefore, reviewed the literature with specific reference...... fever, headaches, nausea and vomiting, lethargy, and peritumoral edema. Out of 189 patients treated from 1973 to 2007, only five patients (3%) had severe and six patients (3%) had moderate adverse effects. One death was directly related to this treatment, where very high doses were used. Two patients...

Clinical usefulness of bleomycin combined with preoperative irradiation for cancer of the esophagus

International Nuclear Information System (INIS)

Morita, Kozo; Takagi, Iwao

1988-01-01

The clinical usefulness of bleomycin combined with irradiation was evaluated using 154 preoperatively treated cases with cancer of the esophagus. With the appearance rate Ef-3 (highly effective: no viable tumor cell in the esophageal specimen resected after preoperative treatment) the radiation effect was observed, in comparison with those three groups (30 Gy alone, 40 Gy alone and 30 Gy + 67.5 mg of bleomycin). Dose modifying actor (DMF) of bleomycin for the preoperatively irradiated esophageal cancer was 1.2 - 1.3. As a serious interstitial pneumonitis was sometimes caused by the administration of bleomycin, it was concluded that the usage of bleomycin combind with preoperative irradiation for cancer of the esophagus, is less useful than that for cancer of the uterine cervix and the head and neck region. (author)

Tocopherol Supplementation Reduces NO Production and Pulmonary Inflammatory Response to Bleomycin

Science.gov (United States)

Shi, Jin Dong; Golden, Thea; Guo, Chang-Jiang; Tu, Shui Ping; Scott, Pamela; Lee, Mao-Jung; Yang, Chung S.; Gow, Andrew J.

2013-01-01

Bleomycin causes acute lung injury through production of reactive species and initiation of inflammation. Previous work has shown alteration to the production of reactive oxygen species results in attenuation of injury. Vitamin E, in particular, γ-tocopherol, isoform, has the potential to scavenge reactive oxygen and nitrogen species. This study examines the utility of dietary supplementation with tocopherols in reducing bleomycin-mediated acute lung injury. Male C57BL6/J mice were intratracheally instilled with PBS or 2 units/kg bleomycin. Animals were analyzed 3 and 8 days post instillation at the cellular, tissue, and organ levels. Results showed successful delivery of tocopherols to the lung via dietary supplementation. Also, increases in reactive oxygen and nitrogen species due to bleomycin are normalized in those mice fed tocopherol diet. Injury was not prevented but inflammation progression was altered, in particular macrophage activation and function. Inflammatory scores based on histology demonstrate limited progression of inflammation in those mice treated with bleomycin and fed tocopherol diet compared to control diet. Upregulation of enzymes and cytokines involved in pro-inflammation were limited by tocopherol supplementation. Day 3 functional changes in elastance in response to bleomycin are prevented, however, 8 days post injury the effect of the tocopherol diet is lost. The effect of tocopherol supplementation upon the inflammatory process is demonstrated by a shift in the phenotype of macrophage activation. The effect of these changes on resolution and the progression of pulmonary fibrosis has yet to be elucidated. PMID:23669183

Bleomycin resistance : a new dominant selectable marker for plant cell transformation

NARCIS (Netherlands)

Hille, Jacques; Verheggen, Frank; Roelvink, Peter; Franssen, Henk; Kammen, Ab van; Zabel, Pim

1986-01-01

Plant cells are sensitive to the antibiotic bleomycin, a DNA damaging glycopeptide. A bleomycin resistance determinant, located on transposon Tn5 and functional in bacteria, has been cloned in a plant expression vector and introduced into Nicotiana plumbaginifolia using Agrobacterium tumefaciens.

Effects of intratracheal instillation of bleomycin on phospholipid synthesis in hamster lung tissue slices

International Nuclear Information System (INIS)

Giri, S.N.

1987-01-01

Bleomycin, an antineoplastic drug, is known to produce interstitial pulmonary fibrosis (IPF). As a result, it is commonly employed in various species to produce animal models of fibrosis. We have examined the uptake of [ 14 C] acetate by lung slices and its incorporation into lipids in the slices at various times following intratracheal administration of a fibrogenic dose of bleomycin in hamsters. As compared to saline controls, bleomycin had no effect on [ 14 C] acetate uptake at 4 and 7 days but it increased the uptake at 2 and 14 days after treatment. The incorporation of [ 14 C] acetate into total lipid was significantly reduced to 44, 62, 62, and 75% of the control at 2, 4, 7, and 14 days after bleomycin treatment, respectively. The incorporation into lipid as a percentage of the uptake was 12.2 in control animals whereas in bleomycin-treated animals, it was 4.7, 8.0, 7.3, and 6.9 at the corresponding times. Separation of lipids into various fractions revealed that bleomycin treatment specifically inhibited the synthesis of phosphatidylcholine and neutral lipid at all times of the study. The synthesis of all other phospholipids except phosphatidylethanolamine was depressed at 2 days. The latter was, however, depressed at 7 and 14 days after bleomycin treatment. It was concluded from the present study that bleomycin treatment inhibits the synthesis of phospholipid and neutral lipid and this may eventually lead to decreased surfactant production

Effects of ICRF-187 and L-Carnitine on bleomycin-induced lung toxicity in rats

International Nuclear Information System (INIS)

Shouman, Samia A.; Abdel-Hamid, M.A.; Hassan, Zeinab A.; Mansour, Heba H.

2002-01-01

The possible modulatory effects of ICRF-187 and L-carnitine against bleomycin-induced pulmonary toxicity in male rats were investigated. Repeated administration of bleomycin (10 mg/kg, twice weekly for 6 consecutive weeks) produced significant lung toxicity. The toxicity was manifested by significant increase in normal contents of lipid peroxide (LPO, 91.7%) reduced glutathione (GSH, 73.2%) and oxidized glutathione (GSSG, 135.4%) as well as the activity of superoxide dismutase (SOD, 222.7%). Thirty minutes prior to bleomycin treatment, other groups of rats received either ICRF-187 (95 mg/kg) or L-carnitine (500 mg/kg) adopting the same schedule of treatment as in bleomycin-treated group. L-carnitine decreased bleomycin-induced elevations in SOD activity, GSH and GSSG contents, however, it failed to suppress the increase in LPO level. On the other hand, treatment with ICRF-187 returned back all the elevated biochemical parameters induced by bleomycin to nearly normal levels. In conclusion, the results of this study showed a potential capability of ICRF-187 to mitigate the bleomycin-induced lung injury. Moreover, despite the inability of L-carnitine to change the elevated LPO content, it was able however, to decrease the elevated endogenous antioxidant parameters. (author)

Efficacy of a bleomycin microneedle patch for the treatment of warts.

Science.gov (United States)

Ryu, Ha Ryeong; Jeong, Hye-Rin; Seon-Woo, Hye-Seung; Kim, Jung Soo; Lee, Seul Ki; Kim, Hee Joo; Baek, Jin Ok; Park, Jung-Hwan; Roh, Joo Young

2018-02-01

Warts are a common skin disease caused by infection of the human papilloma virus. Most treatments involving physical destruction of the infected cells, such as cryotherapy and electrocautery, are limited by intense pain, failure, or recurrences. Our aim was to compare the therapeutic effects of a newly developed bleomycin microneedle patch with cryotherapy in the treatment of warts. Forty-two patients with more than two wart lesions were included in the study. The two treatment modalities were randomly applied to different warts on each patient. Treatment efficacy was assessed using the Physician's Global Assessment (PGA) and the Patient's Global Assessment (PaGA). Mean PGA and PaGA scores were not significantly different between cryotherapy and bleomycin microneedle patch treatment. It was also determined that the mean size of all the warts treated with either modality shrank about equally at weeks 8 and 16 after initial treatment. Thus, treatment efficacy of the bleomycin microneedle patch was comparable to that of conventional cryotherapy. According to a visual analogue scale of pain, bleomycin microneedle patch treatment was significantly less painful than cryotherapy (p microneedle patch was more tolerable for patients who were reluctant to receive the painful treatment. Thus, the bleomycin microneedle patch can be an effective, convenient, and innovative treatment modality for warts.

Results of combined therapy of irradiation and bleomycin suppository for advanced uterine cervical cancer

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Saito, Haruo; Asakawa, Hiroshi; Otawa, Hirokazu; Nemoto, Kenji; Saito, Hiroyuki (Miyagi Prefectural Adult Disease Center, Natori (Japan))

1984-09-01

Efficacy, survival rates and adverse effects of the combined therapy of irradiation with intravaginal bleomycin suppositories were analyzed and discussed in 49 patients with uterine cervical cancer. The results were as follows: 1. Histological examination of biopsy specimens from the uterine cervix taken just after the completion of this treatment showed favorable control over the primary lesions. However, the efficacy of the bleomycin suppositories was too mild to form a basis for treatment without intracavitary irradiation. Because of the low concentration of bleomycin in serum after suppository administration, it is thought that bleomycin would have little effect on distant metastases. 2. Survival rates in stage III patients were 83% at 12 months, 77% at 24 months and 70% at 36 months. These were superior to those for irradiation alone. 3. The major adverse effect of bleomycin suppositories was fever, reduction of the bleomycin dose in each suppository but controlled this to some extent Lung fibrosis or severe damage to the liver, kidney and bone marrow were not found.

Results of combined therapy of irradiation and bleomycin suppository for advanced uterine cervical cancer

International Nuclear Information System (INIS)

Saito, Haruo; Asakawa, Hiroshi; Otawa, Hirokazu; Nemoto, Kenji; Saito, Hiroyuki

1984-01-01

Efficacy, survival rats and adverse effects of the combined therapy of irradiation with intravaginal bleomycin suppositories were analyzed and discussed in 49 patients with uterine cervical cancer. The results were as follows: 1. Histological examination of biopsy specimens from the uterine cervix taken just after the completion of this treatment showed favorable control over the primary lesions. However, the efficacy of the bleomycin suppositories was too mild to form a basis for treatment without intracavitary irradiation. Because of the low concentration of bleomycin in serum after suppository administration, it is thought that bleomycin would have little effect on distant metastases. 2. Survival rates in stage III patients were 83% at 12 months, 77% at 24 months and 70% at 36 months. These were superior to those for irradiation alone. 3. The major adverse effect of bleomycin suppositories was fever, reduction of the bleomycin dose in each suppository but controlled this to some extent Lung fibrosis or severe damage to the liver, kidney and bone marrow were not found. (author)

Effect of bleomycin-radiotherapy combination in management of head and neck squamous cell carcinoma

International Nuclear Information System (INIS)

Shah, P.M.; Shukla, S.N.; Patel, K.M.; Patel, N.L.; Baboo, H.A.; Patel, D.D.

1981-01-01

Twenty-five patients with head and neck squamous cell carcinoma were treated with bleomycin-radiotherapy protocol, 15 mg bleomycin I.V. on alternate days followed by radiation within half an hour. The average total dose of bleomycin was 150 mg. Radiotherapy was given daily. Two patients were lost to follow-up very early in the course of the treatment and were removed from the study for statistical purposes. Thirty-six patients with head and neck squamous cell carcinoma who were treated with radiotherapy alone during the same period were used as controls. The patients were followed for two years. The incidence of response rate did not differ significantly between regimens; however, the incidence of side effects with bleomycin-radiotherapy, 82.61%, is significantly more than that of radiotherapy alone (52.78%). Median survial time (MST) of those responding to bleomycin-radiotherapy protocol was seven months and 12 days and for radiotherapy responders was six months. Neither the response rate nor the MST improve significantly after pretreatment with bleomycin. On the contrary, the incidence of side effects increased significantly

Protective effects of a bacterially expressed NIF-KGF fusion protein against bleomycin-induced acute lung injury in mice.

Science.gov (United States)

Li, Xinping; Li, Shengli; Zhang, Miaotao; Li, Xiukun; Zhang, Xiaoming; Zhang, Wenlong; Li, Chuanghong

2010-08-01

Current evidence suggests that the keratinocyte growth factor (KGF) and the polymorphonuclear leukocyte may play key roles in the development of lung fibrosis. Here we describe the construction, expression, purification, and identification of a novel NIF (neutrophil inhibitory factor)-KGF mutant fusion protein (NKM). The fusion gene was ligated via a flexible octapeptide hinge and expressed as an insoluble protein in Escherichia coli BL21 (DE3). The fusion protein retained the activities of KGF and NIF, as it inhibited both fibroblast proliferation and leukocyte adhesion. Next, the effects of NKM on bleomycin-induced lung fibrosis in mice were examined. The mice were divided into the following four groups: (i) saline group; (ii) bleomycin group (instilled with 5 mg/kg bleomycin intratracheally); (iii) bleomycin plus dexamethasone (Dex) group (Dex was given intraperitoneally (i.p.) at 1 mg/kg/day 2 days prior to bleomycin instillation and daily after bleomycin instillation until the end of the treatment); and (iv) bleomycin plus NKM group (NKM was given i.p. at 2 mg/kg/day using the same protocol as the Dex group). NKM significantly improved the survival rates of mice exposed to bleomycin. The marked morphological changes and increased hydroxyproline levels resulted from the instillation of bleomycin (on Day 17) in the lungs were significantly inhibited by NKM. These results revealed that NKM can attenuate bleomycin-induced lung fibrosis, suggesting that NKM could be used to prevent bleomycin-induced lung damage or other interstitial pulmonary fibrosis.

Evaluation of carcinoma of the cervix using 111In-bleomycin

International Nuclear Information System (INIS)

Woolfenden, J.M.; Waxman, A.D.; Disaia, P.J.; Siemsen, J.K.

1975-01-01

Indium-111 attached to bleomycin is useful in the scintigraphic localization of a variety of tumors. Since it does not normally accumulate in bowel and feces, it is superior to other radiopharmaceuticals, such as gallium-67-citrate, in the demonstration of abnormalities in the abdomen and pelvis. Twenty-eight patients with known carcinoma of the cervix were studied with whole body 111 In-bleomycin scans. Two ''false-positive'' scans were produced by local inflammation. Six ''false-negative'' scans were attributed to small tumors escaping scintigraphic detection. In the remaining 20 patients, scan findings correlated well with site and extent of the tumor as determined by other means. 111 In-bleomycin scintiscanning may prove to be a highly useful adjunct in the evaluation of patients with carcinoma of the cervix

Protective role of andrographolide in bleomycin-induced pulmonary fibrosis in mice.

Science.gov (United States)

Zhu, Tao; Zhang, Wei; Xiao, Min; Chen, Hongying; Jin, Hong

2013-12-03

Idiopathic pulmonary fibrosis (IPF) is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT), apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB) is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF) were measured. HE staining and Masson's trichrome (MT) staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA). On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

Protective Role of Andrographolide in Bleomycin-Induced Pulmonary Fibrosis in Mice

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Tao Zhu

2013-12-01

Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic devastating disease with poor prognosis. Multiple pathological processes, including inflammation, epithelial mesenchymal transition (EMT, apoptosis, and oxidative stress, are involved in the pathogenesis of IPF. Recent findings suggested that nuclear factor-κB (NF-κB is constitutively activated in IPF and acts as a central regulator in the pathogenesis of IPF. The aim of our study was to reveal the value of andrographolide on bleomycin-induced inflammation and fibrosis in mice. The indicated dosages of andrographolide were administered in mice with bleomycin-induced pulmonary fibrosis. On day 21, cell counts of total cells, macrophages, neutrophils and lymphocytes, alone with TNF-α in bronchoalveolar lavage fluid (BALF were measured. HE staining and Masson’s trichrome (MT staining were used to observe the histological alterations of lungs. The Ashcroft score and hydroxyproline content of lungs were also measured. TGF-β1 and α-SMA mRNA and protein were analyzed. Activation of NF-κB was determined by western blotting and electrophoretic mobility shift assay (EMSA. On day 21 after bleomycin stimulation, andrographolide dose-dependently inhibited the inflammatory cells and TNF-α in BALF. Meanwhile, our data demonstrated that the Ashcroft score and hydroxyproline content of the bleomycin-stimulated lung were reduced by andrographolide administration. Furthermore, andrographloide suppressed TGF-β1 and α-SMA mRNA and protein expression in bleomycin-induced pulmonary fibrosis. Meanwhile, andrographolide significantly dose-dependently inhibited the ratio of phospho-NF-κB p65/total NF-κB p65 and NF-κB p65 DNA binding activities. Our findings indicate that andrographolide compromised bleomycin-induced pulmonary inflammation and fibrosis possibly through inactivation of NF-κB. Andrographolide holds promise as a novel drug to treat the devastating disease of pulmonary fibrosis.

Short-term side effects and patient-reported outcomes of bleomycin sclerotherapy in vascular malformations.

Science.gov (United States)

Mack, Joana M; Richter, Gresham T; Becton, David; Salem, Omar; Hill, Sarah E M; Crary, Shelley E

2018-06-01

Vascular malformations (VM) are congenital lesions that can be debilitating and cause significant aesthetic and functional limitations. The chemotherapeutic agent bleomycin has been utilized as a sclerosant, directly injected percutaneously into the VM. Unfortunately, little is known about the benefits and short-term side effects of bleomycin with intralesional injections. An IRB approved, retrospective chart review was performed on patients with VM who had been treated with intralesional bleomycin. Data included type of VM, number of treatments, total bleomycin dose per m², and adverse effects. A questionnaire was administered to available patients to assess subjective outcomes and side effects. Forty-six patients were treated with 141 procedures of bleomycin sclerotherapy for VM. Patient ages ranged from 1 to 20 years (median age 10 years). The median cumulative bleomycin dose was 16.3 units/m²/person (range of 1.7-97.0 units/m²/person). Sixty-three percent of patients were reached for a questionnaire to assess short-term side effects. Ninety percent of patients surveyed were satisfied to very satisfied with the results from the procedure. About 24% of patients experienced transient nausea, vomiting and/or local hyperpigmentation. Bleomycin sclerotherapy can be an effective treatment of VM with repeat exposure with minor risk of short-term side effects, however, long-term risks are of great concern. Further studies are required to assess systemic absorption and long-term risks. © 2018 Wiley Periodicals, Inc.

Interactive lethal and mutagenic effects of ultraviolet light and bleomycin in yeast: synergism or antagonism?

Science.gov (United States)

Lillo, O L; Severgnini, A A; Nunes, E M

1997-11-01

The mutagenic interactions of ultraviolet light and bleomycin in haploid populations of Saccharomyces cerevisiae were analyzed. Survival and mutation frequency as a function of different bleomycin concentrations after one conditioning dose of UV radiation were determined. Furthermore, corresponding interaction functions and sensitization factors were calculated. A synergistic interaction between UV light and bleomycin was shown for both lethal and mutagenic events when the cells were in nutrient broth during the treatments. Conversely, the interaction between UV light and bleomycin was antagonistic when the cells were in deionized water during the treatment. The magnitude of lethal and mutagenic interactions depends on dose, and thus presumably on the number of lesions. The observed interactions between UV light and bleomycin suggest that the mechanism that is most likely involved is the induction of repair systems with different error probabilities during the delay of cell division.

Effects of a combined Bleomycin/radiotherapy on the increase of cell numbers in Ehrlich ascitic carcinoma

International Nuclear Information System (INIS)

Mueller, W.A.

1980-01-01

The effects of separate and combined application of the cytostatic Bleomycin and X-radiation on the multiplication of the Ehrlich ascitic tumour cells in vivo and on the survival time of tumourous mice was examined by applying automatic, electronic cell counting. If this cytostatic is administered alone up to 100 mg/kg the growth curve of the EAT-cells shows, after a 24 hours' delay, hardly any difference to that of untreated tumour cells. The separate administration of such Bleomycin doses and the separate X-radiation of the EAT cells with doses of up to 1000 rad had no significant influence on the survival time of tumourous mice. The combined application of Bleomycin and X-radiation elongates the 50%-survival time of the tumourous mice. If the X-radiation takes place 12 hours after the Bleomycin treatment the animals survive longer than is the case with simultaneous treatment. Although no dose effect curves could be set up the results obtained let assume a synergistic effect of Bleomycin and irradiation which is especially significant if the radiation is carried out 12 hours after a Bleomycin treatment. The reasons of this are assumed to lie in the increased radiation sensitivity of the tumour cells caused by the bleomycin-induced partial synchronisation of the EAT cells. (orig.) [de

Preventing cleavage of Mer promotes efferocytosis and suppresses acute lung injury in bleomycin treated mice

International Nuclear Information System (INIS)

Lee, Ye-Ji; Lee, Seung-Hae; Youn, Young-So; Choi, Ji-Yeon; Song, Keung-Sub; Cho, Min-Sun; Kang, Jihee Lee

2012-01-01

Mer receptor tyrosine kinase (Mer) regulates macrophage activation and promotes apoptotic cell clearance. Mer activation is regulated through proteolytic cleavage of the extracellular domain. To determine if membrane-bound Mer is cleaved during bleomycin-induced lung injury, and, if so, how preventing the cleavage of Mer enhances apoptotic cell uptake and down-regulates pulmonary immune responses. During bleomycin-induced acute lung injury in mice, membrane-bound Mer expression decreased, but production of soluble Mer and activity as well as expression of disintegrin and metalloproteinase 17 (ADAM17) were enhanced . Treatment with the ADAM inhibitor TAPI-0 restored Mer expression and diminished soluble Mer production. Furthermore, TAPI-0 increased Mer activation in alveolar macrophages and lung tissue resulting in enhanced apoptotic cell clearance in vivo and ex vivo by alveolar macrophages. Suppression of bleomycin-induced pro-inflammatory mediators, but enhancement of hepatocyte growth factor induction were seen after TAPI-0 treatment. Additional bleomycin-induced inflammatory responses reduced by TAPI-0 treatment included inflammatory cell recruitment into the lungs, levels of total protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, as well as caspase-3 and caspase-9 activity and alveolar epithelial cell apoptosis in lung tissue. Importantly, the effects of TAPI-0 on bleomycin-induced inflammation and apoptosis were reversed by coadministration of specific Mer-neutralizing antibodies. These findings suggest that restored membrane-bound Mer expression by TAPI-0 treatment may help resolve lung inflammation and apoptosis after bleomycin treatment. -- Highlights: ►Mer expression is restored by TAPI-0 treatment in bleomycin-stimulated lung. ►Mer signaling is enhanced by TAPI-0 treatment in bleomycin-stimulated lung. ►TAPI-0 enhances efferocytosis and promotes resolution of lung injury.

Clinical Evaluation of 57Co-labelled Bleomycin for Tumor Localization

International Nuclear Information System (INIS)

Ryu, Yong Wun; Kim, Jang Hee; Lee, Jhin Oh

1987-01-01

Investigation with 57 Co-Bleomycin in patients with the various cancers and in tumor bearing animals are described. In the patients, 57 Co-Bleomycin appears to be one of the useful tumor- seeking radiopharmaceuticals, and worth applicable to clinical uses. Labelled yield of 57 Co-Bleo was about 97% by thin layer chromatography. The pyrogen free tests were performed to meet U.S.P. critical ranges. In clinical studies with 57 Co-Bleo, 4 cases out of 5 patients with lung cancer, 2 cases among 3 thyroid cancer patients, and all 3 hepatoma patients showed positive tumor scans. The patients with stomach cancer, and the esophageal cancer showed false negative scintigraphy. A case with pulmonary tuberculosis showed a positive scan while liver abscess showed a negative picture. The merits of 57 Co-Bleomycin scintigraphy seems to be its relatively high affinity to tumors and low radiation hazard in spite of long physical half life.

Proliferative kinetics and chromosome damage in trisomy 21 lymphocyte cultures exposed to gamma-rays and bleomycin

International Nuclear Information System (INIS)

Morimoto, K.; Kaneko, T.; Iijima, K.; Koizumi, A.

1984-01-01

Lymphocytes from patients with Down's syndrome (trisomy 21) have been investigated for cell cycle kinetics, cell proliferation delays, and chromosomal aberrations after exposure to gamma-rays or bleomycin. Analysis by sister chromatid differential staining revealed that trisomy 21 lymphocytes started cell cycling about 5 hr earlier than did normal diploid lymphocytes after phytohemagglutinin stimulation as a whole, but that cycling trisomic and normal cells had the same mean cell cycle times. When exposed to gamma-rays or bleomycin in G0, trisomy 21 lymphocytes showed a 30% or, on average, 50% longer duration of cell turnover times, respectively, than normal cells; only bleomycin-treated trisomic cells had a biphasic dose-response. Frequencies of dicentrics and rings in first-division cells after gamma-ray or bleomycin exposure were twice as high in trisomic cells as in normal cells. The frequency of aberrations decreased by 50% (gamma-ray-exposed) or 65 to 85% (bleomycin-treated) through successive divisions; trisomic cells showed a more marked decline in aberration yields compared to normal cells after bleomycin treatment. These data support the idea that circulating lymphocytes in trisomy 21 patients have a shorter average life span or a younger average age

The effect of ionizing radiation and bleomycin on transfecting ability of Bacillus subtilis phage DNA

International Nuclear Information System (INIS)

Schafers, F.; Kohnlein, W.

1979-01-01

Infectious DNA of Bacillus subtilis phage 029 and SPP1 has been subjected to ionizing radiation and/or bleomycin treatment. The extent of degradation of the treated DNA was determined on sucrose gradients and biological activity was analyzed using the transfection principle. It was found that loss of biological activity following irradiation or bleomycin treatment of the DNA cannot be accounted for by the production of single- or double-strand breaks. Furthermore, it was observed that pre-irradiation exhibits a synergistic effect on loss of biological activity and production of strand breaks following bleomycin treatment. The authors propose here a simple system capable of detecting biological damage in DNA following irradiation doses as low as 0.5 Gy prior to bleomycin treatment. (Auth.)

Enhanced pulmonary toxicity with bleomycin and radiotherapy in oat cell lung cancer

International Nuclear Information System (INIS)

Einhorn, L.; Krause, M.; Hornback, N.; Furnas, B.

1976-01-01

In a recently completed study, combination chemotherapy consisting of bleomycin, adriamycin, cyclophosphamide, and vincristine was given to 29 patients with oat cell lung cancer. There were no cases of pulmonary fibrosis in these 29 patients. Although several of these patients had prior radiotherapy, none had concomitant radiotherapy and chemotherapy. This same four-drug chemotherapy regimen was combined with concomitant radiotherapy in 13 patients with oat cell lung cancer. There were three cases of fatal pulmonary fibrosis and two other cases of clinically significant pulmonary fibrosis. All five cases of pulmonary fibrosis occurred several weeks after completion of a six-week course of bleomycin (total dosage 90 units). It is concluded that bleomycin cannot be safely administered while patients are receiving radiotherapy of the lung

Characterization of the association of radiolabeled bleomycin A2 with HeLa cells

International Nuclear Information System (INIS)

Roy, S.N.; Horwitz, S.B.

1984-01-01

The association of [ 3 H]bleomycin A2 and Cu(II):[ 3 H]bleomycin A2 with HeLa cells has been characterized. Under the conditions of our experiments, approximately 0.1% of the total drug in the medium associates with HeLa cells. Both forms of the drug bind to HeLa cells in a specific and saturable manner, with a Km of 20 microM and a Vmax of 2.5 pmol/min/10(6) cells. Scatchard analysis of the specific binding data demonstrates a single set of high-affinity binding sites. Cytotoxic activities of both forms of the drug are similar, with a 50% lethal dose of 0.5 microM at 48 hr. The specific binding in HeLa cells of either the labeled metal-free drug or its copper complex is reversible by a 100-fold excess of either unlabeled drug. Interaction of the drug with cells is temperature sensitive but is unaffected by metabolic poisons, suggesting that this process is not energy dependent. Isolation of DNA from HeLa cells incubated with the drug indicates that 1 mol of either [ 3 H]bleomycin A2 or Cu(II):[ 3 H]bleomycin A2 binds per 10(8) nucleotides. Further studies with the radiolabeled drug are required to define precisely the mechanisms involved in bleomycin uptake and compartmentalization within the cell

In-111 BLEDTA: a conjugate of bleomycin with a bifunctional chelating agent for tumor localization

International Nuclear Information System (INIS)

Goodwin, D.A.; Meares, C.F.; DeRiemer, L.H.; Diamanti, C.I.; Goode, R.L.

1979-01-01

BLEDTA, a bleomycin A 2 analog containing an EDTA group was labeled in the EDTA group to a specific activity of 70 mCi/mg and used for animal and human studies. KHJJ mouse tumor uptake was higher than the orange Co-57 bleomycin isomer and the tumor/organ ratios were >1 for all organs except the kidney. In 29 biopsy proven cancer patients the scan done 24 hours post I.V. with 1-2 mCi of In-111 BLEDTA was positive in all clinically known sites in 18, and in some clinically known sites in 11. The In-111 BLEDTA clinical results are similar to reported Co-57 bleomycin clinical studies, and the method is proposed as an alternate way to produce a stable biologically active bleomycin labeled with In-111

Bleomycin-associated Lung Toxicity in Childhood Cancer Survivors.

Science.gov (United States)

Zorzi, Alexandra P; Yang, Connie L; Dell, Sharon; Nathan, Paul C

2015-11-01

Pulmonary disease is a significant morbidity among childhood cancer survivors. The aim of this study was to characterize the pulmonary dysfunction experienced by childhood cancer survivors treated with bleomycin. A cross-sectional analysis of pulmonary function testing (PFT) in survivors treated with bleomycin was preformed. The most recent posttherapy PFT was assessed. Spirometry and lung volumes were categorized as normal, restrictive, obstructive, or mixed. Diffusing capacity of carbon monoxide (DLCO) was categorized as normal or abnormal. PFT data of 143 survivors was analyzed. PFTs were performed a median of 2.3 years (interquartile range, 1.4 to 4.9) from completion of therapy. Spirometry was abnormal in 58 (41%), only 5 (9%) had respiratory symptoms. Forty-two (70%) had obstructive, 11 (18%) restrictive, and 5 (9%) mixed ventilatory defects. The majority of abnormalities were mild (91%). DLCO was abnormal in 27. Reductions were mild in 96%. Patients with a history of relapse were more likely to develop abnormalities in spirometry and/or DLCO (odds ratio=5.02, 95% confidence interval: 1.3-19.4, P=0.01; odds ratio=3.47, 95% confidence interval: 1.01-11.9, P=0.03). Asymptomatic abnormalities of PFT are common among childhood cancer survivors treated with bleomycin and associated with a history of relapse. Research studying the risk for clinical progression of this dysfunction is warranted.

Clinical evaluation of tumor scintigraphy with /sup 57/Co-bleomycin

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Watanabe, K; Kawahira, K; Nakayama, C; Kamoi, I; Matsuura, K [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

1975-06-01

Of 84 patients to whom tumor scintigraphy with /sup 57/Co-bleomycin was performed, 76 patients were clinically evaluated. 47 per cent of the patients with malignant tumor were positive, and 3 of 10 patients with benign diseases showed positive picture. The positive rate was examined according to diseases, and 65.4% was found to be positive in primary lung cancer and 50% in malignant lymphoma. As positive rate was relatively low and count efficiency was also low in spite of the accumulation in the lesion in the scintigraphy with /sup 57/Co-bleomycin, the examination took long time and there was a difficulty in the management of urine excretions. It was therefore, inferior to that with /sup 67/Ga-citrate which was widely utilized at present. However, /sup 57/Co-bleomycin distributed in the bones in a small amount and the radioactivity level in the blood was low, so that it was considered to be effective to the diagnosis of tumors localized in the regions that were not above the bones. This point should be investigated as a future program.

Kaposi's sarcoma: Good outcome with doxorubicin, bleomycin and ...

African Journals Online (AJOL)

KS) in children in low-income countries. We prospectively treated 12 patients with an institutional review board-approved protocol consisting of four monthly courses of doxorubicin (Adriamycin), bleomycin and vincristine sulphate (ABV), with ...

Repetitive intradermal bleomycin injections evoke T-helper cell 2 cytokine-driven pulmonary fibrosis.

Science.gov (United States)

Singh, Brijendra; Kasam, Rajesh K; Sontake, Vishwaraj; Wynn, Thomas A; Madala, Satish K

2017-11-01

IL-4 and IL-13 are major T-helper cell (Th) 2 cytokines implicated in the pathogenesis of several lung diseases, including pulmonary fibrosis. In this study, using a novel repetitive intradermal bleomycin model in which mice develop extensive lung fibrosis and a progressive decline in lung function compared with saline-treated control mice, we investigated profibrotic functions of Th2 cytokines. To determine the role of IL-13 signaling in the pathogenesis of bleomycin-induced pulmonary fibrosis, wild-type, IL-13, and IL-4Rα-deficient mice were treated with bleomycin, and lungs were assessed for changes in lung function and pulmonary fibrosis. Histological staining and lung function measurements demonstrated that collagen deposition and lung function decline were attenuated in mice deficient in either IL-13 or IL-4Rα-driven signaling compared with wild-type mice treated with bleomycin. Furthermore, our results demonstrated that IL-13 and IL-4Rα-driven signaling are involved in excessive migration of macrophages and fibroblasts. Notably, our findings demonstrated that IL-13-driven migration involves increased phospho-focal adhesion kinase signaling and F-actin polymerization. Importantly, in vivo findings demonstrated that IL-13 augments matrix metalloproteinase (MMP)-2 and MMP9 activity that has also been shown to increase migration and invasiveness of fibroblasts in the lungs during bleomycin-induced pulmonary fibrosis. Together, our findings demonstrate a pathogenic role for Th2-cytokine signaling that includes excessive migration and protease activity involved in severe fibrotic lung disease.

Clinical Evaluation of {sup 57}Co-labelled Bleomycin for Tumor Localization

Energy Technology Data Exchange (ETDEWEB)

Ryu, Yong Wun; Kim, Jang Hee; Lee, Jhin Oh [Korea Cancer Center Hospital, Seoul (Korea, Republic of)

1987-03-15

Investigation with {sup 57}Co-Bleomycin in patients with the various cancers and in tumor bearing animals are described. In the patients, {sup 57}Co-Bleomycin appears to be one of the useful tumor- seeking radiopharmaceuticals, and worth applicable to clinical uses. Labelled yield of {sup 57}Co-Bleo was about 97% by thin layer chromatography. The pyrogen free tests were performed to meet U.S.P. critical ranges. In clinical studies with {sup 57}Co-Bleo, 4 cases out of 5 patients with lung cancer, 2 cases among 3 thyroid cancer patients, and all 3 hepatoma patients showed positive tumor scans. The patients with stomach cancer, and the esophageal cancer showed false negative scintigraphy. A case with pulmonary tuberculosis showed a positive scan while liver abscess showed a negative picture. The merits of {sup 57}Co-Bleomycin scintigraphy seems to be its relatively high affinity to tumors and low radiation hazard in spite of long physical half life.

The use of 57Co-labeled bleomycin in the diagnosis of round lung images

International Nuclear Information System (INIS)

Vaillant, G.; Bertrand, A.; Nouel, J.P.

1975-01-01

As a result of its antimitotic nature, it has been affirmed that labeled bleomycin represents considerable progress in the diagnostic approach to the pulmonary intraparenchymatous round image. A comparative study of uptake of bleomycin, labeled with 57 Co, 67 Ga and 197 Hg, at the level of pulmonary intraparenchymatous round neoplastic foci, was performed on 15 ill subjects. The highest uptakes were obtained with labeled bleomycin. The long half-life of cobalt, however, necessitates extensive precautions to avoid contamination. This justifies the ongoing search for another tracer which can substitute for cobalt and has a shorter period. In addition, examination with cobalt should be reserved for very special cases [fr

Bleomycin toxicity post injection into craniopharyngioma | Norval ...

African Journals Online (AJOL)

Craniopharyngioma is a common suprasellar mass that is frequently encountered in radiology. These tumours are difficult to treat, with a combination of resection and radiation therapy having been the gold standard. Our case highlights a complication of a newer approach to treatment in which bleomycin is administered ...

/sup 51/Cr-bleomycin, a new oncophilic radiopharmaceutical. Pt. 1

Energy Technology Data Exchange (ETDEWEB)

Rembelska, M J; Liniecki, J

1982-04-01

A method was developed for labelling bleomycin with /sup 51/Cr. The complex was administered to mice (Swiss and C57-B1/6) bearing 5 transplantable tumours: Ehrlich ascites tumour, NK/Ly lymphoma, Lewis lung carcinoma, melanoma B-16, and Sarcoma 180. Activity concentration in neoplasms, blood and numerous organs was determined 12, 24 and 48 hrs after injection. An identical procedure was applied using /sup 58/Co-bleomycin as a reference oncophilic substance. Tumour/non-tumor ratios exceeding substantially unity were found for blood, muscle and bone indicating preferential accumulation of both /sup 58/Co and /sup 51/Cr in all the neoplasms tested. The ratios were lower (by a factor 2-3) for /sup 51/Cr than for /sup 58/Co; however, it is postulated that the gamma-quantum energy of /sup 51/Cr which is higher than that of the commonly used /sup 57/Co, should offset to some degree this difference when scintigraphic tumour detection in a patient is to be attempted. In conclusion, clinical trials with /sup 51/Cr-bleomycin, which is cheaper than its /sup 57/Co-counterpart, appear warranted.

Bleomycin toxicity post injection into craniopharyngioma

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Ivan Norval

2012-02-01

Full Text Available Craniopharyngioma is a common suprasellar mass that is frequently encountered in radiology. These tumours are difficult to treat, with a combination of resection and radiation therapy having been the gold standard. Our case highlights a complication of a newer approach to treatment in which bleomycin is administered into the tumour via a catheter, usually an Ommaya reservoir that is surgically placed.

Stimulation of toll-like receptor 2 with bleomycin results in cellular activation and secretion of pro-inflammatory cytokines and chemokines

International Nuclear Information System (INIS)

Razonable, Raymund R.; Henault, Martin; Paya, Carlos V.

2006-01-01

The clinical use of bleomycin results in systemic and pulmonary inflammatory syndromes that are mediated by the production of cytokines and chemokines. In this study, we demonstrate that cell activation is initiated upon the recognition of bleomycin as a pathogen-associated molecular pattern by toll-like receptor (TLR) 2. The THP1 human monocytic cell line, which constitutively expresses high levels of TLR2, secretes interleukin (IL)-1β, IL-8, and tumor necrosis factor (TNF)-α during bleomycin exposure. The TLR2-dependent nature of cell activation and cytokine secretion is supported by (1) the inability of TLR2-deficient human embryonic kidney (HEK) 293 cells to exhibit nuclear factor-kappa B (NF-κB) activation and secrete IL-8 in response to bleomycin; (2) the acquired ability of HEK293 to exhibit NF-κB activation and secrete IL-8 upon experimental expression of TLR2; and (3) the inhibition of cell activation in TLR2-expressing HEK293 and THP1 by anti-TLR2 monoclonal antibody. Collectively, these observations identify TLR2 activation as a critical event that triggers NF-κB activation and secretion of cytokines and chemokines during bleomycin exposure. Our in vitro findings could serve as a molecular mechanism underlying the pro-inflammatory toxicity associated with bleomycin. Whether bleomycin engages with other cellular receptors that results in activation of alternate signaling pathways and whether the TLR2-agonist activity of bleomycin contribute to its anti-neoplastic property deserve further study

Role of intralesional bleomycin in the treatment of complicated hemangiomas: prospective clinical study.

Science.gov (United States)

Omidvari, Shapour; Nezakatgoo, Nosrat; Ahmadloo, Niloofar; Mohammadianpanah, Mohammad; Mosalaei, Ahmad

2005-05-01

Hemangioma is the most common tumor of infancy. Although it has a basically benign nature and usually spontaneously regresses, a small percentage (5%) have complications that need treatment. Many different therapeutic modalities can be used in this tumor. To investigate the effect of a new method of treatment (intralesional bleomycin injection) in complicated hemangiomas. In the Department of Radiation Oncology at Nemazee Hospital in Shiraz, Iran, from April 1992 to October 1998, 32 patients with complicated hemangioma were treated with four to six courses of direct injection of bleomycin into the lesion. After a minimum follow-up of 6 years, there was 70 to 100% regression in 18 patients, 50 to 70% in 7 cases, and less than 50% reduction in 7 patients. Intralesional injection of bleomycin is an easy, safe, and effective therapeutic modality in complicated cutaneous hemangiomas.

Bleomycin Can Cleave an Oncogenic Noncoding RNA.

Science.gov (United States)

Angelbello, Alicia J; Disney, Matthew D

2018-01-04

Noncoding RNAs are pervasive in cells and contribute to diseases such as cancer. A question in biomedical research is whether noncoding RNAs are targets of medicines. Bleomycin is a natural product that cleaves DNA; however, it is known to cleave RNA in vitro. Herein, an in-depth analysis of the RNA cleavage preferences of bleomycin A5 is presented. Bleomycin A5 prefers to cleave RNAs with stretches of AU base pairs. Based on these preferences and bioinformatic analysis, the microRNA-10b hairpin precursor was identified as a potential substrate for bleomycin A5. Both in vitro and cellular experiments demonstrated cleavage. Importantly, chemical cleavage by bleomycin A5 in the microRNA-10b hairpin precursors occurred near the Drosha and Dicer enzymatic processing sites and led to destruction of the microRNA. Evidently, oncogenic noncoding RNAs can be considered targets of cancer medicines and might elicit their pharmacological effects by targeting noncoding RNA. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparison of gamma radiation and radiomimmetic chemical, bleomycin in leukocytes from certain genetic disorders

International Nuclear Information System (INIS)

Saraswathy, Radha

2004-01-01

Full text: To compare the frequency and distribution pattern of bleomycin and gamma radiation induced chromosomal aberrations in human genetic disorders. To study if the induced chromosomal break points are specific for specific human genetic disorders. Human genetics disorders such as; retinitis pigmentosa, retinoblastoma, xeroderma pigmentosa and gonadal dysgenesis were used in our study. Suitable controls were maintained. The frequency and distribution pattern of chromosomal break points in individual chromosomes were determined in lymphocytes exposed to 50r of gamma radiation and 10μg/ml of bleomycin for 3h at G2. In normal individuals none of the unirradiated leukocyte cultures of any syndrome showed any accountable number of chromosomal aberrations. The frequency of radiation induced chromosomal break points showed a non random distribution pattern and frequently clustered at some specific chromosome regions to form hot spots. Lack of linear-quadratic dose response was observed in the lymphocyte exposed to bleomycin in normal individual. The frequency of chromosomal aberrations in the whole genome for the genetic disorders were higher than the controls and a varying distribution pattern of bleomycin induced breaks per cell was observed

Enhancement of Bleomycin Sensitivity in Human Lung Cancer Cell ...

African Journals Online (AJOL)

Methods: The inhibitory effect of bleomycin on A549 cells was determined by incubating the cells for 24 h in different .... also include advantageous psychological effects such as .... cyclooxygenase-2 enzyme inhibitors: A rational advance?

Study of the cellular uptake and distribution of 57cobalt bleomycin in Ehrlich ascites tumor cells

International Nuclear Information System (INIS)

Metelmann, H.R.

1980-01-01

We investigated the dependence of the cellular uptake of 57 cobalt-bleomycin on the exposure time and on the dose. In addition we observed the influences due to the incubation temperature, to the growth phase of the tumor cells and due to the composition of the suspensory medium. In supplementary experiments we investigated the binding of the labelled cytostatic agent to erythrocytes, its adsorption to broken Ehrlich ascites tumor cells and the 57 cobalt-bleomycin outflow from pre-loaded intact Ehrlich ascites tumor cells. The 57 cobalt-bleomycin uptake of intact Ehrlich ascites tumor cells is determined by characteristic kinetics. Moreover, the erythrocytes and injured Ehrlich ascites tumor cells show a qualitatively similar graph of the 57 cobalt-bleomycin binding, which can clearly be distinguished from the kinetics found with intact Ehrlich ascites tumor cells. The uptake of this cytostatic agent depends on an unequivocal time-dose-temperature relationship. The transport mechanism of the 57 cobalt-bleomycin uptake was considered as endocytosis. An endocytosis-stimulating inducer could not be detected. However, we obtained indications that the cell-bound cytostatic agent is taken up in two compartments: on the cellular surface and in the interior of the cell. (orig./MG) [de

A Comparative Analysis of Saffron and Methylprednisolone on Bleomycin-Induced Pulmonary Fibrosis in Rats

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Mehrzad Bahtouee

2018-04-01

Full Text Available Background: The purpose of this study was to compare the effects of saffron and methylprednisolone on bleomycin-induced pulmonary fibrosis in rats. Methods: This study was conducted in Bushehr, southern Iran in 2017.The animals were divided into four groups of five rats each. Three groups were injected with a single intratracheal dose of bleomycin (5 mg/kg. The fourth group was administered with normal saline at the same volume (200 µl. Saffron extract dissolved in water was given to one group (100 mg /body weight orally while intraperitoneal injection of methylprednisolone (2.5 mg/kg injected to another one for 16 days. The rats were sacrificed 28 days following surgery and their right and left lungs were removed and washed for measuring lung indices, myeloperoxidase activities and finally histopathological examination. Results: Injection of bleomycin caused decrement of body weight aggravated by intraperitoneal methylprednisolone treatment. Lung indices were increased in the bleomycin-treated group compared with the control, while methylprednisolone, unlike saffron, had no preventive effects on it. Both saffron and methylprednisolone treatment prevented the increase in lung myeloperoxidase as a destructive enzyme. In addition, excessive collagen deposition and thickening of alveolar septa were significantly prevented with saffron treatment as compared to methylprednisolone injection following hematoxylin and eosin staining. Conclusion: Saffron with established antioxidant properties could prevent some detrimental effects in bleomycin-induced pulmonary fibrosis even more than methylprednisolone injection known as a standard therapy in this murine model. More investigations must be carried out to examine the beneficial or harmful effects of this remedy.

Contribution of cobalt 57 labelled bleomycin in the diagnosis of pulmonary round intraparenchymatous lesions

International Nuclear Information System (INIS)

Vaillant, G.; Bertrand, A.; Robert, J.; Hocquart, C.; Zuck, P.; Anthoine, D.; Lamy, P.

1975-01-01

One hundred and eleven patients with a round lesion within the lung parenchyma were submitted to a lung scan using cobalt 57 labelled bleomycin. In all cases, the diagnosis of benign or malignant disease was made definitely by bronchoscopy, fiber endoscopy, transparietal needle biopsy or thoracotomy. Out of 89 neoplasic foci, 87 took up labelled bleomycin with a fixation ratio greater than 13. On the other hand, the 22 benign round foci, except for the large silico-tuberculous nodule, remained silent on radio-isotope scanning. The great value of scanning using cobalt 57 labelled bleomycin in the detection of the malignant or benign nature of round images within the lung is emphasized, the clinical and radiological pre-operative diagnosis remains one of the most difficult in lung disease problems [fr

Variation in bleomycin hydrolase gene is associated with reduced survival after chemotherapy for testicular germ cell cancer

NARCIS (Netherlands)

de Haas, Esther C.; Zwart, Nynke; Meijer, Coby; Nuver, Janine; Boezen, H. Marike; Suurmeijer, Albert J. H.; Hoekstra, Harald J.; van der Steege, Gerrit; Sleijfer, Dirk Th.; Gietema, Jourik A.

2008-01-01

Purpose Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular

Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

Science.gov (United States)

Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

2016-01-01

Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.

Science.gov (United States)

Peng, Ruoqi; Sridhar, Sriram; Tyagi, Gaurav; Phillips, Jonathan E; Garrido, Rosario; Harris, Paul; Burns, Lisa; Renteria, Lorena; Woods, John; Chen, Leena; Allard, John; Ravindran, Palanikumar; Bitter, Hans; Liang, Zhenmin; Hogaboam, Cory M; Kitson, Chris; Budd, David C; Fine, Jay S; Bauer, Carla M T; Stevenson, Christopher S

2013-01-01

The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

Bleomycin induces molecular changes directly relevant to idiopathic pulmonary fibrosis: a model for "active" disease.

Directory of Open Access Journals (Sweden)

Ruoqi Peng

Full Text Available The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF, has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.

Photochemical Internalization of Bleomycin Before External-Beam Radiotherapy Improves Locoregional Control in a Human Sarcoma Model

International Nuclear Information System (INIS)

Norum, Ole-Jacob; Bruland, Oyvind Sverre; Gorunova, Ludmila; Berg, Kristian

2009-01-01

Purpose: The aim of this study was to explore the tumor growth response of the combination photochemical internalization and external-beam radiotherapy. Photochemical internalization is a technology to improve the utilization of therapeutic macromolecules in cancer therapy by photochemical release of endocytosed macromolecules into the cytosol. Methods and Materials: A human sarcoma xenograft TAX-1 was inoculated subcutaneously into nude mice. The photosensitizer AlPcS 2a and bleomycin were intraperitoneally administrated 48 h and 30 min, respectively, before diode laser light exposure at 670 nm (20 J/cm 2 ). Thirty minutes or 7 days after photochemical treatment, the animals were subjected to 4 Gy of ionizing radiation. Results: Using photochemical internalization of bleomycin as an adjunct to ionizing radiation increased the time to progression for the tumors from 17 to 33 days as compared with that observed with photodynamic therapy combined with ionizing radiation as well as for radiochemotherapy with bleomycin. The side effects observed when photochemical internalization of bleomycin was given shortly before ionizing radiation were eliminated by separating the treatment modalities in time. Conclusion: Photochemical internalization of bleomycin combined with ionizing radiation increased the time to progression and showed minimal toxicity and may therefore reduce the total radiation dose necessary to obtain local tumor control while avoiding long-term sequelae from radiotherapy.

Radiotherapy using bleomycin, ACNU, and vincristine for malignant brain tumors

Energy Technology Data Exchange (ETDEWEB)

Tanaka, Ryuichi; Murakami, Naoto; Suzuki, Yasuo; Takeda, Norio; Arai, Hiroyuki; Konno, Kimikazu; Tanimura, Ken-ichi

1984-08-01

Radiotherapy combined with bleomycin, ACNU, and vincristine was performed on 106 patients with malignant brain tumors. The treatment protocol was based on the concept of combination chemotherapy or chemoradiotherapy and synchronized chemoradiotherapy. For the purpose of synchronized chemoradiotherapy, bleomycin, ACNU, and vincristine were used as G/sub 2/M cell cycle phase accumulator, and radiation and bleomycin were used as agents to which G/sub 2/M or G/sub 2/ phase cells are sensitive. The short-term results of the chemoradiotherapy were evaluated by measuring tumor regression by computerized tomography (CT) in 80 patients with evaluable CT lesions. The response rate was 67% (6/9) for astrocytoma, 29% (7/24) for anaplastic glioma, 67% (4/6) for pontine glioma, 100%(5/5) for malignant lymphoma, 100% (8/8) for germ cell tumors and 65% (15/23) for metastatic tumors. A control study was performed using radiation alone on another 18 patients with metastatic tumors, and the response rate was 50% (9/18). Among the 106 patients treated with chemoradiotherapy, the major side effects observed were as follows: leukopenia in 33 patients (31%), thrombocytopenia in 14 (13%), paralytic ileus in 2 (2%), peripheral neuropathy in 2 (2%), and lung fibrosis in 1 (1%). Contrary to expectation, low-grade astrocytomas responded much better to the chemoradiotherapy than high-grade astrocytomas.

Preparation of phase I of clinical testing of kit for bleomycin labelling with 57Co

International Nuclear Information System (INIS)

Brousil, J.; Svihovcova, P.; Seblova, J.; Raban, P.

1986-01-01

Experience is described gained in preclinical trials with a kit for bleomycin labelling with 57 Co, of original manufacture. The 57 Co-labelled bleomycin shows a positive tumor imaging potential. As against other labelled bleomycins described in the literature, it best meets the requirements of imaging tumors in the highest possible number of tissues and of good differentiation of tumors from the adjacent tissues. The three-component kit uses a phosphate buffer which makes it more suitable for i.v. administration and significantly increases bleomycin stability. The kit was found to show advantages over previously described radiopharmaceuticals of this type in that that it can quickly be reconstituted immediately prior to the application and that it is significantly cheaper to use, namely 140-fold cheaper than most other similar radiopharmaceuticals. Its disadvantage, i.e., the long half-life is balanced with a short biological half-life; within 24 hours following application 80 to 90% of the applied activity was found to be excreted from the organism. The short biological half-life is also beneficial for the patient in that the radiation load of the patient is 10 times lower than in the application of 67 Ga. (L.O.)

The growth of hemopoietic precursor cells (CFU-C) of adriamycin-treated or whole-body-irradiated dogs with or without bleomycin in vitro

International Nuclear Information System (INIS)

Volkamer, A.

1984-01-01

The effect of the cytostatic drug bleomycin (BLM) on the growth of canine hemopoietic stem-cells in vitro was tested in order to detect a stem-cell deficiency after in vivo-treatment with adriamycin (ADM) or whole-body-irradiation. Stem-cells damaged by irradiation or cytostatics are suppressed by bleomycin-induced strand-breaks in vitro. After stem-cell recovery the increased sensitivity towards bleomycin can no longer be detected. After whole-body-irradiation and cytostatical treatment the stem-cells who remained intact have to compensate the quantitative change of the stem-cells by increased proliferation. The proliferating cells show a particular bleomycin-sensitivity. Especially after irradiation a long persistence of the bleomycin-sensitivity can be reckoned on. (orig./MG) [de

Irradiation combined with Bleomycin treatment of synchronized cells in culture under oxic and hypoxic conditions

International Nuclear Information System (INIS)

Midander, J.; Littbrand, B.; Edsmyr, F.

1980-01-01

Bleomycin-treated cells are sensitized to radiation delivered under oxic conditions both in the early S and G 2 phases of the cycle, irradiated under hypoxic conditions, sensitization occurs only in the early S phase. This difference in the sensitizing effect of the drug is discussed in regard to the possible clinical advantages of a combined treatment of tumours with irradiation and Bleomycin. (Auth.)

Bleomycin-Induced Pulmonary Changes on Restaging Computed Tomography Scans in Two Thirds of Testicular Cancer Patients Show No Correlation With Fibrosis Markers.

Science.gov (United States)

den Hollander, Martha W; Westerink, Nico-Derk L; Lubberts, Sjoukje; Bongaerts, Alfons H H; Wolf, Rienhart F E; Altena, Renska; Nuver, Janine; Oosting, Sjoukje F; de Vries, Elisabeth G E; Walenkamp, Anna M E; Meijer, Coby; Gietema, Jourik A

2016-08-01

In metastatic testicular cancer patients treated with bleomycin, etoposide, and cisplatin (BEP) chemotherapy, bleomycin-induced pneumonitis is a well-known and potentially fatal side effect. We sought to determine the prevalence of lesions as signs of bleomycin-induced pulmonary changes on restaging computed tomography (CT) scans after treatment and to ascertain whether fibrosis markers were predictive of these changes. This prospective nonrandomized cohort study included metastatic testicular cancer patients, 18-50 years of age, treated with BEP chemotherapy. Restaging CT scans were examined for lesions as signs of bleomycin-induced pulmonary changes by two independent radiologists and graded as minor, moderate, or severe. Plasma samples were collected before, during, and after treatment and were quantified for transforming growth factor-β1 (TGF-β1), growth differentiation factor-15 (GDF-15), and high-sensitivity C-reactive protein (hs-CRP). In total, 66 patients were included: forty-five (68%) showed signs of bleomycin-induced pulmonary changes on the restaging CT scan, 37 of which were classified as minor and 8 as moderate. No differences in TGF-β1, GDF-15, or hs-CRP plasma levels were found between these groups. Bleomycin-induced pulmonary changes are common on restaging CT scans after BEP chemotherapy for metastatic testicular cancer. Changes in TGF-β1, GDF-15, and hs-CRP plasma levels do not differ between patients with and without radiological lesions as signs of bleomycin-induced pulmonary changes and are therefore not helpful as predictive biomarkers. Bleomycin-induced pneumonitis (BIP) is a well-known and potentially fatal side effect in metastatic testicular cancer patients treated with bleomycin, etoposide, and cisplatin chemotherapy. Currently, the decision to discontinue bleomycin administration is made during treatment and is based on clinical signs. An upfront or early marker or biomarker that identifies patients likely to develop BIP would be

Bleomycin Induces Molecular Changes Directly Relevant to Idiopathic Pulmonary Fibrosis: A Model for “Active” Disease

Science.gov (United States)

Tyagi, Gaurav; Phillips, Jonathan E.; Garrido, Rosario; Harris, Paul; Burns, Lisa; Renteria, Lorena; Woods, John; Chen, Leena; Allard, John; Ravindran, Palanikumar; Bitter, Hans; Liang, Zhenmin; Hogaboam, Cory M.; Kitson, Chris; Budd, David C.; Fine, Jay S.; Bauer, Carla MT.; Stevenson, Christopher S.

2013-01-01

The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease. PMID:23565148

The pathogenesis of bleomycin-induced lung injury in animals and its applicability to human idiopathic pulmonary fibrosis.

Science.gov (United States)

Williamson, James D; Sadofsky, Laura R; Hart, Simon P

2015-03-01

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown etiology, for which there is no curative pharmacological therapy. Bleomycin, an anti-neoplastic agent that causes lung fibrosis in human patients has been used extensively in rodent models to mimic IPF. In this review, we compare the pathogenesis and histological features of human IPF and bleomycin-induced pulmonary fibrosis (BPF) induced in rodents by intratracheal delivery. We discuss the current understanding of IPF and BPF disease development, from the contribution of alveolar epithelial cells and inflammation to the role of fibroblasts and cytokines, and draw conclusions about what we have learned from the intratracheal bleomycin model of lung fibrosis.

Preparation and quality control of radiolabelled cobalt-57 bleomycins for oncological studies

International Nuclear Information System (INIS)

Jalilian, A. R.; Rowshanfarzad, P.; Moafian, J.; Ensaf, M. R.; Sabet, M.

2007-01-01

[ 55 Co] bleomycin has been widely used in ontological studies. Due to relative short half life of cobalt-55, optimization and feasibility studies for determination of the best labeling conditions is preferably performed using cobalt-57. In this study, the optimization of complexation conditions for time, temperature and ligand concentration were performed. The best labeling yield was obtained at room temperature in pH of 4-7, using 0.4 mCi of 57 CoCl 2 with 0.3mg of BLM in 30 minutes. The final radiopharmaceutical solution underwent common quality control tests, validating our future studies for animal scanning studies using [ 55 Co]bleomycin complex

Combined local and systemic bleomycin administration in electrochemotherapy to reduce the number of treatment sessions

International Nuclear Information System (INIS)

Maglietti, Felipe; Tellado, Matias; Olaiz, Nahuel; Michinski, Sebastian; Marshall, Guillermo

2016-01-01

Electrochemotherapy (ECT), a medical treatment widely used in human patients for tumor treatment, increases bleomycin toxicity by 1000 fold in the treated area with an objective response rate of around 80%. Despite its high response rate, there are still 20% of cases in which the patients are not responding. This could be ascribed to the fact that bleomycin, when administered systemically, is not reaching the whole tumor mass properly because of the characteristics of tumor vascularization, in which case local administration could cover areas that are unreachable by systemic administration. We propose combined bleomycin administration, both systemic and local, using companion animals as models. We selected 22 canine patients which failed to achieve a complete response after an ECT treatment session. Eleven underwent another standard ECT session (control group), while 11 received a combined local and systemic administration of bleomycin in the second treatment session. According to the WHO criteria, the response rates in the combined administration group were: complete response (CR) 54% (6), partial response (PR) 36% (4), stable disease (SD) 10% (1). In the control group, these were: CR 0% (0), PR 19% (2), SD 63% (7), progressive disease (PD) 18% (2). In the combined group 91% objective responses (CR+PR) were obtained. In the control group 19% objective responses were obtained. The difference in the response rate between the treatment groups was significant (p < 0.01). Combined local and systemic bleomycin administration was effective in previously to ECT non responding canine patients. The results indicate that this approach could be useful and effective in specific population of patients and reduce the number of treatment sessions needed to obtain an objective response

DNA degradation by bleomycin: evidence for 2'R-proton abstraction and for C-O bond cleavage accompanying base propenal formation

International Nuclear Information System (INIS)

Ajmera, S.; Wu, J.C.; Worth, L. Jr.; Rabow, L.E.; Stubbe, J.; Kozarich, J.W.

1986-01-01

Reaction of poly(dA-[2'S- 3 H]dU) with activated bleomycin yields [ 3 H] uracil propenal that completely retains the tritium label. In contrast, the authors have previously shown that reaction of poly(dA-[2'R- 3 H]dU) with activated bleomycin affords unlabeled uracil propenal. They have also prepared both cis- and trans-thymine propenals by chemical synthesis and have observed that the trans isomer is the exclusive product of the bleomycin reaction. Moreover, the cis isomer was found to be stable to the conditions of bleomycin-induced DNA degradation. Taken together, these results establish that the formation of trans-uracil propenal occurs via an anti-elimination mechanism with the stereospecific abstraction of the 2R proton. The question of phosphodiester bond cleavage during base propenal formation has also been addressed by the analysis of the fate of oxygen-18 in poly(dA-[3'- 18 O]dT) upon reaction with activated bleomycin. The 5'-monophosphate oligonucleotide ends produced from thymine propenal formation have been converted to inorganic phosphate by the action of alkaline phosphatase, and the phosphate has been analyzed for 18 O content by 31 P NMR spectroscopy. The oxygen-18 is retained in the inorganic phosphate, establishing that the formation of thymine propenal by activated bleomycin proceeds with C-O bond cleavage at the 3-position

Tumor scanning with /sup 57/Co-bleomycin

Energy Technology Data Exchange (ETDEWEB)

Nakano, S; Hasegawa, Y; Matsuda, Minoru; Ho, T; Doi, O [Osaka Prefectural Center for Adult Diseases (Japan)

1975-06-01

The clinical application of /sup 57/Co-bleomycin as a tumor scanning radiopharmaceutical was firstly reported by Nouel and Maeda respectively. The authors conducted studies on the diagnostic significance of this tumor scanning agent and presented the results obtained in 40 patients with malignant and non malignant lesions. Six hours and 24 hours after the injection of 500 ..mu..Ci of /sup 57/Co-bleomycin, scintigrams were taken with a 3-inch scintiscanner. Positive scans were found in 20 out of 36 patients with various malignant tumors. Of 20 patients with lung cancer, positive scans were obtained in 17 cases (85%) and of 6 with breast cancer, 3 cases showed positive scans. False negative scans were obtained in another 10 cases of malignant tumors (3 cases of thyroid carcinoma, 4 cases of hepatoma, and 1 case each of gastric carcinoma, peritoneal carcinomatosis, and reticulum cell sarcoma). Of 4 patients with non malignant disease, one case of pulmonary tuberculosis showed a positive scan. In 8 cases of lung cancer and 6 of breast cancer, the relationship between the size of the excised tumor and the scintigram findings was studied. The smallest tumors detected by scintigram were 2 cm in lung cancer and 3.2 cm in breast cancer.

Randomized phase III study comparing paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer

DEFF Research Database (Denmark)

de Wit, Ronald; Skoneczna, Iwona; Daugaard, Gedske

2012-01-01

To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC)....

51Cr-bleomycin in the diagnosis of tumours of the chest

International Nuclear Information System (INIS)

Brykalski, D.; Liniecki, J.; Dobek, J.; Pertynski, T.; Fajndt, S.; Studniarek, M.; Durski, K.; Mussur, M.; Akademia Medyczna, Lodz; Akademia Medyczna, Lodz; Osrodek Onkologiczny, Lodz

1985-01-01

51 Cr-bleomycin was used for the scintigraphic diagnosis of primary and secondary tumours of the thorax. The study was based on observations in 104 patients. The scintigraphy was performed using a gamma camera coupled to an on-line computer. Active lesions were scored using a semiquantitative scale of scores 0 to 5. Images were subdivided into 222 regions considered. In 72 of these, the presence of disease was diagnosed (64 malignant, 8 non-malignant) and 150 regions were classified as free from disease. At the decision threshold of score 2, over-all sensitivity and specificity of the scintigraphic detection of malignant tumours amounted to 97 and 79%, respectively. Inflammatory changes displaced some detectable accumulation of 51 Cr-bleomycin but scores attributed to these lesions did not exceed the value of 2. (orig.) [de

Prevention of Pulmonary Fibrosis via Trichostatin A (TSA) in Bleomycin Induced Rats.

Science.gov (United States)

Ye, Qing; Li, Yanqin; Jiang, Handong; Xiong, Jianfei; Xu, Jiabo; Qin, Hui; Liu, Bin

2014-10-20

To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A (TSA)on bleomycin-induced pulmonary fibrosis. To investigate the effects of non selective histone deacetylase inhibitors Trichostatin A ( TSA ) on HDAC2, p-SMAD2, HDAC2 mRNA, SMAD2mRNA in pulmonary fibrosis rats and investigate impossible mechanism. 46 SPF level male SD rats were randomly divided into four groups: ten for normal control group, fourteen for model control group I, twelve for model control group II and ten for treatment group. Rat pulmonary fibrosis was induced by bleomycin(5mg/kg) via single intratracheal perfusion in the two model control groups and treatment group. Normal control mice were instilled with a corresponding volume of 0.9% saline intratracheally. Treatment group was treated by the dilution of TSA 2mg/kg DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day ,once a day for three days. Model control group II was treated by the dilution of DMSO 60ul and0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. Model control group I and normal control group were treated by 0.9% saline 1.2ml intraperitoneal injection from the next day once a day for three days. All the animals were sacrificed on the 21 day after modeling. The pathological changes were observed by hematoxylin and eosin(HE)stain and masson trichrome stain. The expression of HDAC2 mRNA,SMAD2 mRNA were measured by real-time PCR. The protein level of HDAC2 and p-SMAD2 in serum was measured by Western blot. The pulmonary fibrosis in treatment group were significantly alleviated compared to the two model control groups (P0.05). Western blot indicated that the protein level of HDAC2 and p-SMAD2 in serum increased in the two model control groups compared with normal control group(P0.05). Non selective histone deacetylase inhibitors of Trichostatin A (TSA) can reduce the bleomycin induced pulmonary fibrosis in rats. TSA attenuates pulmonary

The role of bleomycin combination in radiation therapy for squamous cell carcinoma in the oral cavity

International Nuclear Information System (INIS)

Masaki, Norie

1986-01-01

In an effort to improve tumor control by radiation therapy, a treatment regimen consisting of concurrent combination of bleomycin (90 mg/3 weeks) and radiation (30 Gy/3 weeks) was applied. Between 1972 and 1981, 287 patients with squamous cell carcinoma in the oral cavity were subjected to this bleomycin-radiation combination regimen. All except 4 patients experienced marked response after treatment using the bleomycin-radiation combination alone. One hundred thirty-four patients (47 %) obtained CR and 149 (53 %) PR. Higher CR rates were obtained in patients with carcinoma of the lower gum (62 %), of the upper gum (68 %), and of the cheek mucosa (43 %), compared to patients with carcinoma of the floor of the mouth (21 %), and of the tongue (15 %). In each of the tumor sites, small lesions (T1, T2) obtained higher CR rates, compared with large lesions (T3, T4). Of the 134 patients who experienced CR, 83 were observed without any further treatment after bleomycin-radiation combination alone. Local recurrence-free rates of these patients were 72 % for T1, T2 lesions and 48 % for T3, T4 lesions. Local control rates were increased to 85 % and 78 %, respectively, with successful salvage treatment involving surgery or interstitial radiotherapy for post-irradiation failures. (author)

Local delivery of biodegradable pirfenidone nanoparticles ameliorates bleomycin-induced pulmonary fibrosis in mice

Science.gov (United States)

Trivedi, Ruchit; Redente, Elizabeth F.; Thakur, Ashish; Riches, David W. H.; Kompella, Uday B.

2012-12-01

Our purpose was to assess sustained delivery and enhanced efficacy of pirfenidone-loaded nanoparticles after intratracheal instillation. Poly(lactide-co-glycolide) nanoparticles containing pirfenidone (NPs) were prepared and characterized. Biodistribution of NPs and solution was assessed using LC-MS after intratracheal administration in C57Bl/6 mice at 3 and 24 h and 1 week post-administration. Efficacy was tested in C57Bl/6 mice in a bleomycin-induced pulmonary fibrosis model. Mice received 10 μg pirfenidone intratracheally in solution or NPs, once a week, for 3 weeks after bleomycin administration. Drug effects were monitored on day 28. Lung hydroxyproline content, total number of cells, and numbers of macrophages, lymphocytes, and neutrophils in bronchoalveolar lavage (BAL) were assessed. Numbers of macrophages, lymphocytes, and neutrophils were assessed in the lung as well. NPs sustained significantly higher levels of pirfenidone in the lungs and BAL at 24 h and 1 week, compared to the solution group. Pirfenidone solution and NPs significantly reduced hydroxyproline levels by 57 and 81%, respectively, compared to bleomycin alone. At the end of 4 weeks, BAL cellularity was reduced by 25.4% and 56% with solution and NP treatment, respectively. The numbers of lymphocytes and neutrophils in the BAL were also reduced by 58.9 and 82.4% for solution and 74.5% and 89.7% for NPs, respectively. The number of inflammatory macrophages in the lung was reduced by 62.8% and the number of neutrophils was reduced by 59.1% in the NP group and by 37.7% and 44.5%, respectively, in the solution group, compared to bleomycin alone. In conclusion, nanoparticles sustain lung pirfenidone delivery and enhance its anti-fibrotic efficacy.

Combined local and systemic bleomycin administration in electrochemotherapy to reduce the number of treatment sessions

Directory of Open Access Journals (Sweden)

Maglietti Felipe

2016-03-01

Full Text Available Electrochemotherapy (ECT, a medical treatment widely used in human patients for tumor treatment, increases bleomycin toxicity by 1000 fold in the treated area with an objective response rate of around 80%. Despite its high response rate, there are still 20% of cases in which the patients are not responding. This could be ascribed to the fact that bleomycin, when administered systemically, is not reaching the whole tumor mass properly because of the characteristics of tumor vascularization, in which case local administration could cover areas that are unreachable by systemic administration.

Radiogenic male breast cancer with in vitro sensitivity to ionizing radiation and bleomycin

International Nuclear Information System (INIS)

Greene, M.H.; Goedert, J.J.; Bech-Hansen, N.T.; McGuire, D.; Paterson, M.C.; Fraumeni, J.F. Jr.

1983-01-01

A cytogenetically normal man with gynecomastia and a family history of diverse cancers developed adenocarcinoma of the breast 30 years following thymic irradiation. In vitro experiments measuring colony-forming ability of cultured skin fibroblasts from family members implied that the patient had a small but significant increase in sensitivity to ionizing radiation, and a moderate increase in sensitivity to bleomycin, a radiomimetic drug. Enhanced radiosensitivity of fibroblasts from the patient's mother, and bleomycin sensitivity of fibroblasts from the sister suggested, but did not prove, that genetic susceptibility affected the risk of radiogenic cancer in this individual. In vitro studies of cancer-prone kindreds are a useful research strategy in delineating mechanisms of carcinogenesis

Variation in the HFE gene is associated with the development of bleomycin-induced pulmonary toxicity in testicular cancer patients.

Science.gov (United States)

van der Schoot, Gabriela G F; Westerink, Nico-Derk L; Lubberts, Sjoukje; Nuver, Janine; Zwart, Nynke; Walenkamp, Annemiek M E; Wempe, Johan B; Meijer, Coby; Gietema, Jourik A

2016-05-01

Bleomycin and cisplatin are of key importance in testicular cancer treatment. Known potential serious adverse effects are bleomycin-induced pulmonary toxicity (BIP) and cisplatin-induced renal toxicity. Iron handling may play a role in development of this toxicity. Carriage of allelic variants of the HFE gene induces altered iron metabolism and may contribute to toxicity. We investigated the association between two common allelic variants of the HFE gene, H63D and C282Y, with development of pulmonary and renal toxicity during and after treatment with bleomycin- and cisplatin-containing chemotherapy. In 369 testicular cancer patients treated with bleomycin and cisplatin at the University Medical Center Groningen between 1978 and 2006, H63D and/or C282Y genotypes were determined with an allelic discrimination assay. Data were collected on development of BIP, pulmonary function parameters, renal function, and survival. BIP developed more frequently in patients who were heterozygote (16 in 75, 21%) and homozygote (2 in 4, 50%) for the H63D variant, compared with those who had the HFE wild-type gene (31 in 278, 11%) (p = 0.012). Overall survival, testicular cancer-related survival, and change in renal function were not associated with the H63D variant. We observed an association between presence of one or both H63D alleles and development of BIP in testicular cancer patients treated with bleomycin combination chemotherapy. In patients heterozygote and homozygote for the H63D variant, BIP occurred more frequently compared with wild-type patients. When validated and confirmed, HFE H63D genotyping may be used to identify patients with increased risk for pulmonary bleomycin toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Radio-isotope scanning using labelled bleomycin in positive and differential diagnosis of primary and secondary malignant pulmonary lesions

International Nuclear Information System (INIS)

Robert, J.; Bertrand, A.; Nouel, J.P.; Witz, H.

1975-01-01

A lung scan using bleomycin labelled with cobalt 57 was carried out in 308 patients representing 191 primary malignant tumours, 48 pulmonary metastases and 69 benign lesions. The primary and secondary malignant lesions always gave rise to a hyperactive focus except in 8 cases of primary lung tumour. The negative examination may be explained, either by the small size of the lesion or by radiotherapy in progress. Among the benign lesions, only advanced tuberculosis and very inflammatory lung diseases frequently took up labelled bleomycin (15 hyperactive foci out of 69 benign lesions). Quantitative measurements, i.e. ratio of the lesional activity/activity of healthy lung tissue, were carried out in all patients. The malignant lesions were usually more active than the benign lesions. There was no definite correlation between the uptake of labelled bleomycin and the histological nature of the lesion. However, undifferentiated and anaplastic carcinomas were often more active. One should emphasize that these results show that a hyperactive focus has a 94% chance of being a carcinoma. The absence of bleomycin uptake means that there is a 92% chance of a benign lesion [fr

Esophageal cancer treated by low dose irradiation, crescendo cisplatin and bleomycin polyacrylate pasta

International Nuclear Information System (INIS)

Mishina, Hitoshi; Okuyama, Shinichi; Lim, In-Su; Yamagata, Rin; Taima, Tadashi

1983-01-01

Eight patients with esophageal cancer were treated by a new treatment schedule consisting of low dose irradiation, crescendo cisplatin and bleomycin polyacrylate pasta. As monitored endoscopically, therapeutic responses were satisfactory : seven out of 8 patients have survived for a range of 3 to 20 months and still active at work or cancer-free. However, one patient suffered from a second malignancy of adenocarcinoma of the upper esophagus different from the initial squamous cell carcinoma at the lower esophagus which had successfully been treated 3 months before. The present therapeutic design aims at treatment of lymphatic spreads in the adjacent structures as well as the original tumor in the esophagus and submucosal invasions. It is basically a consecutive, multimodal integration of selective concentration of therapeutic effects (extensive radiotherapy, topical application of bleomycin polyacrylate pasta, lymphatic chasing with colloidal bleomycin, and spatial concentration of cisplatin as the result of radiation-induced inflammation), perpetuation of the repairable DNA damage, and biological amplifications (protection against esophageal perforation with polyacrylate coating, and specific cancer cell recruitment). Application of the present theraeputic design is being expanded to the treatment of cancer of other specific sites such as the head and neck tumors and rectal cancer with undeniable prospects. (author)

Esophageal cancer treated by low dose irradiation, crescendo cisplatin and bleomycin polyacrylate pasta

International Nuclear Information System (INIS)

Mishina, Hitoshi; Okuyama, Shinichi; Lin, In-Su; Yamagata, Rin; Taima, Tadashi

1982-01-01

Eight patients with esophageal cancer were treated by a new treatment schedule consisting of low dose irradiation, crescendo cisplatin and bleomycin polyacrylate pasta. As monitored endoscopically, their therapeutic responses were satisfactory, and seven out of the eight survived for a range of 3 to 18 months and still active at work or ''cancer-free''. The seventh of the eight suffers from a second malignancy of adenocarcinoma of the cardia, different from the initial squamous cell carcinoma at the lower esophagus which had successfully been treated 3 months before. The present therapeutic design aims at treatment of lymphatic spreads in the adjacent structures as well as the original tumor in the esophagus and submucosal invasions. It is basically a consecutive, multimodal integration of selective concentration of therapeutic effects (extensive radiotherapy, topical application of bleomycin polyacrylate pasta, lymphatic chasing with colloidal bleomycin, and spatial concentration of cisplatin as the result of radiation-induced inflammations), perpetuation of the repairable DNA damage, and biological amplifications (protection against esophageal perforation with polyacrylate coating, and specific cancer cell recruitment). Application of the present therapeutic design is being expanded to treatment of cancer at other specific sites such as the head and neck tumors and rectal cancer with undeniable prospects. (author)

The anti-tumor drug bleomycin preferentially cleaves at the transcription start sites of actively transcribed genes in human cells.

Science.gov (United States)

Murray, Vincent; Chen, Jon K; Galea, Anne M

2014-04-01

The genome-wide pattern of DNA cleavage at transcription start sites (TSSs) for the anti-tumor drug bleomycin was examined in human HeLa cells using next-generation DNA sequencing. It was found that actively transcribed genes were preferentially cleaved compared with non-transcribed genes. The 143,600 identified human TSSs were split into non-transcribed genes (82,596) and transcribed genes (61,004) for HeLa cells. These transcribed genes were further split into quintiles of 12,201 genes comprising the top 20, 20-40, 40-60, 60-80, and 80-100 % of expressed genes. The bleomycin cleavage pattern at highly transcribed gene TSSs was greatly enhanced compared with purified DNA and non-transcribed gene TSSs. The top 20 and 20-40 % quintiles had a very similar enhanced cleavage pattern, the 40-60 % quintile was intermediate, while the 60-80 and 80-100 % quintiles were close to the non-transcribed and purified DNA profiles. The pattern of bleomycin enhanced cleavage had peaks that were approximately 200 bp apart, and this indicated that bleomycin was identifying the presence of phased nucleosomes at TSSs. Hence bleomycin can be utilized to detect chromatin structures that are present at actively transcribed genes. In this study, for the first time, the pattern of DNA damage by a clinically utilized cancer chemotherapeutic agent was performed on a human genome-wide scale at the nucleotide level.

Synthesis of samarium binding bleomycin - a possible NCT radiosensitizer

Energy Technology Data Exchange (ETDEWEB)

Mendes, B.M., E-mail: bmm@cdtn.b [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Mendes, T.M.; Campos, T.P.R., E-mail: campos@nuclear.ufmg.b [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil)

2011-07-01

Bleomycin (BLM) is a drug that has attractive features for the development of a new radiopharmaceutical, particularly with regard to neutron capture therapy (NCT) sensitized by Sm-149. It has the ability to chelate many metal ions. In vitro studies have shown that up to 78% of BLM present in a cell is accumulated inside the nucleus or in the nuclear membrane. In addition, this drug has higher affinity for tumor tissues than for normal tissues. Radioactive isotopes carried by this antibiotic would be taken preferentially to one important cellular targets DNA. Besides, BLM displays intrinsic anti-tumor activity - it is a chemotherapic antibiotic clinically used against some cancers. This study aimed to obtain bleomycin molecules bound to samarium (BLM-Sm) for NCT studies in vitro and in vivo. The binding technique employed in this work has great simplicity and low cost. Thin layer chromatography, high performance liquid chromatography, fast protein liquid chromatography and analysis by ICP-AES were applied to verify the binding molecule. ICP-AES results showed the presence of samarium in the sample peaks related to BLM-Sm. However, efficiency and stability of this bond needs to be investigated. (author)

Synthesis of samarium binding bleomycin - a possible NCT radiosensitizer

International Nuclear Information System (INIS)

Mendes, B.M.; Mendes, T.M.; Campos, T.P.R.

2011-01-01

Bleomycin (BLM) is a drug that has attractive features for the development of a new radiopharmaceutical, particularly with regard to neutron capture therapy (NCT) sensitized by Sm-149. It has the ability to chelate many metal ions. In vitro studies have shown that up to 78% of BLM present in a cell is accumulated inside the nucleus or in the nuclear membrane. In addition, this drug has higher affinity for tumor tissues than for normal tissues. Radioactive isotopes carried by this antibiotic would be taken preferentially to one important cellular targets DNA. Besides, BLM displays intrinsic anti-tumor activity - it is a chemotherapic antibiotic clinically used against some cancers. This study aimed to obtain bleomycin molecules bound to samarium (BLM-Sm) for NCT studies in vitro and in vivo. The binding technique employed in this work has great simplicity and low cost. Thin layer chromatography, high performance liquid chromatography, fast protein liquid chromatography and analysis by ICP-AES were applied to verify the binding molecule. ICP-AES results showed the presence of samarium in the sample peaks related to BLM-Sm. However, efficiency and stability of this bond needs to be investigated. (author)

Pingyangmycin and Bleomycin Share the Same Cytotoxicity Pathway

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Yanli He

2016-06-01

Full Text Available Pingyangmycin is an anticancer drug known as bleomycin A5 (A5, discovered in the Pingyang County of Zhejiang Province of China. Bleomycin (BLM is a mixture of mainly two compounds (A2 and B2, which is on the World Health Organization’s list of essential medicines. Both BLM and A5 are hydrophilic molecules that depend on transporters or endocytosis receptors to get inside of cells. Once inside, the anticancer activities rely on their abilities to produce DNA breaks, thus leading to cell death. Interestingly, the half maximal inhibitory concentration (IC50 of BLMs in different cancer cell lines varies from nM to μM ranges. Different cellular uptake, DNA repair rate, and/or increased drug detoxification might be some of the reasons; however, the molecules and signaling pathways responsible for these processes are largely unknown. In the current study, we purified the A2 and B2 from the BLM and tested the cytotoxicities and the molecular mechanisms of each individual compound or in combination with six different cell lines, including a Chinese hamster ovary (CHO cell line defective in glycosaminoglycan biosynthesis. Our data suggested that glycosaminoglycans might be involved in the cellular uptake of BLMs. Moreover, both BLM and A5 shared similar signaling pathways and are involved in cell cycle and apoptosis in different cancer cell lines.

Antifibrotic effects of crocetin in scleroderma fibroblasts and in bleomycin-induced sclerotic mice

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Yinghua Song

2013-10-01

Full Text Available OBJECTIVE: To investigate the antifibrotic effects of crocetin in scleroderma fibroblasts and in sclerotic mice. METHODS: Skin fibroblasts that were isolated from three systemic scleroderma (SSc patients and three healthy subjects were treated with crocetin (0.1, 1 or 10 μM. Cell proliferation was measured with an MTT assay. Alpha-smooth muscle actin was detected via an immunohistochemical method. Alpha 1 (I procollagen (COL1A1, alpha 1 (III procollagen (COL3A1, matrix metalloproteinase (MMP-1 and tissue inhibitor of matrix metalloproteinase (TIMP-1 mRNA levels were measured using real-time PCR. SSc mice were established by the subcutaneous injection of bleomycin. Crocetin (50 mg/kg/d was injected intraperitoneally for 14 days. Dermal thickness and lung fibrosis were assessed with Masson's trichrome staining. Plasma ET-1 was detected with an enzyme-linked immunosorbent assay (ELISA. Skin and lung ET-1 and COL1A1 mRNA levels were measured via real-time PCR. RESULTS: Crocetin inhibited the proliferation of SSc and normal fibroblasts, an effect that increased with crocetin concentration and incubation time. Crocetin decreased the expression of α-SMA and the levels of mRNA for COL1A1, COL3A1 and matrix metalloproteinase-1, while crocetin increased TIMP-1 mRNA levels in both SSc and normal fibroblasts. Skin and lung fibrosis was induced, and the levels of ET-1 in the plasma, skin and lungs were elevated in bleomycin-injected mice. Crocetin alleviated the thickening of the dermis and lung fibrosis; decreased COL1A1 mRNA levels in the skin and lung; and simultaneously decreased ET-1 concentrations in the plasma and ET-1 mRNA levels in the skin and lungs of the bleomycin-induced sclerotic mice, especially during the early phase (weeks 1-3. CONCLUSION: Crocetin inhibits cell proliferation, differentiation and collagen production in SSc fibroblasts. Crocetin alleviates skin and lung fibrosis in a bleomycin-induced SSc mouse model, in part due to a

Cellular Response to Bleomycin-Induced DNA Damage in Human Fibroblast Cells in Space

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Lu, Tao; Zhang, Ye; Wong, Michael; Stodieck, Louis; Karouia, Fathi; Wu, Honglu

2015-01-01

Outside the protection of the geomagnetic field, astronauts and other living organisms are constantly exposed to space radiation that consists of energetic protons and other heavier charged particles. Whether spaceflight factors, microgravity in particular, have effects on cellular responses to DNA damage induced by exposure to radiation or cytotoxic chemicals is still unknown, as is their impact on the radiation risks for astronauts and on the mutation rate in microorganisms. Although possible synergistic effects of space radiation and other spaceflight factors have been investigated since the early days of the human space program, the published results were mostly conflicting and inconsistent. To investigate effects of spaceflight on cellular responses to DNA damages, human fibroblast cells flown to the International Space Station (ISS) were treated with bleomycin for three hours in the true microgravity environment, which induced DNA damages including double-strand breaks (DSB) similar to the ionizing radiation. Damages in the DNA were measured by the phosphorylation of a histone protein H2AX (g-H2AX), which showed slightly more foci in the cells on ISS than in the ground control. The expression of genes involved in DNA damage response was also analyzed using the PCR array. Although a number of the genes, including CDKN1A and PCNA, were significantly altered in the cells after bleomycin treatment, no significant difference in the expression profile of DNA damage response genes was found between the flight and ground samples. At the time of the bleomycin treatment, the cells on the ISS were found to be proliferating faster than the ground control as measured by the percentage of cells containing positive Ki-67 signals. Our results suggested that the difference in g-H2AX focus counts between flight and ground was due to the faster growth rate of the cells in space, but spaceflight did not affect initial transcriptional responses of the DNA damage response genes to

Effectiveness of rosiglitazone on bleomycin-induced lung fibrosis: Assessed by micro-computed tomography and pathologic scores

International Nuclear Information System (INIS)

Jin, Gong Yong; Bok, Se Mi; Han, Young Min; Chung, Myung Ja; Yoon, Kwon-Ha; Kim, So Ri; Lee, Yong Chul

2012-01-01

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists exhibit potent anti-fibrotic effects in the lung and other tissues. Recently, micro-computed tomography (CT) has been a useful tool for the investigation of lung diseases in small animals and is now increasingly applied to visualize and quantify the pulmonary structures. However, there is little information on the assessment for therapeutic effects of PPARγ agonists on the pulmonary fibrosis in mice using micro-CT. This study was aimed to determine the capability of micro-CT in examining the effects of rosiglitazone on pulmonary fibrosis. We used a murine model of bleomycin-induced lung fibrosis to evaluate the feasibility of micro-CT in evaluating the therapeutic potential of rosiglitazone on pulmonary fibrosis, comparing with pathologic scores. On micro-CT findings, ground glass opacity (80%) and consolidation (20%) were observed predominantly at 3 weeks after the instillation of bleomycin, and the radiologic features became more complex at 6 weeks. In bleomycin-instilled mice treated with rosiglitazone, the majority (80%) showed normal lung features on micro-CT. Radiological-pathologic correlation analyses revealed that ground glass opacity and consolidation were correlated closely with acute inflammation, while reticular opacity was well correlated with histological honeycomb appearance. These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis in mice and that the visualization of bleomycin-induced pulmonary fibrosis using micro-CT is satisfactory to assess the effects of rosiglitazone. It implies that micro-CT can be applied to evaluate therapeutic efficacies of a variety of candidate drugs for lung diseases.

Effectiveness of rosiglitazone on bleomycin-induced lung fibrosis: Assessed by micro-computed tomography and pathologic scores

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Jin, Gong Yong; Bok, Se Mi; Han, Young Min [Department of Radiology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Chung, Myung Ja [Department of Pathology, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Yoon, Kwon-Ha [Department of Radiology, Iksan Hospital, Iksan (Korea, Republic of); Kim, So Ri [Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju (Korea, Republic of); Lee, Yong Chul, E-mail: leeyc@jbnu.ac.kr [Department of Internal Medicine and Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Jeonju (Korea, Republic of)

2012-08-15

Peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) agonists exhibit potent anti-fibrotic effects in the lung and other tissues. Recently, micro-computed tomography (CT) has been a useful tool for the investigation of lung diseases in small animals and is now increasingly applied to visualize and quantify the pulmonary structures. However, there is little information on the assessment for therapeutic effects of PPAR{gamma} agonists on the pulmonary fibrosis in mice using micro-CT. This study was aimed to determine the capability of micro-CT in examining the effects of rosiglitazone on pulmonary fibrosis. We used a murine model of bleomycin-induced lung fibrosis to evaluate the feasibility of micro-CT in evaluating the therapeutic potential of rosiglitazone on pulmonary fibrosis, comparing with pathologic scores. On micro-CT findings, ground glass opacity (80%) and consolidation (20%) were observed predominantly at 3 weeks after the instillation of bleomycin, and the radiologic features became more complex at 6 weeks. In bleomycin-instilled mice treated with rosiglitazone, the majority (80%) showed normal lung features on micro-CT. Radiological-pathologic correlation analyses revealed that ground glass opacity and consolidation were correlated closely with acute inflammation, while reticular opacity was well correlated with histological honeycomb appearance. These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis in mice and that the visualization of bleomycin-induced pulmonary fibrosis using micro-CT is satisfactory to assess the effects of rosiglitazone. It implies that micro-CT can be applied to evaluate therapeutic efficacies of a variety of candidate drugs for lung diseases.

Oxidation of extracellular cysteine/cystine redox state in bleomycin-induced lung fibrosis.

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Iyer, Smita S; Ramirez, Allan M; Ritzenthaler, Jeffrey D; Torres-Gonzalez, Edilson; Roser-Page, Susanne; Mora, Ana L; Brigham, Kenneth L; Jones, Dean P; Roman, Jesse; Rojas, Mauricio

2009-01-01

Several lines of evidence indicate that depletion of glutathione (GSH), a critical thiol antioxidant, is associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, GSH synthesis depends on the amino acid cysteine (Cys), and relatively little is known about the regulation of Cys in fibrosis. Cys and its disulfide, cystine (CySS), constitute the most abundant low-molecular weight thiol/disulfide redox couple in the plasma, and the Cys/CySS redox state (E(h) Cys/CySS) is oxidized in association with age and smoking, known risk factors for IPF. Furthermore, oxidized E(h) Cys/CySS in the culture media of lung fibroblasts stimulates proliferation and expression of transitional matrix components. The present study was undertaken to determine whether bleomycin-induced lung fibrosis is associated with a decrease in Cys and/or an oxidation of the Cys/CySS redox state and to determine whether these changes were associated with changes in E(h) GSH/glutathione disulfide (GSSG). We observed distinct effects on plasma GSH and Cys redox systems during the progression of bleomycin-induced lung injury. Plasma E(h) GSH/GSSG was selectively oxidized during the proinflammatory phase, whereas oxidation of E(h) Cys/CySS occurred at the fibrotic phase. In the epithelial lining fluid, oxidation of E(h) Cys/CySS was due to decreased food intake. Thus the data show that decreased precursor availability and enhanced oxidation of Cys each contribute to the oxidation of extracellular Cys/CySS redox state in bleomycin-induced lung fibrosis.

Simultaneous treatment of tongue cancer with interstitial brachytherapy and bleomycin

International Nuclear Information System (INIS)

Watarai, Jiro; Itagaki, Takatomo; Yamaguchi, Kouichi

1983-01-01

During a period of 5 years, from 1977 to 1982, twenty five patients with tongue cancer were treated by radium needle implantation and bleomycin at Yamagata University Hospital. In this paper, authors analysed seventeen patients followed over two years. All had biopsy proven squamous cell carcinoma. According to the TNM system (UICC, 1978), primary tumor was classified into 4 cases of T1, 8 cases of T2 and 5 cases of T3. The main purpose of this study was to obtain a high local control rate and reduce subsequent regional lymphnode metastasis. Our curative treatment method was simultaneous combination of 70 Gy of brachy-therapy and 40 mg of bleomycin. The results of this study were as follows: 1. A control rate in the primary lesion was 91% (10/11) in survivors having survived more than 2 years. 2. Radioosteonecrosis of mandible was found in 6% (1/17) and transient ulcer formation in the primary site was observed in 35% (6/17) of patients treated. However, all patients were cured by conservative treatment. 3. This treatment method did not reduce subsequent lymph node metastasis. (author)

Effects of bleomycin and x irradiation on the frequency of chromosomal aberrations in selected connective tissue diseases

International Nuclear Information System (INIS)

Burkhardt, W.C. Jr.

1978-01-01

Whole blood lymphocytes from 28 patients with selected connective tissue disorders (6 progressive systemic sclerosis (PSS), 6 anti-nuclear antibody positive rheumatoid arthritis, 6 anti-nuclear antibody negative rheumatoid arthritis, 6 systemic lupus erythematosus, and 4 mixed connective tissue disease) and 17 controls matched for sex, age, and race were studied to determine the frequency of spontaneous as well as bleomycin and/or x-irradiation induced chromosomal aberrations. The effects of bleomycin on cultured lymphocytes were tested, but differential susceptibilities to this clastogen were not demonstrated among the disease groups and controls investigated. However, the combined effect of bleomycin and x irradiation were found to be additive in control lymphocytes, nearly additive in PSS, RA+, and SLE cultures, but reduced considerably from the expected additive value in Ra- cultures. This study indicated that peripheral blood lymphocytes from patients with connective tissue disease, as a whole, possess greater frequencies of spontaneous chromosomal aberrations than matched controls and that x rays can produce greater frequencies of chromosomal aberrations in whole blood lymphocytes of PSS patients than in suitably matched control individuals

B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis.

Science.gov (United States)

François, Antoine; Gombault, Aurélie; Villeret, Bérengère; Alsaleh, Ghada; Fanny, Manoussa; Gasse, Paméla; Adam, Sylvain Marchand; Crestani, Bruno; Sibilia, Jean; Schneider, Pascal; Bahram, Seiamak; Quesniaux, Valérie; Ryffel, Bernhard; Wachsmann, Dominique; Gottenberg, Jacques-Eric; Couillin, Isabelle

2015-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A. Copyright © 2014 Elsevier Ltd. All rights reserved.

Randomized phase III study comparing paclitaxel-bleomycin, etoposide, and cisplatin (BEP) to standard BEP in intermediate-prognosis germ-cell cancer: Intergroup study EORTC 30983

NARCIS (Netherlands)

R. de Wit (Ronald); I. Skoneczna (I.); G. Daugaard (Gedske); M. de Santis (Maria); A. Garin (A.); N. Aass (N.); J.A. Witjes (Alfred); P. Albers (Peter); J.D. White (Jeffrey); J.R. Germa-Lluch; S. Marreaud (Sandrine); L.A.J. Collette (Lau)

2012-01-01

textabstractPurpose: To compare the efficacy of four cycles of paclitaxel-bleomycin, etoposide, and cisplatin (T-BEP) to four cycles of bleomycin, etoposide, and cisplatin (BEP) in previously untreated patients with intermediate-prognosis germ-cell cancer (GCC). Patients and Methods: Patients were

Effects of iloprost on bleomycin-induced pulmonary fibrosis in rats compared with methyl-prednisolone

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Z.A. Aytemur

2012-11-01

Full Text Available Objective: Prostacyclin (PGI2 has been shown to inhibit the expression of pro-inflammatory and pro-fibrotic mediators in pulmonary fibrosis. In this study, we aimed to test the preventive effects of intraperitoneally administered iloprost, a stable PGI2 analog, on bleomycin-induced pulmonary fibrosis in rats and to compare the effects of iloprost with the effects of methyl-prednisolone, a traditional therapy. Methods: Rats were randomly allocated into four groups: 1. Saline alone (n = 6; 2. Bleomycin + placebo (n = 7; 3. Bleomycin + methyl-prednisolone (n = 7; 4. Bleomycin + iloprost (n = 7. Fibrotic changes in the lungs were demonstrated by analyzing the cellular composition of bronchoalveolar lavage fluid, histological evaluation and lung hydroxyproline content. Results: Fibrosis was made in the lungs of rats by bleomycin experimentally. Fibrosis scores in the methyl-prednisolone and the iloprost groups were significantly lower than in the placebo group (p < 0.05. Furthermore, the score of the iloprost group was significantly lower than the score of the methyl-prednisolone group. The hydroxyproline content was significantly less in the methyl-prednisolone and the iloprost groups (p < 0.05. In the placebo group, the neutrophil percentage in bronchoalveolar lavage was significantly higher than in the other groups, whereas the macrophage percentage in placebo group was significantly lower (p < 0.05. Conclusion: Iloprost has protective effect on the pulmonary fibrosis induced by bleomycin and it may be more effective in decreasing fibrotic changes than methyl-prednisolone. Resumo: Objetivo: A prostaciclina (PGI2 é conhecida por inibir a expressão de mediadores pró-inflamatórios e pró-fibróticos na fibrose pulmonar. Neste estudo, procurou-se testar os efeitos preventivos do iloprost administrado por via intraperitoneal, um análogo estável do PGI2, na fibrose

Structural features facilitating tumor cell targeting and internalization by bleomycin and its disaccharide.

Science.gov (United States)

Yu, Zhiqiang; Paul, Rakesh; Bhattacharya, Chandrabali; Bozeman, Trevor C; Rishel, Michael J; Hecht, Sidney M

2015-05-19

We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide-cytotoxin conjugates.

Percutaneous sclerotherapy of sialoceles after parotidectomy with fibrin glue, OK-432, and bleomycin.

Science.gov (United States)

Chen, Wei-liang; Zhang, Li-ping; Huang, Zhi-quan; Zhou, Bin

2013-12-01

We evaluated the curative effect of fibrin glue combined with OK-432 (streptococcal pyrogenic exotoxin A, Picibanil™) and bleomycin on 9 patients with sialoceles after parotidectomy. The primary lesions included pleomorphic adenomas in 6 cases and Warthin's tumours in 3 cases. After a sialocele had been diagnosed each patient had repeated aspirations and pressure dressings for 3-4 weeks, but these treatments failed. The patients were then treated with percutaneous sclerotherapy with the injection of fibrin glue 8-10 ml combined with OK-432 5 mg and bleomycin 15 mg. All the sialoceles disappeared completely after a single procedure in 2-3 weeks. The patients have been followed up for more than 6 months with no evidence of recurrent sialocele or injury to the facial nerve related to sclerotherapy. This simple, safe technique can be successfully used to treat sialoceles after parotidectomy. Copyright © 2013 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Radiotherapy and bleomycin-containing chemotherapy in the treatment of advanced head and neck cancer: report of six patients and review of the literature

International Nuclear Information System (INIS)

Forastiere, A.A.; Uikram, B.; Spiro, R.H.; Wittes, R.E.

1981-01-01

In an effort to improve the complete remission rate achievable with bleomycin and cisplatin, administered prior to radiotherapy in previously untreated patients with unresectable epidermoid carcinoma of the head and neck, we initiated a pilot study employing simultaneous chemotherapy and radiotherapy. Six patients were treated with bleomycin (B) 15 mg i.m. t.i.w. 30-60 minutes prior to radiotherapy (RT) treatment with conventional fractionation, 180-200 rad/fx, 5 fx/week. During interruptions in B + RT for healing of mucocutaneous reactions, patients received cisplatin 40 mg/mg m 2 once weekly. Toxicity included severe mucositis within the radiation port in all patients, three episodes of infection, and significant myelosuppression in one patient. Transient mild serum creatinine elevation occurred in four patients. Three patients did not complete treatment because of severity of toxicity. Response was: primary--4/6CR, 1/6 PR; regional nodes--1/5 CR, 4/5 PR. Review of the literature of concurrent bleomycin and radiotherapy trials in head and neck cancer indicates that other investigators have encountered severe toxicity using bleomycin dose and radiation fractionation schedules similar to ours. Toxicity may be reduced when lower doses of concurrent bleomycin and/or alternative radiation fractionation schedules are employed. Although results of uncontrolled trials suggest a possible therapeutic advantage to treatment with the combination compared to radiotherapy alone, this has not clearly been established in the four randomized trials reviewed

Percutaneous sclerotherapy of massive macrocystic lymphatic malformations of the face and neck using fibrin glue with OK-432 and bleomycin.

Science.gov (United States)

Chen, W-l; Huang, Z-q; Chai, Q; Zhang, D-m; Wang, Y-y; Wang, H-j; Wang, L; Fan, S

2011-06-01

Picibanil (OK-432) and bleomycin have been used as alternative sclerosing agents for lymphatic malformations. This study evaluated the clinical curative effect of sclerotherapy using fibrin glue combined with OK-432 and bleomycin for the treatment of macrocystic lymphatic malformations of the face and neck. Fifteen paediatric patients (6 males; 9 females, aged 13 months to 14 years) who had received percutaneous sclerotherapy for massive macrocystic lymphatic malformations of the face and neck were retrospectively reviewed. Affected regions included the neck, parotid region and parapharynx, mouth floor, face and cheek, and orbital regions. All patients showed preoperative symptoms of space-occupying lesions between 4 cm × 5 cm and 12 cm × 16 cm in size. Fibrin glue with OK-432 and bleomycin was injected under general anaesthesia. All patients received preoperative and follow-up CT scans. Outcomes were assessed by three surgeons. All patients exhibited mid-facial swelling for 3-4 weeks after surgery, but no major complications. Follow-up periods ranged from 8 to 16 months. Eight lesions were completely involuted, five were mostly involuted, and two were partially involuted. Percutaneous sclerotherapy using fibrin glue with OK-432 and bleomycin provided a simple, safe, and reliable alternative treatment for massive macrocystic lymphatic malformations of the face and neck. Copyright © 2011 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Effect of bleomycin and irradiation on G2 progression

International Nuclear Information System (INIS)

Kimler, B.F.

1979-01-01

The interaction of bleomycin and x-irradiation on the induction of G 2 delay in Chinese hamster ovary cells was investigated utilizing the mitotic selection procedure for cell cycle analysis. Following the addition of BLM, the number of cells selected in mitosis remained at control level for a refractory period and then decreased. The location of the transition point, i.e., the age in G 2 at which cells become refractory to a progression blockade, was concentration-dependent, ranging from the S/G 2 boundary at low concentrations to the G 2 /M boundary at high concentrations. Depending upon the concentration of the drug used and the duration of exposure, the mitotic rate either decreased to zero or else leveled off at some intermediate value and then recovered to the control level. The duration of BLM-induced division delay was thus dependent upon the concentration used and the duration of exposure. When cells were treated with pulses of bleomycin (10-500 μg/ml) in addition to x-irradiation, the mitotic rate declined as with exposure to x-ray alone. However, the recovery from radiation-induced division delay and the subsequent reappearance of mitotic cells in the selection window was delayed until the cells had recovered from their BLM-induced division delay. This implies that, in contrast to the synergistic effects observed for cell lethality, BLM and radiation do not interact in the production of a progression blockade and the resultant division delay

Structural Features Facilitating Tumor Cell Targeting and Internalization by Bleomycin and Its Disaccharide

Science.gov (United States)

2016-01-01

We have shown previously that the bleomycin (BLM) carbohydrate moiety can recapitulate the tumor cell targeting effects of the entire BLM molecule, that BLM itself is modular in nature consisting of a DNA-cleaving aglycone which is delivered selectively to the interior of tumor cells by its carbohydrate moiety, and that there are disaccharides structurally related to the BLM disaccharide which are more efficient than the natural disaccharide at tumor cell targeting/uptake. Because BLM sugars can deliver molecular cargoes selectively to tumor cells, and thus potentially form the basis for a novel antitumor strategy, it seemed important to consider additional structural features capable of affecting the efficiency of tumor cell recognition and delivery. These included the effects of sugar polyvalency and net charge (at physiological pH) on tumor cell recognition, internalization, and trafficking. Since these parameters have been shown to affect cell surface recognition, internalization, and distribution in other contexts, this study has sought to define the effects of these structural features on tumor cell recognition by bleomycin and its disaccharide. We demonstrate that both can have a significant effect on tumor cell binding/internalization, and present data which suggests that the metal ions normally bound by bleomycin following clinical administration may significantly contribute to the efficiency of tumor cell uptake, in addition to their characterized function in DNA cleavage. A BLM disaccharide-Cy5** conjugate incorporating the positively charged dipeptide d-Lys-d-Lys was found to associate with both the mitochondria and the nuclear envelope of DU145 cells, suggesting possible cellular targets for BLM disaccharide–cytotoxin conjugates. PMID:25905565

Anti-Ma2 paraneoplastic encephalitis associated with testicular germ cell tumor treated by carboplatin, etoposide and bleomycin.

Science.gov (United States)

Kimura, Masaki; Onozawa, Mizuki; Fujisaki, Akira; Arakawa, Takashi; Takeda, Katsuhiko; Dalmau, Joseph; Hattori, Kazunori

2008-10-01

Anti-Ma2-associated encephalitis is a paraneoplastic disorder that predominantly affects the limbic system, diencephalon and brainstem, and is usually associated with tumors of the testis. We report a 35-year-old man with a right testicular mass who presented with multiple neurological complains, and clinical, serological and radiological features compatible with anti-Ma2-associated encephalitis. After three courses of carboplatin, etoposide and bleomycin for metastatic testicular germ-cell tumor, all elevated tumor markers normalized and the retroperitoneal metastases disappeared, but the neurological disorder deteriorated. To our knowledge, this is the first case in which orchiectomy followed by carboplatin, etoposide and bleomycin for a testicular tumor with anti-Ma2 encephalitis was performed.

The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis.

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Abdulaleem Alnajar

Full Text Available Fibrogenesis is usually initiated when regenerative processes have failed and/or chronic inflammation occurs. It is characterised by the activation of tissue fibroblasts and dysregulated synthesis of extracellular matrix proteins. FHL2 (four-and-a-half LIM domain protein 2 is a scaffolding protein that interacts with numerous cellular proteins, regulating signalling cascades and gene transcription. It is involved in tissue remodelling and tumour progression. Recent data suggest that FHL2 might support fibrogenesis by maintaining the transcriptional expression of alpha smooth muscle actin and the excessive synthesis and assembly of matrix proteins in activated fibroblasts. Here, we present evidence that FHL2 does not promote bleomycin-induced lung fibrosis, but rather suppresses this process by attenuating lung inflammation. Loss of FHL2 results in increased expression of the pro-inflammatory matrix protein tenascin C and downregulation of the macrophage activating C-type lectin receptor DC-SIGN. Consequently, FHL2 knockout mice developed a severe and long-lasting lung pathology following bleomycin administration due to enhanced expression of tenascin C and impaired activation of inflammation-resolving macrophages.

Intracellular distribution of 57Bleomycin

International Nuclear Information System (INIS)

Konings, A.W.T.; Rasker, J.J.; Posthuma, G.A.

1978-01-01

Since the first promising results of Nouel et al. 1972, additional positive experience has been obtained with 57 Co-Bleomycin ( 57 Co-BLM) as a tumour-localizing agent. In this preclinical study, mice with transplanted osteosarcoma and lymphosarcoma were used and rats with transplanted rhabdomyosarcoma. 57 CoCl 2 served as a control substance. 57 Co-BLM had concentrated in the tumours with a factor 2 to 10 as compared to the (normal) liver of the animals. No preferential concentration in the tumours was found when 57 CoCl 2 was used. The highest specific activity of 57 Co-BLM (cpm/mg protein) was found in a fraction containing mitochondria and lysosomes. Evidence for a lysosomal localization of this diagnostic compound was obtained from experiments in which the mitochondrial-lysosomal fraction was treated with hypertonic media of different osmolarities. Conditions could be found in which many lysosomes burst while almost all mitochondria were intact. From these experiments it appeared that the radioactivity in the particles obtained from animals injected with 57 Co-BLM was released very rapidly. (Auth.)

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

International Nuclear Information System (INIS)

Fukunaga, Satoki; Kakehashi, Anna; Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki; Gi, Min; Wanibuchi, Hideki

2015-01-01

To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis

Integrative analyses of miRNA and proteomics identify potential biological pathways associated with onset of pulmonary fibrosis in the bleomycin rat model

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Fukunaga, Satoki [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Kakehashi, Anna [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Sumida, Kayo; Kushida, Masahiko; Asano, Hiroyuki [Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., 3-1-98 Kasugade-Naka, Konohana-ku, Osaka 554-8558 (Japan); Gi, Min [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Wanibuchi, Hideki, E-mail: wani@med.osaka-cu.ac.jp [Department of Molecular Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

2015-08-01

To determine miRNAs and their predicted target proteins regulatory networks which are potentially involved in onset of pulmonary fibrosis in the bleomycin rat model, we conducted integrative miRNA microarray and iTRAQ-coupled LC-MS/MS proteomic analyses, and evaluated the significance of altered biological functions and pathways. We observed that alterations of miRNAs and proteins are associated with the early phase of bleomycin-induced pulmonary fibrosis, and identified potential target pairs by using ingenuity pathway analysis. Using the data set of these alterations, it was demonstrated that those miRNAs, in association with their predicted target proteins, are potentially involved in canonical pathways reflective of initial epithelial injury and fibrogenic processes, and biofunctions related to induction of cellular development, movement, growth, and proliferation. Prediction of activated functions suggested that lung cells acquire proliferative, migratory, and invasive capabilities, and resistance to cell death especially in the very early phase of bleomycin-induced pulmonary fibrosis. The present study will provide new insights for understanding the molecular pathogenesis of idiopathic pulmonary fibrosis. - Highlights: • We analyzed bleomycin-induced pulmonary fibrosis in the rat. • Integrative analyses of miRNA microarray and proteomics were conducted. • We determined the alterations of miRNAs and their potential target proteins. • The alterations may control biological functions and pathways in pulmonary fibrosis. • Our result may provide new insights of pulmonary fibrosis.

Comparison of therapeutic response of keloids and hypertrophic scars to cryotherapy plus intralesional steroid and bleomycin tattoo

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Farahnaz Fatemi

2005-01-01

Full Text Available Keloids and hypertrophic scars are abnormal responses of body to skin injuries. Overproduction of compacted fibrous tissue is the basic cause of these lesions. In this study the result of treatment of these skin conditions with bleomycin tattoo are compared with cryotherapy and triamcinolone injection. This study involved 45 patients with hypertrophic scar or keloid. Patients were divided into two groups consecutively. Group A (23 patients was treated with bleomycin tattoo and the group B with cryotherapy and triamcinolone injection. There were four therapeutic sessions one month apart. All patients were followedup for three month after the end of treatment .The therapeutic response was determined as reduction of lesion size or flattening relative to initial size. Therapeutic response was 88.3±14% in group A and 67.4 ±22.5% in group B (p<0.001. In group A 69%, but in group B only 49% of patients were asymptomatic after the end of treatment. In group A there was no relation between therapeutic response and lesion size (p=0.58 but in group B lesions those were smaller (<100mm2 had better therapeutic response than larger ones (p=0.007. It was concluded that bleomycin tattoo is more effective in treatment of hypertrophic scar and keloid than traditional treatment, cryotherapy plus triamcinolone injection especially in larger ones.

Rapamycin attenuates bleomycin-induced pulmonary fibrosis in rats and the expression of metalloproteinase-9 and tissue inhibitors of metalloproteinase-1 in lung tissue.

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Jin, Xiaoguang; Dai, Huaping; Ding, Ke; Xu, Xuefeng; Pang, Baosen; Wang, Chen

2014-01-01

Idiopathic pulmonary fibrosis (IPF) is the most common and devastating form of interstitial lung disease (ILD) in the clinic. There is no effective therapy except for lung transplantation. Rapamycin is an immunosuppressive drug with potent antifibrotic activity. The purpose of this study was to examine the effects of rapamycin on bleomycin-induced pulmonary fibrosis in rats and the relation to the expression of metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1). Sprague-Dawley rats were treated with intratracheal injection of 0.3 ml of bleomycin (5 mg/kg) in sterile 0.9% saline to make the pulmonary fibrosis model. Rapamycin was given at a dose of 0.5 mg/kg per gavage, beginning one day before bleomycin instillation and once daily until animal sacrifice. Ten rats in each group were sacrificed at 3, 7, 14, 28 and 56 days after bleomycin administration. Alveolitis and pulmonary fibrosis were semi-quantitatively assessed after HE staining and Masson staining under an Olympus BX40 microscope with an IDA-2000 Image Analysis System. Type I and III collagen fibers were identified by Picro-sirius-polarization. Hydroxyproline content in lung tissue was quantified by a colorimetric-based spectrophotometric assay, MMP-9 and TIMP-1 were detected by immunohistochemistry and by realtime quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Bleomycin induced alveolitis and pulmonary fibrosis of rats was inhibited by rapamycin. Significant inhibition of alveolitis and hydroxyproline product were demonstrated when daily administration of rapamycin lasted for at least 14 days. The inhibitory efficacy on pulmonary fibrosis was unremarkable until rapamycin treatment lasted for at least 28 days (P pulmonary fibrosis, which is associated with decreased expression of MMP-9 and TIMP-1.

Longitudinal assessment of bleomycin-induced lung fibrosis by Micro-CT correlates with histological evaluation in mice

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Ruscitti, F. (Francesca); Ravanetti, F. (Francesca); J. Essers (Jeroen); Y. Ridwan (Yanto); Belenkov, S. (Sasha); W.G. Vos (Wim G.); Ferreira, F. (Francisca); A. Kleinjan (Alex); P.M. van Heijningen (Paula ); C. Van Holsbeke (Cedric); Cacchioli, A. (Antonio); Villetti, G. (Gino); Stellari, F.F. (Franco Fabio)

2017-01-01

textabstractBackground: The intratracheal instillation of bleomycin in mice induces early damage to alveolar epithelial cells and development of inflammation followed by fibrotic tissue changes and represents the most widely used model of pulmonary fibrosis to investigate human IPF. Histopathology

Grape seed extract ameliorates bleomycin-induced mouse pulmonary fibrosis.

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Liu, Qi; Jiang, Jun-Xia; Liu, Ya-Nan; Ge, Ling-Tian; Guan, Yan; Zhao, Wei; Jia, Yong-Liang; Dong, Xin-Wei; Sun, Yun; Xie, Qiang-Min

2017-05-05

Pulmonary fibrosis is common in a variety of inflammatory lung diseases, such as interstitial pneumonia, chronic obstructive pulmonary disease, and silicosis. There is currently no effective clinical drug treatment. It has been reported that grape seed extracts (GSE) has extensive pharmacological effects with minimal toxicity. Although it has been found that GSE can improve the lung collagen deposition and fibrosis pathology induced by bleomycin in rat, its effects on pulmonary function, inflammation, growth factors, matrix metalloproteinases and epithelial-mesenchymal transition remain to be researched. In the present study, we studied whether GSE provided protection against bleomycin (BLM)-induced mouse pulmonary fibrosis. ICR strain mice were treated with BLM in order to establish pulmonary fibrosis models. GSE was given daily via intragastric administration for three weeks starting at one day after intratracheal instillation. GSE at 50 or 100mg/kg significantly reduced BLM-induced inflammatory cells infiltration, proinflammatory factor protein expression, and hydroxyproline in lung tissues, and improved pulmonary function in mice. Additionally, treatment with GSE also significantly impaired BLM-induced increases in lung fibrotic marker expression (collagen type I alpha 1 and fibronectin 1) and decreases in an anti-fibrotic marker (E-cadherin). Further investigation indicated that the possible molecular targets of GSE are matrix metalloproteinases-9 (MMP-9) and TGF-β1, given that treatment with GSE significantly prevented BLM-induced increases in MMP-9 and TGF-β1 expression in the lungs. Together, these results suggest that supplementation with GSE may improve the quality of life of lung fibrosis patients by inhibiting MMP-9 and TGF-β1 expression in the lungs. Copyright © 2017 Elsevier B.V. All rights reserved.

Some experience with 57Co-labeled bleomycin as a tumor-seeking agent

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Rasker, J.J.; van de Poll, M.A.P.C.; Beekhuis, H.; Woldring, M.G.; Nieweg, H.O.

1975-01-01

Bleomycin labeled with 57 Co was used as a tumor-localizing agent in 132 patients. In patients with pulmonary tumors the primary localization concentrated radioactivity in 52 of the 54 appropriate cases; out of the 22 clinically known metastases, 19 were visible on the scan; 40 unknown metastases especially in hilus and mediastinum were found by this method and subsequently confirmed. In 22 patients with malignant lymphomas, 18 out of 22 known pathologic lymph glands above the diaphragm were visible on the scan; below the diaphragm the results of scanning in lymph glands and spleen were disappointing, probably because of the disturbing concentration of radioactivity in the kidneys, the bladder, the liver, and sometimes the gut. In 25 patients with various other tumors, 16 out of 22 known localizations above the diaphragm were visible; 2 were uncertain and 4 negative. Below the diaphragm the results were usually negative. In 24 patients with benign lesions, uptake of 57 Co-bleomycin was visible on the scintigram in 4 patients with cavitating pulmonary tuberculosis, in 2 with pulmonary infections, in 1 with Caplan lesions of rheumatoid arthritis in the lung, and in 1 with sinusitis ethmoidalis. The significance of these results is discussed

Effect of polyunsaturated fatty acids and their metabolites on bleomycin-induced cytotoxic action on human neuroblastoma cells in vitro.

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Sailaja Polavarapu

Full Text Available In the present study, we noted that bleomycin induced growth inhibitory action was augmented by all the polyunsaturated fatty acids (PUFAs tested on human neuroblastoma IMR-32 (0.5 × 10(4 cells/100 µl of IMR cells (EPA > DHA > ALA = GLA = AA > DGLA = LA: ∼ 60, 40, 30, 10-20% respectively at the maximum doses used. Of all the prostaglandins (PGE1, PGE2, PGF2α, and PGI2 and leukotrienes (LTD4 and LTE4 tested; PGE1, PGE2 and LTD4 inhibited the growth of IMR-32 cells to a significant degree at the highest doses used. Lipoxin A4 (LXA4, 19,20-dihydroxydocosapentaenoate (19, 20 DiHDPA and 10(S,17(S-dihydroxy-4Z,7Z,11E,13Z,15E,19Z-docosahexaenoic acid (protectin: 10(S,17(SDiHDoHE, metabolites of DHA, significantly inhibited the growth of IMR-32 cells. Pre-treatment with AA, GLA, DGLA and EPA and simultaneous treatment with all PUFAs used in the study augmented growth inhibitory action of bleomycin. Surprisingly, both indomethacin and nordihydroguaiaretic acid (NDGA at 60 and 20 µg/ml respectively enhanced the growth of IMR-32 cells even in the presence of bleomycin. AA enhanced oxidant stress in IMR-32 cells as evidenced by an increase in lipid peroxides, superoxide dismutase levels and glutathione peroxidase activity. These results suggest that PUFAs suppress growth of human neuroblastoma cells, augment growth inhibitory action of bleomycin by enhancing formation of lipid peroxides and altering the status of anti-oxidants and, in all probability, increase the formation of lipoxins, resolvins and protectins from their respective precursors that possess growth inhibitory actions.

Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model.

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Huleihel, Luai; Sellares, Jacobo; Cardenes, Nayra; Álvarez, Diana; Faner, Rosa; Sakamoto, Koji; Yu, Guoying; Kapetanaki, Maria G; Kaminski, Naftali; Rojas, Mauricio

2017-07-01

Although different preclinical models have demonstrated a favorable role for bone marrow-derived mesenchymal stem cells (B-MSC) in preventing fibrosis, this protective effect is not observed with late administration of these cells, when fibrotic changes are consolidated. We sought to investigate whether the late administration of B-MSCs overexpressing microRNAs (miRNAs) let-7d (antifibrotic) or miR-154 (profibrotic) could alter lung fibrosis in a murine bleomycin model. Using lentiviral vectors, we transduced miRNAs (let-7d or miR-154) or a control sequence into human B-MSCs. Overexpression of let-7d or miR-154 was associated with changes in the mesenchymal properties of B-MSCs and in their cytokine expression. Modified B-MSCs were intravenously administered to mice at day 7 after bleomycin instillation, and the mice were euthanized at day 14 Bleomycin-injured animals that were treated with let-7d cells were found to recover quicker from the initial weight loss compared with the other treatment groups. Interestingly, animals treated with miR-154 cells had the lowest survival rate. Although a slight reduction in collagen mRNA levels was observed in lung tissue from let-7d mice, no significant differences were observed in Ashcroft score and OH-proline. However, the distinctive expression in cytokines and CD45-positive cells in the lung suggests that the differential effects observed in both miRNA mice groups were related to an effect on the immunomodulation function. Our results establish the use of miRNA-modified mesenchymal stem cells as a potential future research in lung fibrosis. Copyright © 2017 the American Physiological Society.

Modifiers of free radicals inhibit in vitro the oncogenic actions of x-rays, bleomycin, and the tumor promoter 12-O-tetradecanoylphorbol 13-acetate

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Borek, C.; Troll, W.

1983-01-01

Using short-term cultures of hamster embryo cells, we have examined the effects of the free-radical scavenger superoxide dismutase (superoxide:superoxide oxidoreductase, EC 1.15.1.1) and the enzyme catalase (hydrogen-peroxide:hydrogen-peroxide oxidoreductase, EC 1.11.1.6) on x-ray-and bleomycin-induced transformation and on the enhancement of radiogenic transformation by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). We find that superoxide dismutase inhibits (i) transformation induced by x-ray and bleomycin and (ii) promotional action of TPA in vitro. The results suggest that the oncogenic action of x-rays and bleomycin and the enhancement of oncogenic transformation by TPA are mediated in part by free radicals. The findings also suggest that superoxide dismutase can serve as an inhibitor of oncogenesis and that its actions, as seen in this in vitro system, are most predominantly on inhibiting late events in the progression of cellular transformation--those associated with promotion

Does Bleomycin Lung Toxicity Increase the Risk of Radiation Pneumonitis in Hodgkin Lymphoma?

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Abou Yehia, Zeinab; Mikhaeel, George N.; Smith, Grace; Pinnix, Chelsea C.; Milgrom, Sarah A.; Tang, Chad; Jiang, Wen; Fanale, Michelle A.; Oki, Yasuhiro; Shank, JoAnn H.; Horace, Trisha; Reddy, Jay; Akhtari, Mani; Gunther, Jillian R.; Suki, Tina; Allen, Pamela K.; Turner, Shryll; Mawlawi, Osama; Dabaja, Bouthaina S.

2016-01-01

Purpose: Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in patients with Hodgkin lymphoma (HL). We undertook the present study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation therapy (RT) in these patients. Methods and Materials: We identified 123 HL patients treated with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) followed by RT to the chest from January 2009 to December 2014. The medical records were reviewed for clinical, pathologic, and treatment information and toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analyses were used to assess the association of BPT, baseline patient characteristics, and treatment variables with the incidence of RP. Results: A total of 123 patients were included, of whom 99 (80%) received consolidation intensity modulated RT after ABVD treatment. We identified 31 patients (25.2%) with BPT after frontline ABVD. Seventeen patients (13.8%) developed RP a median of 8 weeks (range 1-39) after RT completion. BPT did not correlate with the risk of developing RP (P=.36). We evaluated the RP outcomes with respect to the bleomycin to RT interval (≤6 weeks vs >6 weeks), and we found that this interval did not predict for RP risk (P=.60). Dosimetric parameters such as the volume covered by 5 Gy and the mean lung dose were analyzed. A volume covered by 5 Gy of >55% and mean lung dose >13.5 Gy increased the risk of RP by 1.14-fold (P=.002) and 4.24-fold (P=.007), respectively. Conclusions: The results of our study suggest that BPT does not increase the risk of developing RP. Furthermore, RT initiation does not need to be delayed after chemotherapy, except to allow for the completion of steroid therapy or clinical recovery from BPT.

Does Bleomycin Lung Toxicity Increase the Risk of Radiation Pneumonitis in Hodgkin Lymphoma?

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Abou Yehia, Zeinab [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mikhaeel, George N. [Department of Clinical Oncology, Guy' s & St Thomas' Hospital, London (United Kingdom); Smith, Grace; Pinnix, Chelsea C.; Milgrom, Sarah A.; Tang, Chad; Jiang, Wen [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Fanale, Michelle A.; Oki, Yasuhiro [Department of Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Shank, JoAnn H.; Horace, Trisha; Reddy, Jay [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Akhtari, Mani [Department of Radiation Oncology, The University of Texas Medical Branch Hospitals, Galveston, Texas (United States); Gunther, Jillian R. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Suki, Tina [The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Allen, Pamela K.; Turner, Shryll [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mawlawi, Osama [Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Dabaja, Bouthaina S., E-mail: bdabaja@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

2016-12-01

Purpose: Bleomycin pulmonary toxicity (BPT) is a well-known complication of treatment in patients with Hodgkin lymphoma (HL). We undertook the present study to investigate the risk of radiation pneumonitis (RP) in the setting of BPT and to determine the need for delay or omission of radiation therapy (RT) in these patients. Methods and Materials: We identified 123 HL patients treated with ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) followed by RT to the chest from January 2009 to December 2014. The medical records were reviewed for clinical, pathologic, and treatment information and toxicities. Our primary outcome was RP of any grade. Univariate and multivariate analyses were used to assess the association of BPT, baseline patient characteristics, and treatment variables with the incidence of RP. Results: A total of 123 patients were included, of whom 99 (80%) received consolidation intensity modulated RT after ABVD treatment. We identified 31 patients (25.2%) with BPT after frontline ABVD. Seventeen patients (13.8%) developed RP a median of 8 weeks (range 1-39) after RT completion. BPT did not correlate with the risk of developing RP (P=.36). We evaluated the RP outcomes with respect to the bleomycin to RT interval (≤6 weeks vs >6 weeks), and we found that this interval did not predict for RP risk (P=.60). Dosimetric parameters such as the volume covered by 5 Gy and the mean lung dose were analyzed. A volume covered by 5 Gy of >55% and mean lung dose >13.5 Gy increased the risk of RP by 1.14-fold (P=.002) and 4.24-fold (P=.007), respectively. Conclusions: The results of our study suggest that BPT does not increase the risk of developing RP. Furthermore, RT initiation does not need to be delayed after chemotherapy, except to allow for the completion of steroid therapy or clinical recovery from BPT.

Radiotherapy, combined with simultaneous chemotherapy with mitomycin C and bleomycin for inoperable head and neck cancer--preliminary report

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Smid, Lojze; Lesnicar, Hotimir; Zakotnik, Brane; Soba, Erika; Budihna, Marjan; Furlan, Ladica; Zargi, Miha; Rudolf, Zvone

1995-01-01

Purpose: Prospectively designed randomized clinical study was undertaken to assess the efficacy of simultaneous application of irradiation, Mitomycin C, and Bleomycin in treatment of patients with inoperable head and neck carcinoma. Methods and Materials: Between March 1991 and October 1993, 49 patients with inoperable head and neck carcinoma were randomly assigned to receive either radiation therapy alone (group A) or radiotherapy combined with simultaneous application of Mitomycin C and Bleomycin (group B). Patients in both groups were irradiated five times weekly with 2 Gy to the total dose of 66-70 Gy. Chemotherapy regimen included intramuscular application of Bleomycin 5 units twice a week, with the planned dose being 70 units and Mitomycin C 15 mg/m 2 applied intravenously after delivery of 9-10 Gy of irradiation. The application of Mitomycin C was planned to be repeated on last day of radiotherapy in the dose of 10 mg/m 2 . In attempt to enhance the effect of chemotherapeutic drugs, patients in group B received also Nicotinamide, Chlorpromazine, and Dicoumarol. Results: The difference in complete response rate between both treatment groups (24% in group A and 63% in group B) was statistically significant (p = 0.015). The difference in response rate was much more pronounced in patients with oropharyngeal carcinoma only (18% in group A compared to 81% in group B; p = 0.0003), while for all other subgroups added together, there was observed no benefit of multidrug therapy. Median follow-up was 18 months. Disease-free survival of patients in group A (9%) was significantly lower then in group B (48%) (p 0.001). The difference between both treatment groups was even greater in patients with oropharyngeal carcinoma only: disease-free survival of these patients in group B was 66%, while in group A, all recurred (p = 0.00001). Conclusion: From results of our prospective randomized study it seems that the group of patients that received multidrug treatment with

Nucleobase-Based Barbiturates: Their Protective Effect against DNA Damage Induced by Bleomycin-Iron, Antioxidant, and Lymphocyte Transformation Assay

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Bhaveshkumar D. Dhorajiya

2014-01-01

Full Text Available A number of nucleobase-based barbiturates have been synthesized by combination of nucleic acid bases and heterocyclic amines and barbituric acid derivatives through green and efficient multicomponent route and one pot reaction. This approach was accomplished efficiently using aqueous medium to give the corresponding products in high yield. The newly synthesized compounds were characterized by spectral analysis (FT-IR, 1H NMR, 13C NMR, HMBC, and UV spectroscopy and elemental analysis. Representative of all synthesized compounds was tested and evaluated for antioxidant, bleomycin-dependent DNA damage, and Lymphocyte Transformation studies. Compounds TBC > TBA > TBG showed highest lymphocyte transformation assay, TBC > TBA > BG showed inhibitory antioxidant activity using ABTS methods, and TBC > BPA > BAMT > TBA > 1, 3-TBA manifested the best protective effect against DNA damage induced by bleomycin.

Photochemical internalization (PCI) of bleomycin is equally effective in two dissimilar leiomyosarcoma xenografts in athymic mice.

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Sellevold, Simen; Peng, Qian; Fremstedal, Ane Sofie Viset; Berg, Kristian

2017-12-01

Photochemical internalization (PCI) is a novel technique for delivery of active macromolecules into cancerous cells, via light activation of a specific photosensitizer and a low dose systemic drug. Numerous pre-clinical studies and one clinical trial have confirmed the treatment potential in carcinomas. Soft tissue sarcomas are rare and generally resistant to radio- and chemotherapy. Due to treatment resistance and surgical morbidity in sarcoma care, we seek to increase knowledge on PCI effects in sarcomas by studying two different, but closely related leiomyosarcomas. MES-SA and SK-LMS-1 tumours were established in the leg muscles of athymic mice. Treatment effects after AlPcS 2a -PCI of bleomycin, PCI with no drug (photodynamic therapy, PDT) and control groups were evaluated by: 1) assessment of tumour growth, 2) uptake of contrast agent during MRI and 3) histopathology. PCI of bleomycin induced a similar and significant increase in time to reach the end point in both tumour models, while neither responded to AlPcS 2a -PDT. In the MES-SA tumours PCI reduced the growth rate, while in the SK-LMS-1 tumours the growth was blocked for 12days followed by exponential growth close to that of untreated tumours. SK-LMS-1 tumours were more homogenously and better vascularized than MES-SA. After PCI the vascular shutdown was more complete in the SK-LMS-1 tumours than in the MES-SA tumours. AlPcS2a-based PCI, but not PDT, induced significant tumour growth delay in the evaluated sarcomas. Cellular responsiveness to bleomycin and tumour vascularity are identified as predictive markers for PCI treatment effects. Copyright © 2017 Elsevier B.V. All rights reserved.

The disaccharide moiety of bleomycin facilitates uptake by cancer cells.

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Schroeder, Benjamin R; Ghare, M Imran; Bhattacharya, Chandrabali; Paul, Rakesh; Yu, Zhiqiang; Zaleski, Paul A; Bozeman, Trevor C; Rishel, Michael J; Hecht, Sidney M

2014-10-01

The disaccharide moiety is responsible for the tumor cell targeting properties of bleomycin (BLM). While the aglycon (deglycobleomycin) mediates DNA cleavage in much the same fashion as bleomycin, it exhibits diminished cytotoxicity in comparison to BLM. These findings suggested that BLM might be modular in nature, composed of tumor-seeking and tumoricidal domains. To explore this possibility, BLM analogues were prepared in which the disaccharide moiety was attached to deglycobleomycin at novel positions, namely, via the threonine moiety or C-terminal substituent. The analogues were compared with BLM and deglycoBLM for DNA cleavage, cancer cell uptake, and cytotoxic activity. BLM is more potent than deglycoBLM in supercoiled plasmid DNA relaxation, while the analogue having the disaccharide on threonine was less active than deglycoBLM and the analogue containing the C-terminal disaccharide was slightly more potent. While having unexceptional DNA cleavage potencies, both glycosylated analogues were more cytotoxic to cultured DU145 prostate cancer cells than deglycoBLM. Dye-labeled conjugates of the cytotoxic BLM aglycons were used in imaging experiments to determine the extent of cell uptake. The rank order of internalization efficiencies was the same as their order of cytotoxicities toward DU145 cells. These findings establish a role for the BLM disaccharide in tumor targeting/uptake and suggest that the disaccharide moiety may be capable of delivering other cytotoxins to cancer cells. While the mechanism responsible for uptake of the BLM disaccharide selectively by tumor cells has not yet been established, data are presented which suggest that the metabolic shift to glycolysis in cancer cells may provide the vehicle for selective internalization.

Serial micro-CT assessment of the therapeutic effects of rosiglitazone in a bleomycin-induced lung fibrosis mouse model

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Choi, Eun Jung; Jin, Gong Yong; Bok, Se Mi; Han, Young Min; Lee, Young Sun; Jung, Myung Ja; Kwon, Keun Sang [Research Institute of Clinical Medicine of Chonbuk National University, Biomedical Research Institute of Chonbuk National University Hospital, Institute for Medical Sciences, Jeonju (Korea, Republic of)

2014-08-15

The aim of this study was to assess the therapeutic effects of rosiglitazone with serial micro-CT findings before and after rosiglitazone administration in a lung fibrosis mouse model induced with bleomycin. We instilled the bleomycin solution directly into the trachea in twenty mice (female, C57BL/6 mice). After the instillation with bleomycin, mice were closely observed for 3 weeks and then all mice were scanned using micro-CT without sacrifice. At 3 weeks, the mice were treated with rosiglitazone on days 21 to 27 if they had abnormal CT findings (n = 9, 45%). For the mice treated with rosiglitazone, we performed micro-CT with mouse sacrifice 2 weeks after the rosiglitazone treatment completion. We assessed the abnormal CT findings (ground glass attenuation, consolidation, bronchiectasis, reticular opacity, and honeycombing) using a five-point scale at 3 and 6 weeks using Wilcoxon-signed ranked test. The micro-CT findings were correlated with the histopathologic results. One out of nine (11.1%) mice improved completely. In terms of consolidation, all mice (100%) showed marked decrease from 3.1 ± 1.4 at 3 weeks to 0.9 ± 0.9 at 6 weeks (p = 0.006). At 6 weeks, mild bronchiectasis (n = 6, 66.7%), mild reticular opacity (n 7, 77.8%) and mild honeycomb patterns (n = 3, 33.3%) appeared. A serial micro-CT enables the evaluation of drug effects in a lung fibrosis mouse model.

Comparative study of fixation of Co57 labelled bleomycin, labelled gallium citrate and Hg197 labelled mercury chloride, benign or malignant pulmonary lesions

International Nuclear Information System (INIS)

Bertrand, A.; Vaillant, G.; Robert, J.; Vaillant, D.; Nouel, J.P.; Delorme, J.; Lamy, P.

1975-01-01

Over the last ten years, numerous labelled molecules have been used in lung diseases, in order to attempt definite localisation of primary or secondary carcinoma. Three of these substances are now used: cobalt 57-labelled bleomycin, Hg 197 Cl 2 and Ga 67 citrate. A study of 34 patient with malignant or tuberculous lung disease with definite diagnosis, permitted demonstration of the fact that the highest uptake, or the best images, were obtained with labelled bleomycin. However, the long period of Co 57 limits its indications in young subjects and, in these cases, HgCl 2 is indicated [fr

Changes in sensitivity to radiation and to bleomycin occurring during the life history of monolayer cultures of a mouse tumour cell line

International Nuclear Information System (INIS)

Twentyman, P.R.; Bleehen, N.M.

1975-01-01

The response to X-radiation and to bleomycin has been measured at a number of times during the life of monolayer cultures of EMT6 mouse tumour cells. Little change in radiation sensitivity was seen at any time and no loss of the shoulder to the survival curve occurred. Cultures in early plateau phase (where a considerable amount of cell proliferation is balanced by cell loss) showed a reduced sensitivity to bleomycin when compared with cells in exponential growth. However, after a longer period in plateau phase, when proliferation had virtually ceased, the sensitivity became greater than that of exponential phase cells. These findings are discussed with reference to the conflicting results of other workers. (author)

Modulation of bleomycin-induced lung fibrosis by pegylated hyaluronidase and dopamine receptor antagonist in mice.

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Evgenii Germanovich Skurikhin

Full Text Available Hyaluronidases are groups of enzymes that degrade hyaluronic acid (HA. To stop enzymatic hydrolysis we modified testicular hyaluronidase (HYAL by activated polyethylene oxide with the help of electron-beam synthesis. As a result we received pegylated hyaluronidase (pegHYAL. Spiperone is a selective D2 dopamine receptor antagonist. It was demonstrated on the model of a single bleomycin damage of alveolar epithelium that during the inflammatory phase monotherapy by pegHYAL or spiperone reduced the populations of hematopoietic stem /progenitor cells in the lung parenchyma. PegHYAL also reduced the levels of transforming growth factor (TGF-β, interleukin (IL-1β, tumor necrosis factor (TNF-α in the serum and lungs, while spiperone reduced the level of the serum IL-1β. Polytherapy by spiperone and pegHYAL caused the increase of the quantity of hematopoietic stem/ progenitor cells in the lungs. Such an influx of blood cell precursors was observed on the background of considerable fall level of TGF-β and the increase level of TNF-α in the serum and lungs. These results show pegHYAL reduced the bleomycin-induced fibrosis reaction (production and accumulation of collagen in the lung parenchyma. This effect was observed at a single and repetitive bleomycin damage of alveolar epithelium, the antifibrotic activity of pegHYAL surpassing the activity of testicular HYAL. The antifibrotic effect of pegHYAL is enhanced by an additional instillation of spiperone. Therapy by pegHYAL causes the flow of CD31‒ CD34‒ CD45‒ CD44+ CD73+ CD90+ CD106+-cells into the fibrous lungs. These cells are incapable of differentiating into fibroblast cells. Spiperone instillation separately or together with pegHYAL reduced the MSC-like cells considerably. These data enable us to assume, that pegHYAL is a new and promising instrument both for preventive and therapy of toxic pneumofibrosis. The blockage of D2 dopamine receptors with the following change of hyaluronan

Advanced and rapidly progressing head and neck cancer: good palliation following intralesional bleomycin.

LENUS (Irish Health Repository)

Quintyne, Keith Ian

2011-09-01

The authors herein report the case of a 61-year-old man undergoing adjuvant therapy for locally advanced laryngeal cancer, who developed parastomal recurrence in his radiation field around his tracheotomy site, while he was undergoing radiation therapy, and compromised the secure placement of his tracheotomy tube and maintenance of his upper airway. MRI restaging and biopsy confirmed recurrence and progressive disease in his mediastinum. He underwent local therapy with intralesional bleomycin with good palliation, and ability to maintain the patency of his upper airway.

Lung-specific loss of α3 laminin worsens bleomycin-induced pulmonary fibrosis.

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Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L; Hamill, Kevin J; Soberanes, Saul; Nigdelioglu, Recep; Chi, Monica; Cho, Takugo; Radigan, Kathryn A; Ridge, Karen M; Misharin, Alexander V; Woychek, Alex; Hopkinson, Susan; Perlman, Harris; Mutlu, Gokhan M; Pardo, Annie; Selman, Moises; Jones, Jonathan C R; Budinger, G R Scott

2015-04-01

Laminins are heterotrimeric proteins that are secreted by the alveolar epithelium into the basement membrane, and their expression is altered in extracellular matrices from patients with pulmonary fibrosis. In a small number of patients with pulmonary fibrosis, we found that the normal basement membrane distribution of the α3 laminin subunit was lost in fibrotic regions of the lung. To determine if these changes play a causal role in the development of fibrosis, we generated mice lacking the α3 laminin subunit specifically in the lung epithelium by crossing mice expressing Cre recombinase driven by the surfactant protein C promoter (SPC-Cre) with mice expressing floxed alleles encoding the α3 laminin gene (Lama3(fl/fl)). These mice exhibited no developmental abnormalities in the lungs up to 6 months of age, but, compared with control mice, had worsened mortality, increased inflammation, and increased fibrosis after the intratracheal administration of bleomycin. Similarly, the severity of fibrosis induced by an adenovirus encoding an active form of transforming growth factor-β was worse in mice deficient in α3 laminin in the lung. Taken together, our results suggest that the loss of α3 laminin in the lung epithelium does not affect lung development, but plays a causal role in the development of fibrosis in response to bleomycin or adenovirally delivered transforming growth factor-β. Thus, we speculate that the loss of the normal basement membrane organization of α3 laminin that we observe in fibrotic regions from the lungs of patients with pulmonary fibrosis contributes to their disease progression.

Effects of bleomycin and irradiation on euoxic and hypoxic cells

International Nuclear Information System (INIS)

Shrieve, D.C.; Harris, J.W.

1979-01-01

EMT6 cells in vitro were exposed to bleomycin (BLM), either alone (under euoxic or hypoxic conditions) or in conjunction with x-radiation. Hypoxic and euoxic cells were equally sensitive to the drug in both of the systems used to induce hypoxia (ampules or chambers). Exposure to BLM immediately before x-irradiation altered the shape of the radiation survival curve decreasing the D 0 by a factor of 1.3. Simultaneous exposure to x-ray and BLM resulted in lower survivals than when radiation was given either before or after drug treatment. Cells recovered quickly from BLM damage if trypsinization was delayed. The results indicate that BLM and x-rays interact to lower cell survival but that cells recover from this effect if trypsinization is delayed

Stimulation of alveolar macrophages by BCG vaccine enhances the process of lung fibrosis induced by bleomycin.

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Chyczewska, E; Chyczewski, L; Bańkowski, E; Sułkowski, S; Nikliński, J

1993-01-01

It was found that the BCG vaccine injected subcutaneously to the rats enhances the process of lung fibrosis induced by bleomycin. Pretreatment of rats with this vaccine results in accumulation of activated macrophages in lung interstitium and in the bronchoalveolar spaces. It may be suggested that the activated macrophages release various cytokines which may stimulate the proliferation of fibroblasts and biosynthesis of extracellular matrix components.

Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

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Kalayarasan, Srinivasan, E-mail: kalaivasanbio@gmail.com; Sriram, Narayanan; Soumyakrishnan, Syamala; Sudhandiran, Ganapasam, E-mail: sudhandiran@yahoo.com

2013-09-01

Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells.

Diallylsulfide attenuates excessive collagen production and apoptosis in a rat model of bleomycin induced pulmonary fibrosis through the involvement of protease activated receptor-2

International Nuclear Information System (INIS)

Kalayarasan, Srinivasan; Sriram, Narayanan; Soumyakrishnan, Syamala; Sudhandiran, Ganapasam

2013-01-01

Pulmonary fibrosis (PF) can be a devastating lung disease. It is primarily caused by inflammation leading to severe damage of the alveolar epithelial cells. The pathophysiology of PF is not yet been clearly defined, but studying lung parenchymal injury by involving reactive oxygen species (ROS) through the activation of protease activated receptor-2 (PAR-2) may provide promising results. PAR-2 is a G-protein coupled receptor is known to play an important role in the development of PF. In this study, we investigated the inhibitory role of diallylsulfide (DAS) against ROS mediated activation of PAR-2 and collagen production accompanied by epithelial cell apoptosis. Bleomycin induced ROS levels may prompt to induce the expression of PAR-2 as well as extracellular matrix proteins (ECM), such as MMP 2 and 9, collagen specific proteins HSP-47, α-SMA, and cytokines IL-6, and IL-8RA. Importantly DAS treatment effectively decreased the expression of all these proteins. The inhibitory effect of DAS on profibrotic molecules is mediated by blocking the ROS level. To identify apoptotic signaling as a mediator of PF induction, we performed apoptotic protein expression, DNA fragmentation analysis and ultrastructural details of the lung tissue were performed. DAS treatment restored all these changes to near normalcy. In conclusion, treatment of PF bearing rats with DAS results in amelioration of the ROS production, PAR-2 activation, ECM production, collagen synthesis and alveolar epithelial cell apoptosis during bleomycin induction. We attained the first evidence that treatment of DAS decreases the ROS levels and may provide a potential therapeutic effect attenuating bleomycin induced PF. - Highlights: • DAS inhibits PAR-2 activity; bleomycin stimulates PAR-2 activity. • Increase in PAR-2 activity is correlated with pulmonary fibrosis • DAS reduces pro-inflammatory activity linked to facilitating pulmonary fibrosis. • DAS inhibits apoptosis of alveolar epithelial cells

Netrin-1 regulates fibrocyte accumulation in the decellularized fibrotic scleroderma lung microenvironment and in bleomycin induced pulmonary fibrosis

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Sun, Huanxing; Zhu, Yangyang; Pan, Hongyi; Chen, Xiaosong; Balestrini, Jenna L.; Lam, TuKiet T.; Kanyo, Jean E.; Eichmann, Anne; Gulati, Mridu; Fares, Wassim H.; Bai, Hanwen; Feghali-Bostwick, Carol A.; Gan, Ye; Peng, Xueyan; Moore, Meagan W.; White, Eric S.; Sava, Parid; Gonzalez, Anjelica L.; Cheng, Yuwei; Niklason, Laura E.; Herzog, Erica L.

2017-01-01

Objectives Fibrocytes are collagen-producing leukocytes that accumulate in Scleroderma-associated interstitial lung disease (SSc-ILD) via unknown mechanisms. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in Scleroderma has not been explored. This study uses a novel translational platform based on decellularized human lungs to determine whether the scleroderma lung ECM controls fibrocyte development from peripheral blood mononuclear cells. Methods Decellularized scaffolds prepared from healthy and fibrotic Scleroderma lung explants underwent biomechanical evaluation using tensile testing and biochemical analysis using proteomics. Cells from healthy and SSc-ILD subjects were cultured on these scaffolds, and CD45+Pro-ColIα1+ cells meeting criteria for fibrocytes were quantified. The contribution of Netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and via the inhalational administration of bleomycin to Netrin-1+/− mice. Results Compared to control lung scaffold, SSc-ILD lung scaffolds showed aberrant anatomy, enhanced stiffness, and abnormal extracellular matrix composition. Culture of control cells in Scleroderma scaffolds increased Pro-ColIα1+ production, which was stimulated by enhanced stiffness and abnormal ECM composition. SSc-ILD cells demonstrated increased Pro-ColIα1 responsiveness to Scleroderma lung scaffolds, but not enhanced stiffness. Enhanced Netrin-1 expression was seen on CD14lo SSc-ILD cells and antibody mediated Netrin-1 neutralization attenuated CD45+Pro-ColIα1+ detection in all settings. Netrin-1+/− mice were protected from bleomycin induced lung fibrosis and fibrocyte accumulation. Conclusion Factors present in Scleroderma lung matrices regulate fibrocyte accumulation via a Netrin-1-dependent pathway. Netrin-1 regulates bleomycin induced murine pulmonary fibrosis. Netrin-1 might be a novel therapeutic target in SSc-ILD. PMID:26749424

Interaction of Zn(II)bleomycin-A2 and Zn(II)peplomycin with a DNA hairpin containing the 5'-GT-3' binding site in comparison with the 5'-GC-3' binding site studied by NMR spectroscopy.

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Follett, Shelby E; Ingersoll, Azure D; Murray, Sally A; Reilly, Teresa M; Lehmann, Teresa E

2017-10-01

Bleomycins are a group of glycopeptide antibiotics synthesized by Streptomyces verticillus that are widely used for the treatment of various neoplastic diseases. These antibiotics have the ability to chelate a metal center, mainly Fe(II), and cause site-specific DNA cleavage. Bleomycins are differentiated by their C-terminal regions. Although this antibiotic family is a successful course of treatment for some types of cancers, it is known to cause pulmonary fibrosis. Previous studies have identified that bleomycin-related pulmonary toxicity is linked to the C-terminal region of these drugs. This region has been shown to closely interact with DNA. We examined the binding of Zn(II)peplomycin and Zn(II)bleomycin-A 2 to a DNA hairpin of sequence 5'-CCAGTATTTTTACTGG-3', containing the binding site 5'-GT-3', and compared the results with those obtained from our studies of the same MBLMs bound to a DNA hairpin containing the binding site 5'-GC-3'. We provide evidence that the DNA base sequence has a strong impact in the final structure of the drug-target complex.

Minimally Invasive Treatment of Giant Haemangiomas of the Liver: Embolisation With Bleomycin

Energy Technology Data Exchange (ETDEWEB)

Bozkaya, Halil, E-mail: halilbozkaya@yahoo.com; Cinar, Celal, E-mail: celalcinar@hotmail.com [Ege University, Division of Interventional Radiology, Department of Radiology, School of Medicine (Turkey); Besir, Fahri Halit, E-mail: drfhbesir@gmail.com [Duzce University, Department of Radiology, School of Medicine (Turkey); Parıldar, Mustafa, E-mail: mparildar@yahoo.com; Oran, Ismail, E-mail: ismailoran@gmail.com [Ege University, Division of Interventional Radiology, Department of Radiology, School of Medicine (Turkey)

2013-04-12

PurposeThe management of patients with giant haemangioma of the liver remains controversial. Although the usual treatment method for symptomatic giant haemangioma is surgery, the classical paradigm of operative resection remains. In this study, we evaluated the symptomatic improvement and size-reduction effect of embolisation with bleomycin mixed with lipiodol for the treatment of symptomatic giant hepatic haemangioma.MethodsThis study included 26 patients [21 female, five male; age 41–65 years (mean 49.83 ± 1.53)] with symptomatic giant haemangioma unfit for surgery and treated with selective embolisation by bleomycin mixed with lipiodol. The patients were followed-up (mean 7.4 ± 0.81 months) clinically and using imaging methods. Statistical analysis was performed using SPSS version 16.0, and p < 0.05 was considered to indicate statistical significance.ResultsEmbolisation of 32 lesions in 26 patients was performed. The mean volume of the haemangiomas was 446.28 ± 88 cm{sup 3} (range 3.39–1559 cm{sup 3}) before intervention and 244.43 ± 54.38 cm{sup 3} (range 94–967 cm{sup 3}) after intervention. No mortality or morbidity related to the treatment was identified. Symptomatic improvement was observed in all patients, and significant volume reduction was achieved (p = 0.001).ConclusionThe morbidity of surgical treatment in patients with giant liver hemangioma were similar to those obtained in patients followed-up without treatment. Therefore, follow-up without treatment is preferred in most patients. Thus, minimally invasive embolisation is an alternative and effective treatment for giant symptomatic haemangioma of the liver.

The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury.

Science.gov (United States)

Rathinasabapathy, Anandharajan; Horowitz, Alana; Horton, Kelsey; Kumar, Ashok; Gladson, Santhi; Unger, Thomas; Martinez, Diana; Bedse, Gaurav; West, James; Raizada, Mohan K; Steckelings, Ulrike M; Sumners, Colin; Katovich, Michael J; Shenoy, Vinayak

2018-01-01

Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT 2 ) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT 2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention protocol, BCP) or after 3 days (treatment protocol, BCT) of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition), and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT 2 receptor by C21 attenuates

The Selective Angiotensin II Type 2 Receptor Agonist, Compound 21, Attenuates the Progression of Lung Fibrosis and Pulmonary Hypertension in an Experimental Model of Bleomycin-Induced Lung Injury

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Anandharajan Rathinasabapathy

2018-03-01

Full Text Available Idiopathic Pulmonary Fibrosis (IPF is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT2 receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21, a selective AT2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip either immediately (prevention protocol, BCP or after 3 days (treatment protocol, BCT of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition, and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT2 receptor by C21 attenuates

Bleomycin-Treated Chimeric Thy1-Deficient Mice with Thy1-Deficient Myofibroblasts and Thy-Positive Lymphocytes Resolve Inflammation without Affecting the Fibrotic Response

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Pazit Y. Cohen

2015-01-01

Full Text Available Lung fibrosis is characterized by abnormal accumulation of fibroblasts in the interstitium of the alveolar space. Two populations of myofibroblasts, distinguished by Thy1 expression, are detected in human and murine lungs. Accumulation of Thy1-negative (Thy1− myofibroblasts was shown in the lungs of humans with idiopathic pulmonary fibrosis (IPF and of bleomycin-treated mice. We aimed to identify genetic changes in lung myofibroblasts following Thy1 crosslinking and assess the impact of specific lung myofibroblast Thy1-deficiency, in vivo, in bleomycin-injured mouse lungs. Thy1 increased in mouse lung lymphocytes following bleomycin injury but decreased in myofibroblasts when fibrosis was at the highest point (14 days, as assessed by immunohistochemistry. Using gene chip analysis, we detected that myofibroblast Thy1 crosslinking mediates downregulation of genes promoting cell proliferation, survival, and differentiation, and reduces production of extracellular matrix (ECM components, while concurrently mediating the upregulation of genes known to foster inflammation and immunological functions. Chimeric Thy1-deficient mice with Thy1+ lymphocytes and Thy1− myofibroblasts showed fibrosis similar to wild-type mice and an increased number of CD4/CD25 regulatory T cells, with a concomitant decrease in inflammation. Lung myofibroblasts downregulate Thy1 expression to increase their proliferation but to diminish the in vivo inflammatory milieu. Inflammation is not essential for evolution of fibrosis as was previously stated.

Biphasic pulses enhance bleomycin efficacy in a spontaneous canine genital tumor model of chemoresistance: Sticker sarcoma

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Citro Gennaro

2008-11-01

Full Text Available Abstract Sticker's sarcoma (also known as transmissible venereal tumor is a horizontally transmitted neoplasm of the dog, that is passed with coitus. It is a locally aggressive tumor with a low tendency to metastatic spread. The most common locations are the genitals, the nose, the perianal area. Standard treatment consists with chemotherapy with vincristine, however other therapies such as, cryotherapy, immunotherapy or, in selected cases, radiation therapy, have been reported. In this article we describe the outcome of a small cohort of canine patients, with chemotherapy resistant transmissible venereal tumor (TVT, treated with bleomycin selectively driven by trains of biphasic pulses (electrochemotherapy. Three canine patients, with refractory TVT, entered the study and received two sessions of ECT under sedation. The pets had local injection of bleomycin at the concentration of 1.5 mg/ml and five minutes after the chemotherapy, trains of 8 biphasic electric pulses lasting 50 + 50 μs each, with 1 ms interpulse intervals, were delivered by means of modified caliper or, for difficult districts, through paired needle electrode. All the patients responded to the treatment and are still in remission at different times. Electrochemotherapy appears as a safe and efficacious modality for the treatment of TVT and warrants further investigations.

Biological basis of combination therapy with radiation and bleomycin

International Nuclear Information System (INIS)

Fukuda, Hiroshi; Matsuzawa, Taiju; Yokoyama, Kumiko; Okuyama, Shinichi; Yamaura, Hiroshi

1976-01-01

The biological basis for combination therapy with radiation and bleomycin (BLM) was studied on C 2 W cells growing in vitro. When BLM was added to the medium before or after irradiation, a potentiating effect was observed. The potentiation remained for 4-6 hours after irradiation. To make clear the mechanism, both type of repair from radiation damage (Elkind type and PLD) by BLM were examined. BLM didn't inhibit the Elkind type recovery but it did inhibit the repair of potentially lethal damage (PLD repair). Plateau phase C 2 W cells were irradiated, incubated at 37 0 C for a various number of hours, then trypsinized for colony formation. PLD repair was inhibited when BLM was added immediately after irradiation. Based on such experimental results, we treated lung cancer with combination of radiation and BLM. BLM was injected intravenously within 30 minutes after irradiation. Although it seems too early to discuss the result of the combination therapy, it is very promising. (J.P.N.)

Biological basis of combination therapy with radiation and bleomycin

Energy Technology Data Exchange (ETDEWEB)

Fukuda, H; Matsuzawa, T; Yokoyama, K; Okuyama, S; Yamaura, H [Tohoku Univ., Sendai (Japan). Research Inst. for Tuberculosis, Leprosy and Cancer

1976-01-01

The biological basis for combination therapy with radiation and bleomycin (BLM) was studied on C/sub 2/W cells growing in vitro. When BLM was added to the medium before or after irradiation, a potentiating effect was observed. The potentiation remained for 4-6 hours after irradiation. To make clear the mechanism, both type of repair from radiation damage (Elkind type and PLD) by BLM were examined. BLM didn't inhibit the Elkind type recovery but it did inhibit the repair of potentially lethal damage (PLD repair). Plateau phase C/sub 2/W cells were irradiated, incubated at 37/sup 0/C for a various number of hours, then trypsinized for colony formation. PLD repair was inhibited when BLM was added immediately after irradiation. Based on such experimental results, we treated lung cancer with combination of radiation and BLM. BLM was injected intravenously within 30 minutes after irradiation. Although it seems too early to discuss the result of the combination therapy, it is very promising.

Analysis of the dose-response relationships of chromosomal aberrations after irradiation and bleomycin exposure of different human lymphocyte fractions in vitro

International Nuclear Information System (INIS)

Dresp, J.

1979-01-01

Cytogenetic analyses could be carried out on whole blood and pure T-cell cultures and also on cells of the 'buffy-coat'. In pure B-cell cultures even after 96 hours no mitogenic stimulation could be achieved. Parameters of radiosensitivity and bleomycin sensitivity were dicentric chromosomes, for which the dose-response relationships were calculated. Chromosomal investigations on the 'buffy-coat' cells did not provide indications referring to a varying radiosensitivity compared to whole blood cultures. In pure T-cell cultures T-lymphocytes, which had been separated after whole blood irradiation exposure, showed lower aberration rates than lymphocytes, which had been cultured after whole blood irradiation without previous separation. In the case of bleomycin exposure the treatment of previously separated leucocytes and T-lymphocytes respectively, led to lower aberration rates than the treatment before separation. Therefore it is apparently not necessary for a cytogenetic dosimetry or mutagenicity to depart from the whole blood culture method. (orig./MG) [de

Determination of hidden chromosome instability in persons suffered from the action of factors of the Chernobyl accident by the modified 'G2 bleomycin sensitivity assay'

International Nuclear Information System (INIS)

Dibs'kij, S.S.; Dibs'ka, O.B.; Pedan, L.P.; Pyilyins'ka, M.A.

2009-01-01

With the help of the modified 'G 2 -bleomycin sensitivity assay' the voluntary investigation of hidden chromosome instability in 53 persons with different radiation exposures had been fulfilled. In all examined groups, the individual levels of chromosome injuries under identical bleomycin exposure varied in a wide range and didn't depend on their initial values in intact cultures. Among control donors and individuals with low radiation exposure, ∼ 33 % hypertensive persons had been identified that can be considered as a genetically caused phenomenon. In patients recovered from acute radiation, 57.9 % persons expressed the hidden chromosome instability. The data obtained allow us to assume that high doses of ionizing radiation can modify the inherited susceptibility of human chromosomes to a mutagen exposure.

Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis

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Minrui Liang

2013-01-01

Full Text Available Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL- 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM- induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.

Resistance to bleomycin in cancer cell lines is characterized by prolonged doubling time, reduced DNA damage and evasion of G2/M arrest and apoptosis.

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Qi Wang

Full Text Available To establish, characterize and elucidate potential mechanisms of acquired bleomycin (BLM resistance using human cancer cell lines. Seven BLM-resistant cell lines were established by exposure to escalating BLM concentrations over a period of 16-24 months. IC50 values and cell doubling times were quantified using a real time cytotoxicity assay. COMET and γ-H2AX assays, cell cycle analysis, and apoptosis assessment further investigated the mechanisms of BLM resistance in these cell lines.Compared with parental cell lines, real time cytotoxicity assays revealed 7 to 49 fold increases in IC50 and a mean doubling time increase of 147 % (range 64 %-352% in BLM-resistant sub-clones (p<0.05 for both. Higher maintenance BLM concentrations were associated with higher IC50 and increased doubling times (p<0.05. Significantly reduced DNA damage (COMET and γ-H2AX assays, G2/M arrest, and apoptosis (p<0.05 for each set of comparison following high-dose acute BLM exposure was observed in resistant sub-clones, compared with their BLM-sensitive parental counterparts. Three weeks of BLM-free culturing resulted in a partial return to BLM sensitivity in 3/7 BLM-resistant sub-clones (p<0.05.Bleomycin resistance may be associated with reduced DNA damage after bleomycin exposure, resulting in reduced G2/M arrest, and reduced apoptosis.

Effects of turmeric and its active principle, curcumin, on bleomycin-induced chromosome aberrations in Chinese hamster ovary cells

OpenAIRE

Araújo, Maria Cristina P.; Dias, Francisca da Luz; Kronka, Sergio N. [UNESP; Takahashi, Catarina S.

1999-01-01

Naturally occurring antioxidants have been extensively studied for their capacity to protect organisms and cells from oxidative damage. Many plant constituents including turmeric and curcumin appear to be potent antimutagens and antioxidants. The effects of turmeric and curcumin on chromosomal aberration frequencies induced by the radiomimetic agent bleomycin (BLM) were investigated in Chinese hamster ovary (CHO) cells. Three concentrations of each drug, turmeric (100, 250 and 500 mg/ml) and ...

TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis.

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Hou, Jiwei; Ma, Tan; Cao, Honghui; Chen, Yabing; Wang, Cong; Chen, Xiang; Xiang, Zou; Han, Xiaodong

2018-03-01

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease of unknown cause. It has been reported that both lung resident mesenchymal stem cells (LR-MSCs) and tumor necrosis factor-α (TNF-α) play important roles in the development of pulmonary fibrosis. However, the underlying connections between LR-MSCs and TNF-α in the pathogenesis of pulmonary fibrosis are still elusive. In this study, we found that the pro-inflammatory cytokine TNF-α and the transcription factor nuclear factor kappa B (NF-κB) p65 subunit were both upregulated in bleomycin-induced fibrotic lung tissue. In addition, we discovered that TNF-α promotes myofibroblast differentiation of LR-MSCs through activating NF-κB signaling. Interestingly, we also found that TNF-α promotes the expression of β-catenin. Moreover, we demonstrated that suppression of the NF-κB signaling could attenuate myofibroblast differentiation of LR-MSCs and bleomycin-induced pulmonary fibrosis which were accompanied with decreased expression of β-catenin. Our data implicates that inhibition of the NF-κB signaling pathway may provide a therapeutic strategy for pulmonary fibrosis, a disease that warrants more effective treatment approaches. © 2017 Wiley Periodicals, Inc.

Glycyrrhizic acid alleviates bleomycin-induced pulmonary fibrosis in rats

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Lili eGao

2015-10-01

Full Text Available Idiopathic pulmonary fibrosis is a progressive and lethal form of interstitial lung disease that lacks effective therapies at present. Glycyrrhizic acid (GA, a natural compound extracted from a traditional Chinese herbal medicine Glycyrrhiza glabra, was recently reported to benefit lung injury and liver fibrosis in animal models, yet whether GA has a therapeutic effect on pulmonary fibrosis is unknown. In this study, we investigated the potential therapeutic effect of GA on pulmonary fibrosis in a rat model with bleomycin (BLM-induced pulmonary fibrosis. The results indicated that GA treatment remarkably ameliorated BLM-induced pulmonary fibrosis and attenuated BLM-induced inflammation, oxidative stress, epithelial-mesenchymal transition and activation of tansforming growth factor-beta signaling pathway in the lungs. Further, we demonstrated that GA treatment inhibited proliferation of 3T6 fibroblast cells, induced cell cycle arrest and promoted apoptosis in vitro, implying that GA-mediated suppression of fibroproliferation may contribute to the anti-fibrotic effect against BLM-induced pulmonary fibrosis. In summary, our study suggests a therapeutic potential of GA in the treatment of pulmonary fibrosis.

The role of scintigraphy with 57Co-bleomycin in the detection and staging of planocellular carcinomas

International Nuclear Information System (INIS)

Janchar, B.; Shushtarshich, J.; Machkovshek, M.

1990-01-01

Opinions of usefullness of 57 Co-bleomycin in the diagnostics of planocellular carcinomas have been differing. This method was reported in early 70-ties but was never generally accepted because of some physical characteristics of 57 Co (half-life of 57 Co 270 days). The authors report two cases in which radiography and imaging with this agent helped to provide correct diagnosis: an unclear case of Pancoast tumor and a case of metastatic involvement of thoracic wall after laryngeal carcinoma. (author) 7 refs.; 4 figs

N-acetylcysteine-pretreated human embryonic mesenchymal stem cell administration protects against bleomycin-induced lung injury.

Science.gov (United States)

Wang, Qiao; Zhu, Hong; Zhou, Wu-Gang; Guo, Xiao-Can; Wu, Min-Juan; Xu, Zhen-Yu; Jiang, Jun-feng; Shen, Ce; Liu, Hou-Qi

2013-08-01

The transplantation of mesenchymal stem cells (MSCs) has been reported to be a promising approach in the treatment of acute lung injury. However, the poor efficacy of transplanted MSCs is one of the serious handicaps in the progress of MSC-based therapy. Therefore, the purpose of this study was to investigate whether the pretreatment of human embryonic MSCs (hMSCs) with an antioxidant, namely N-acetylcysteine (NAC), can improve the efficacy of hMSC transplantation in lung injury. In vitro, the antioxidant capacity of NAC-pretreated hMSCs was assessed using intracellular reactive oxygen species (ROS) and glutathione assays and cell adhesion and spreading assays. In vivo, the therapeutic potential of NAC-pretreated hMSCs was assessed in a bleomycin-induced model of lung injury in nude mice. The pretreatment of hMSCs with NAC improved antioxidant capacity to defend against redox imbalances through the elimination of cellular ROS, increasing cellular glutathione levels, and the enhancement of cell adhesion and spreading when exposed to oxidative stresses in vitro. In addition, the administration of NAC-pretreated hMSCs to nude mice with bleomycin-induced lung injury decreased the pathological grade of lung inflammation and fibrosis, hydroxyproline content and numbers of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid and apoptotic cells, while enhancing the retention and proliferation of hMSCs in injured lung tissue and improving the survival rate of mice compared with results from untreated hMSCs. The pretreatment of hMSCs with NAC could be a promising therapeutic approach to improving cell transplantation and, therefore, the treatment of lung injury.

Labelling of bleomycin with technetium-99m for diagnosis in nuclear medicine

International Nuclear Information System (INIS)

Nassute, J.C.

1979-01-01

A study about the behavior of the labelling yield of an antineoplastic drug (bleomycin) with a short-leved radionuclide ( 99 sup(m) Tc), using An(II) as a reductor agent, is presented. Parameters like the pH in the labelling, influence of the reaction time and mass of tin on the labelling yield were analysed. To simplify the labelling,, a lyofilized kit of Sn(II)/BLM in evacuated vials was prepared. The quality control involving paper chromatography, sterility and 'in vivo' test was made. The 'in vivo' tests were made both in healthy rats and in those with tumorous tissues, under barbituric action. The biological distribution, the concentration time of the products in tumors, the excretion time and excretion via were studied by means of scintigraphy and scintiphotos. (Author) [pt

Measurement of cross-linked elastin synthesis in bleomycin-induced pulmonary fibrosis using a highly sensitive assay for desmosine and isodesmosine

International Nuclear Information System (INIS)

Cantor, J.O.; Osman, M.; Keller, S.; Cerreta, J.M.; Mandl, I.; Turino, G.M.

1984-01-01

Cross-linked elastin synthesis was measured in the intratracheal bleomycin model of interstitial pulmonary fibrosis by incorporation of 14C-lysine into the elastin-specific crosslinks, desmosine and isodesmosine. Detection of the labeled crosslinks was facilitated by development of a highly sensitive assay utilizing thin-layer electrophoresis. The results indicate that crosslinked elastin synthesis is significantly elevated from controls (p less than 0.05) at 1 to 3 weeks after exposure to bleomycin and returns to normal by 5 weeks. The increases in labeled elastin synthesis are not directly related to changes in either total lung protein synthesis or the pool size of the 14C-lysine. In comparison with collagen and glycosaminoglycan synthesis in this model of lung injury, maximal increases in cross-linked elastin formation occur later, but overlap with the elevated synthesis of these other connective tissue components. The marked increase from normal in cross-linked elastin synthesis in this model suggests that this tissue component is an important part of the fibrotic response of the pulmonary parenchyma and may play a role in the observed alterations in lung structure and function

Application of 111In-bleomycine in the scintigraphy of colorectal cancer

International Nuclear Information System (INIS)

Mladenov, B.; Peshev, N.; Minchev, D.; Tsanev, Ts.

1990-01-01

A gamma camera scintigraphic study of the large intestine was made of 24 patients ( 23 with colorectal cancer and 1 with abscess). 111 In-bleomycin was used. The diagnosis of all patients was verified surgically and histologically. In 88.2% of the patients a positive scintigraphic scan was obtained. Negative scintigraphic result was obtained in 2 patients with colorectal cancer localized in the ileocaecal and the transversal part of the colon. The operation showed the presence of localized tumour with 2 cm in diameter and no data for infiltration of the adjacent tissues. In the patients with benign neoplasms no accumulation of the radiopharmaceutical was registered. Positive scan was also obtained in 1 patient with post-traumatic abscess of the gluteal region. A second scanning after the conduction of appropriate anti-inflammatory therapy could be used for differentiation of the inflammations from the malignant processes. 3 figs., 5 refs

Netrin-1 Regulates Fibrocyte Accumulation in the Decellularized Fibrotic Sclerodermatous Lung Microenvironment and in Bleomycin-Induced Pulmonary Fibrosis.

Science.gov (United States)

Sun, Huanxing; Zhu, Yangyang; Pan, Hongyi; Chen, Xiaosong; Balestrini, Jenna L; Lam, TuKiet T; Kanyo, Jean E; Eichmann, Anne; Gulati, Mridu; Fares, Wassim H; Bai, Hanwen; Feghali-Bostwick, Carol A; Gan, Ye; Peng, Xueyan; Moore, Meagan W; White, Eric S; Sava, Parid; Gonzalez, Anjelica L; Cheng, Yuwei; Niklason, Laura E; Herzog, Erica L

2016-05-01

Fibrocytes are collagen-producing leukocytes that accumulate in patients with systemic sclerosis (SSc; scleroderma)-related interstitial lung disease (ILD) via unknown mechanisms that have been associated with altered expression of neuroimmune proteins. The extracellular matrix (ECM) influences cellular phenotypes. However, a relationship between the lung ECM and fibrocytes in SSc has not been explored. The aim of this study was to use a novel translational platform based on decellularized human lungs to determine whether the lung ECM of patients with scleroderma controls the development of fibrocytes from peripheral blood mononuclear cells. We performed biomechanical evaluation of decellularized scaffolds prepared from lung explants from healthy control subjects and patients with scleroderma, using tensile testing and biochemical and proteomic analysis. Cells obtained from healthy controls and patients with SSc-related ILD were cultured on these scaffolds, and CD45+pro-ColIα1+ cells meeting the criteria for fibrocytes were quantified. The contribution of the neuromolecule netrin-1 to fibrosis was assessed using neutralizing antibodies in this system and by administering bleomycin via inhalation to netrin-1(+/-) mice. Compared with control lung scaffolds, lung scaffolds from patients with SSc-related ILD showed aberrant anatomy, enhanced stiffness, and abnormal ECM composition. Culture of control cells in lung scaffolds from patients with SSc-related ILD increased production of pro-ColIα1+ cells, which was stimulated by enhanced stiffness and abnormal ECM composition. Cells from patients with SSc-related ILD demonstrated increased pro-ColIα1 responsiveness to lung scaffolds from scleroderma patients but not enhanced stiffness. Enhanced detection of netrin-1-expressing CD14(low) cells in patients with SSc-related ILD was observed, and antibody-mediated netrin-1 neutralization attenuated detection of CD45+pro-ColIα1+ cells in all settings. Netrin-1(+/-) mice were

Outcome of patients older than 60 years with classical Hodgkin lymphoma treated with front line ABVD chemotherapy: frequent pulmonary events suggest limiting the use of bleomycin in the elderly.

Science.gov (United States)

Stamatoullas, Aspasia; Brice, Pauline; Bouabdallah, Reda; Mareschal, Sylvain; Camus, Vincent; Rahal, Ilhem; Franchi, Patricia; Lanic, Hélène; Tilly, Hervé

2015-07-01

There is no standard of care in elderly classical Hodgkin lymphoma (cHL) patients. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), the standard chemotherapy for younger patients, is also used in elderly patients but little is known about toxicity and efficacy. We retrospectively analysed 147 patients aged 60 years and over treated with ABVD in three French haematological centres. Treatment regimen modification was applied in 56 patients for toxicity or HL progression. Bleomycin was removed or reduced in 53 patients, mainly for pulmonary toxicity. Neither initial characteristics nor treatment characteristics were found to correlate with lung toxicity. One hundred and seventeen patients achieved a complete remission, 6 a partial remission, 16 had refractory disease and 8 were non-evaluable. Five-year overall survival was estimated at 67%. With a median follow-up of 58 months, 51 patients died and 14% of deaths were related to lung toxicity. Our study confirms the efficacy of ABVD in elderly patients even if results are inferior to those obtained in younger patients with the same regimen. ABVD can be proposed as front-line chemotherapy in selected elderly cHL patients. The frequency of pulmonary events leads us to propose to either reduce the dose of bleomycin or to remove it from the regimen. © 2015 John Wiley & Sons Ltd.

57Co-labelled bleomycin scintigraphy for the detection of lung cancer

International Nuclear Information System (INIS)

Slosman, D.; Polla, B.; Townsend, D.; Egeli, R.; Huber, P.; Megevand, R.; Donath, A.; Junod, A.

1985-01-01

The sensitivity and specificity of scanning with 57 Co-labelled bleomycin for the diagnosis of lung cancer were determined from a prospective study involving a large group of patients with an abnormal chest roentgenogram. A semi-quantitative analysis of the scintigram was obtained by defining an index in terms of the excess isotope uptake within the tumour. Malignant pulmonary lesions were found in 121/175 patients and 113 had a positive scan. Benign pulmonary disorders were found in 54 patients, 45 of whom had a negative scan. The sensitivity and specificity were therefore 93% and 83% respectively. Bayes' theorem was then used to determine the predictive value of this test, either positive or negative, when the prevalence of disease varied from 10 to 90%. A receiver operating characteristic curve permits the choice of an appropriate value of the tumor uptake index to minimize the false positive fraction without classifying too many true positives as false negatives. (author)

Escleroterapia con bleomicina en malformaciones vasculares de bajo flujo: Experiencia y revisión del tema Bleomycin sclerotherapy for low-flow vascular malformations: our experience and literature review

Directory of Open Access Journals (Sweden)

F. Lobo Bailón

2012-12-01

Full Text Available Las anomalías vasculares son lesiones típicas de los pacientes pediátricos y se dividen en dos categorías: tumores vasculares y malformaciones vasculares de alto y bajo flujo. Estas últimas pueden tratarse de diversos modos: laserterapia, drenaje, aspiración, cirugía o escleroterapia, dependiendo del tipo de lesión y de su localización. Entre los agentes esclerosantes utilizados, la bleomicina ha demostrado tener buenos resultados en el tratamiento de estas lesiones. En este artículo presentamos nuestra experiencia en el tratamiento de las malformaciones vasculares de bajo flujo mediante escleroterapia con bleomicina intralesional. Desarrollamos un estudio descriptivo retrospectivo sobre 30 pacientes que presentaban malformación vascular de bajo flujo y fueron tratados con bleomicina intralesional. Los resultados fueron buenos o excelentes en 22 pacientes y regulares o malos en los 8 restantes. De acuerdo a nuestra casuística y a la literatura revisada, la escleroterapia con bleomicina es una alternativa terapéutica eficaz y segura en el tratamiento de las malformaciones vasculares de bajo flujo.Vascular anomalies are common in children and can be divided into two categories, vascular tumours and vascular malformations: high-flow or low-flow. The latter can be treated in different ways such as lasertherapy, drainage, aspiration, surgery or sclerotherapy depending on the type and location of the lesion. Among the accepted sclerosing agents, bleomycin has proven good results in the treatment of this condition. Herein we present our experience in the treatment of low-flow vascular malformations with intralesional bleomycin injection. This is a retrospective, descriptive study with 30 patients presenting a low-flow vascular malformation treated with intralesional bleomycin injection. Our results are good or excellent in 22 patients and poor in the other 8. According to our case series and the consulted literature, sclerotherapy with

Radiotherapy Does Not Influence the Severe Pulmonary Toxicity Observed With the Administration of Gemcitabine and Bleomycin in Patients With Advanced-Stage Hodgkin's Lymphoma Treated With the BAGCOPP Regimen: A Report by the German Hodgkin's Lymphoma Study Group

International Nuclear Information System (INIS)

Macann, Andrew; Bredenfeld, Henning; Mueller, Rolf-Peter; Diehl, Volker; Engert, Andreas; Eich, Hans Theodor

2008-01-01

Purpose: To evaluate the effect of radiotherapy on the severe pulmonary toxicity observed in the pilot study of BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine) for advanced-stage Hodgkin's lymphoma. Methods and Materials: Patients with Stage III or IV Hodgkin's lymphoma or Stage IIB with risk factors participated in this single-arm, multicenter pilot study. Results: Twenty-seven patients were enrolled on the study before its premature closure as a result of the development of serious pulmonary toxicity in 8 patients. The pulmonary toxicity occurred either during or immediately after the BAGCOPP chemotherapy course. Pulmonary toxicity contributed to one early fatality but resolved in the other 7 patients after cessation of gemcitabine and bleomycin, allowing continuation of therapy. Fifteen patients received consolidative radiotherapy, including 4 who previously had pulmonary toxicity. There were no reported cases of radiation pneumonitis and no exacerbation of pulmonary symptoms in the 4 patients who had had previous pulmonary toxicity. Conclusions: The severe pulmonary toxicity observed in this study has been attributed to an interaction between gemcitabine and bleomycin. Gemcitabine (when administered without bleomycin) remains of interest in Hodgkin's lymphoma and is being incorporated into a new German Hodgkin's Lymphoma Study Group protocol that also includes consolidative radiotherapy. This study supports the concept of the integration of radiotherapy in gemcitabine-containing regimens in Hodgkin's lymphoma if there is an interval of at least 4 weeks between the two modalities and with a schedule whereby radiotherapy follows the chemotherapy

Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin

DEFF Research Database (Denmark)

Lauritsen, Jakob; Kier, Maria Gry Gundgaard; Bandak, Mikkel

2016-01-01

PURPOSE: For patients with germ cell cancer, various pulmonary toxicity risk factors have been hypothesized for treatment with bleomycin, etoposide, and cisplatin (BEP). Because existing studies have shortcomings, we present a large, unselected cohort of patients who have undergone close monitoring...... expiratory volume in 1 second and forced vital capacity remained unchanged after BEP but increased significantly to levels above pretreatment during follow-up. International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic group, mediastinal primary, pulmonary metastases, and smoking all...... PFT. CONCLUSION: After 5 years of follow-up, pulmonary impairment in patients with germ cell cancer who were treated with BEP was limited. Exceptions were patients treated with pulmonary surgery, those who suffered pulmonary embolism, and those in the IGCCCG poor prognostic group....

Prognostic Factors and Treatment Results After Bleomycin, Etoposide, and Cisplatin in Germ Cell Cancer

DEFF Research Database (Denmark)

Kier, Maria G; Lauritsen, Jakob; Mortensen, Mette S

2017-01-01

BACKGROUND: First-line treatment for patients with disseminated germ cell cancer (GCC) is bleomycin, etoposide, and cisplatin (BEP). A prognostic classification of patients receiving chemotherapy was published by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, but only...... a small proportion of the patients received BEP. OBJECTIVE: To estimate survival probabilities after BEP, evaluate the IGCCCG prognostic classification, and propose new prognostic factors for outcome. DESIGN, SETTING, AND PARTICIPANTS: Of a Danish population-based cohort of GCC patients (1984-2007), 1889...... received first-line BEP, with median follow-up of 15 yr. Covariates evaluated as prognostic factors were age, year of treatment, primary site, non-pulmonary visceral metastases, pulmonary metastases, and tumor markers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes measured were 5-yr progression...

Bleomycin effect on L5178Y cells

International Nuclear Information System (INIS)

Zaim, J.; Kruszewski, M.; Gradzka, I.

1997-01-01

We analyzed the effects of treatment with bleomycin (BLM) in 2 sublines of L5178Y (LY) murine lymphoma, LY-R, radioresistant, and LY-S, radiosensitive. LY-S cells were 2 times more sensitive to BLM than LY-R cells, similarly as in the case of X rays. Since there was no difference in the activity of drug transport system, this different susceptibility to BLM probably was due to the DNA repair defect in LY-S cells. Growth was impaired proportionally to the lethal effect and continued (days 3-6 after treatment with 50 microM BLM) until the elimination of dead cells from the cell population; 24 h after treatment cell cycle distributions indicated the presence of block in S phase (proportional to the dose of BLM). Contrarily to X or gamma-irradiation, BLM did not induce any block in the G2 phase. Initial DNA damage, estimated by the single cell gel electrophoresis, was linearly related to the dose of BLM in LY-S cells; in LY-R cells the damage level was significantly higher than in LY-S cells. In the higher (>10 microM BLM) dose range both dose - effect curves became identical. In gamma-irradiated LY-R and LY-S cells the dose - effect curves were identical. DNA damage distribution in BLM treated LY cells was much less uniform than in the gamma-irradiated ones; it indicated the presence of heavily damaged cells, a feature typical for BLM action. (author). 29 refs, 28 figs

Effect of time between x-irradiation and chemotherapy on the growth of three solid mouse tumors. V. Bleomycin

International Nuclear Information System (INIS)

Twentyman, P.R.; Kallman, R.F.; Brown, J.M.

1979-01-01

Experiments have been carried out to determine the effect of different time intervals between the administration of x-radiation (1200 rad) and bleomycin (20 mg/kg) on the growth delay produced in three mouse tumors. The tumors used were the EMT6 tumor in BALB/c mice and the KHT and RIF-1 sarcomas in C3H mice. All tumors were grown intramuscularly in the gastrocnemius muscle and treatment was carried out at a mean tumor weight of 450 mg. Time to reach 2X (for KHT) or 4X (for EMT6 and RIF-1) treatment volume was used as the endpoint of response. The drug was administered by the intraperitoneal route either 24, 6, or 2 hr before radiation, immediately before the start of radiation, or 3, 6, or 24 hr after radiation. All irradiations were carried out in unanesthetized mice. For a single administration at this dose level, bleomycin alone did not produce a significant growth delay in any of the tumors. In the RIF-1 tumor, growth delays following combination treatments were equal to the addition of the single agent growth delays. In two experiments with EMT6, contrary results were obtained, one producing longer delays following combination treatments than predicted and the other producing shorter delays. This is apparently due to the variability in the growth delay after treatment with radiation alone for this tumor. For the KHT tumor, only small differences from the addition of single agent delays were seen

The effects of interaction between Nanoanatase TiO2 and bleomycin sulfateon the lactate dehydrogenase activity in vivo

OpenAIRE

Roshanak Ghafarian Zirak; Akram Lotfi; Masoud Saleh Moghadam

2016-01-01

Although it is known that Nano TiO2 can induce various toxicities, the effects of its interaction with organic and biological molecules are still unclear. In this study, the effects of Nanoanatase TiO2 on lactate dehydrogenase (LDH) alone and in the presence of bleomycin sulfate (BLM.S), as an organic chemical, were investigated. Three doses of Nano TiO2 (10, 100, 500 mg/Kg BW) were injected into the abdominal cavity of Balb/C mice for 24 h. In addition, a particular dose of BLM.S (120 mg/...

Meiotic and Mitotic Phenotypes Conferred by the blm1-1 Mutation in Saccharomyces cerevisiae and MSH4 Suppression of the Bleomycin Hypersusceptibility

Directory of Open Access Journals (Sweden)

Carol Wood Moore

2003-01-01

Full Text Available Abstract: Oxidative damage can lead to a number of diseases, and can be fatal. The blm1-1 mutation of Saccharomyces cerevisiae confers hypersusceptibility to lethal effects of the oxidative, anticancer and antifungal agent, bleomycin. For the current report, additional defects conferred by the mutation in meiosis and mitosis were investigated. The viability of spores produced during meiosis by homozygous normal BLM1/BLM1, heterozygous BLM1/blm1-1, and homozygous mutant blm1-1/blm1-1 diploid strains was studied and compared. Approximately 88% of the tetrads derived from homozygous blm1-1/blm1-1 mutant diploid cells only produced one or two viable spores. In contrast, just one tetrad among all BLM1/BLM1 and BLM1/blm1-1 tetrads only produced one or two viable spores. Rather, 94% of BLM1/BLM1 tetrads and 100% of BLM1/blm1-1 tetrads produced asci with four or three viable spores. Thus, at least one copy of the BLM1 gene is essential for the production of four viable spores after meiosis. During mitotic growth, mutant blm1-1 strains grew at reduced rates and produced cells with high frequencies of unusual morphologies compared to wild-type strains. These results indicated BLM1 is also essential for normal mitotic growth. We also investigated the suppression by the MSH4 gene, a meiosis-specific MutS homolog, of the bleomycin hypersusceptibility of blm1-1 mutant cells, and the relationship of MSH4 to BLM1. We screened a genomic library, and isolated the MSH4 gene on the basis of its ability to suppress lethal effects of bleomycin in blm1-1 cells. However, genetic mapping studies indicated that BLM1 and MSH4 are not the same gene. The possibility that chromosomal nondisjunction could be the basis for the inability of blm1-1/blm1-1 mutant cells to produce four viable spores after meiosis is discussed.

Treatment of carcinoma of uterine cervix stage III by adriamycin, bleomycin and cisplatinum, neoadjuvant, modified radical hysterectomy and adjuvant chemotherapy

International Nuclear Information System (INIS)

Valle, J.C. do; Ribeiro, C.W.; Rezende, Magda C.; Figueiredo, E.; Chu, C.

1987-01-01

Forty-eight patients with untreated carcinoma of the cervix stage III A and IIIB, were submitted to 3 to 5 cycles of a combination of adriamycin (ADR), bleomycin (BLEO) and cisplatinum (CDDP), followed by modified radical hysterectomy and adjuvant chemotherapy, 6 cycles, of the same association. The surgical aspect is emphasized and the operative sequence is described. A comparative evaluation between the treatment presented and the radiotherapy is done. The survical rate is studied. (M.A.C.) [pt

Anti-tumour action of 64Cu-bleomycin on Ehrlich ascites tumour cells in vivo

International Nuclear Information System (INIS)

Maki, Hirotoshi; Kawai, Kenichi; Akaboshi, Mitsuhiko

1979-01-01

The anti-tumor action of the complex of Bleomycin (BLM) with high specific-radioactivity 64 Cu on Ehrlich ascites tumour (EAT) was studied in vivo. The 64 Cu-BLM was administered into intraperitoneal cavity of mice from 1 to 4 days after inoculation of EAT cells. The effect of 64 Cu-BLM to suppress the tumour growth as demonstrated by prolonging life span was observed. The amounts of 64 Cu-BLM (800 μCi-8 mg/Kg) were administered at 4, 8 and 16 times separately. Then, the shorter the time interval and the less the amounts of drugs at a time, the higher the suppressing effect for the tumour growth was. It was confirmed that anti-tumour action of 64 Cu-BLM was in all the cases higher than that of BLM alone. (author)

Interaction of the antiemetics ondansetron and granisetron with the cytotoxicity induced by irradiation, epirubicin, bleomycin, estramustine, and cisplatin in vitro

Energy Technology Data Exchange (ETDEWEB)

Behnam Motlagh, P. [Dept. of Oncology, Umeaa Univ. Hospital (Sweden); Henriksson, R. [Dept. of Oncology, Umeaa Univ. Hospital (Sweden); Grankvist, K. [Dept. of Clinical Chemistry, Umeaa Univ. Hospital (Sweden)

1995-12-31

At cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting. Some antiemetics have been shown to interact with the direct cytotoxic effects. The newly developed antiemetics have, so far as we know, not been studied in this respect. In the present study, the effects of the 5-HT{sub 3} receptor antagonists ondansetron and granisetron were evaluated on the cytotoxicity, induced by irradiation, bleomycin, epirubicin, estramustine, and cisplatin using fibroblasts (V79) and lung cancer cells (P31) in vitro. Ondansetron or granisetron (10{sup -5} mol/l) had no effect on the survival of irradiated cells. Granisetron (10{sup -5} mol/l) significantly potentiated cytoxocity of 2.5 mg/l epirubicin on fibroblasts whereas the effect of granisetron (10{sup -7} mol/l) on the cytotoxic effect of 25 mg/l bleomycin, and estramustine (80 mg/l) seemed additive to lung cancer cells. Ondansetron was non-interactive with the cytotoxicity induced by any of the anti-cancer drugs. Although the encountered observation with an enhancing effect of granisetron on the epirubicin-induced cytotoxicity is seen in a specific experimental situation in vitro, the fact that 5-HT{sub 3} receptor antagonists are routinely used during cancer treatment indicate that attention should be given to a possible interaction with the antineoplastic action of cancer treatment. (orig.).

Interaction of the antiemetics ondansetron and granisetron with the cytotoxicity induced by irradiation, epirubicin, bleomycin, estramustine, and cisplatin in vitro

International Nuclear Information System (INIS)

Behnam Motlagh, P.; Henriksson, R.; Grankvist, K.

1995-01-01

At cancer treatment, the use of antiemetics are often needed due to induction of nausea and vomiting. Some antiemetics have been shown to interact with the direct cytotoxic effects. The newly developed antiemetics have, so far as we know, not been studied in this respect. In the present study, the effects of the 5-HT 3 receptor antagonists ondansetron and granisetron were evaluated on the cytotoxicity, induced by irradiation, bleomycin, epirubicin, estramustine, and cisplatin using fibroblasts (V79) and lung cancer cells (P31) in vitro. Ondansetron or granisetron (10 -5 mol/l) had no effect on the survival of irradiated cells. Granisetron (10 -5 mol/l) significantly potentiated cytoxocity of 2.5 mg/l epirubicin on fibroblasts whereas the effect of granisetron (10 -7 mol/l) on the cytotoxic effect of 25 mg/l bleomycin, and estramustine (80 mg/l) seemed additive to lung cancer cells. Ondansetron was non-interactive with the cytotoxicity induced by any of the anti-cancer drugs. Although the encountered observation with an enhancing effect of granisetron on the epirubicin-induced cytotoxicity is seen in a specific experimental situation in vitro, the fact that 5-HT 3 receptor antagonists are routinely used during cancer treatment indicate that attention should be given to a possible interaction with the antineoplastic action of cancer treatment. (orig.)

Bleomycin as adjuvant in radiation therapy of advanced squamous cell carcinoma in head and neck

Energy Technology Data Exchange (ETDEWEB)

Rygaard, J [Koepenhavn Amts. Sygehus, Herlev (Denmark). Dept. of oncology and Radiotherapy; Hansen, H S [Radium Centre, Copenhagen (Denmark)

1979-09-01

Since 1969, Bleomycin (BLM) has been used in three different ways at the Radium Centre in Copenhagen. First BLM given as the sole treatment led to complete regressions in 12% of 138 patients. Secondly BLM was used as simultaneous adjuvant in radiation therapy for 86 previously untreated patients, but 66% developed mucositis which disrupted the treatment. In a third period BLM was therefore combined sequentially with radiation, administered for 2 weeks prior to radiation therapy to 142 patients. The tumour shrinkage achieved with preirradiation BLM was very pronounced in 38 % of cases. 101 patients with T3 tumours have been observed for a minimum of 3 years. The prognostic value of the degree of shrinkage achieved with preirradiation BLM treatment is discussed.

Accurate and rapid modeling of iron–bleomycin-induced DNA damage using tethered duplex oligonucleotides and electrospray ionization ion trap mass spectrometric analysis

OpenAIRE

Harsch, Andreas; Marzilli, Lisa A.; Bunt, Richard C.; Stubbe, Joanne; Vouros, Paul

2000-01-01

Bleomycin B2 (BLM) in the presence of iron [Fe(II)] and O2 catalyzes single-stranded (ss) and double-stranded (ds) cleavage of DNA. Electrospray ionization ion trap mass spectrometry was used to monitor these cleavage processes. Two duplex oligonucleotides containing an ethylene oxide tether between both strands were used in this investigation, allowing facile monitoring of all ss and ds cleavage events. A sequence for site-specific binding and cleavage by Fe–BLM was incorporated into each an...

Diagnostic value of female genital malignant tumors by using 111In-bleomycin scintigraphy

International Nuclear Information System (INIS)

Kida, Toshiyuki; Ikeda, Masanori; Saito, Masaru

1978-01-01

In order to know if it is possible to objectively decide the extent of infiltration of female genital malignant tumors into parametrium by using 111 In-bleomycin scintigraphy, a fundamental and clinical investigation was made. The radiochemical purity and stability of 111 In-BLM were comparatively unchangeable. When this complex was kept at room temperature for a week, there was not more than 2% of the free 111 In. As to blood clearance, when the blood radioactivity of 111 In-BLM 5 minutes after the injection was counted as 100%, about 80% of the radioactivity was cleared from the blood in 48 hours. Over 50% of the radioactivity was excreted into the urine in 48 hours. Of 29 cases of female genital malignant tumors, 23 cases (79%) showed positive images. Therefore 111 In-BLM was found to be one of the suitable radiopharmaceuticals for the diagnosis of female genital malignant tumors. 111 In-BLM scintigraphy was of great use for deciding the extent of the invasion of carcinoma cervicis uteri into parametrium and for the search of metastasis. (author)

57Co-bleomycin imaging study of tumors of the head and neck

International Nuclear Information System (INIS)

Sawas-Dimopoulou, C.; Pantazopoulos, P.; Dokianakis, G.; Apostolopoulos, N.; Papafrangou, C.

1978-01-01

57 Co-Bleomycin ( 57 Co-BLM) was used to visualize malignancies of the head and neck because it does not present the disadvantages of many other radiopharmaceuticals. In a series of 21 patients with 9 control subjects and 12 cases of tumors, 57 Co-BLM showed a high and rapid uptake in primary site and metastases of malignant tumors of various histologic types, but not in benign tumors such as angiofibromas. Compared to 67 Ga-citrate, 57 Co-BLM has many advantages for tumor imaging in the areas of nose, pharynx and larynx: No background activity due to the concentration of 57 Co-BLM in normal structures of the head and neck has ever been observed, as opposed to what happens with 67 Ga-citrate. Furthermore, the blood clearance of 57 Co-BLM is much more rapid than that of 67 Ga-citrate, so that an early study may be performed in a 6 to 24 hr interval instead of 48 to 72 hr with 67 Ga-citrate. 57 Co-BLM scintigraphy is an easy, non-invasive and sensible diagnostic technique in determining the extent of malignant tumors in ORL patients

Treatment results of bleomycin or peplomycin combined with radiotherapy for patients with squamous cell carcinoma of the lower gum

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Matayoshi, Yoshinobu; Masaki, Norie

1986-01-01

Retrospective analysis was made of 108 patients with squamous cell carcinoma of the lower gum treated by radiotherapy(30 Gy/3 W) with chemotherapy(Bleomycin 90 mg or Peplomycin 45 mg). Of these 57 patients(53 %) showed complete regression(CR) of the tumor. 38 patients of CR after radiation-chemotherapy regimen were obserbed without additional treatment. Of these patients local control rate at 2-year were 63 % for T1 · T2 lesions, 40 % for T3 and 33 % for T4. Ultimate control rates were increased to 89 % for T1 · T2, 80 % for T3 and 33 % T4 lesions with successful salvage treatment with surgery. (author)

A Case of Massive Pleural Effusion: Pleurodesis by Bleomycin.

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Hasan, R; Khan, O S; Aftabuddin, M; Razzaque, A M; Chowdhury, G A

2016-04-01

Malignant pleural effusion is a common complication of primary and metastatic pleural malignancies. Pleurodesis for the management of malignant pleural effusion is intended to achieve symphysis between parietal and visceral pleura, and to prevent relapse of pleural effusion. Many chemical agents are tried to induce inflammation and damage of the pleural mesothelial layer to achieve this symphysis. Hemorrhagic pleural effusion, especially in the right hemithorax commonly occurs as presentation of primary and metastatic pleural malignancies. This case reports massive right-sided hemorrhagic pleural effusion as the sole manifestation of primary lung cancer in a 45 year old man. Patient attended our department of thoracic surgery complaining of cough, shortness of breath and right sided chest pain. A chest X-ray and chest computer tomography (CT) radiograph shows right sided massive pleural effusion. Right sided tube thoracotomy done. Pleural fluid study was done. Fluid for cytopathology was positive for malignant cell. Computed tomography guided fine needle aspiration cytology from right lung lesion was also done. Diagnosis was as small cell carcinoma. Pleural effusion resolved after 9(th) post operative day of chest tube insertion. Bleomycin pleurodesis was done. Day after pleurodesis intra thoracic tube was removed and patient was discharged from hospital on 10(th) Post operative day with an advice to attend the oncology department for further treatment. The protocol of tube thoracostomy and chemical pleurodesis was almost always successful in giving symptomatic relief of respiratory distress for a considerable period of time. However, chemical pleurodesis is not possible in all cases of malignant pleural effusion because it has got potential complication including death.

Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

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Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

2014-01-01

Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

Different profiles of notch signaling in cigarette smoke-induced pulmonary emphysema and bleomycin-induced pulmonary fibrosis.

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Li, Shi; Hu, Xiaofei; Wang, Zheng; Wu, Meng; Zhang, Jinnong

2015-05-01

Different profiles of Notch signaling mediate naive T cell differentiation which might be involved in pulmonary emphysema and fibrosis. C57BL/6 mice were randomized into cigarette smoke (CS) exposure, bleomycin (BLM) exposure, and two separate groups of control for sham exposure to CS or BLM. The paratracheal lymph nodes of the animals were analyzed by real-time PCR and immunohistochemistry. Morphometry of the lung parenchyma, measurement of the cytokines, and cytometry of the bronchoalveolar lavage fluid (BALF) were also done accordingly. In comparison with controls, all Notch receptors and ligands were upregulated by chronic CS exposure, especially Notch3 and DLL1 (P emphysema-like morphology and Th1-biased inflammation. While Notch3 and DLL1 were downregulated by BLM exposure (P pulmonary emphysema. Unable to initiate the Th1 response or inhibit it may lead to Th2 polarization and aberrant repair.

MAP3K19 Is a Novel Regulator of TGF-β Signaling That Impacts Bleomycin-Induced Lung Injury and Pulmonary Fibrosis.

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Boehme, Stefen A; Franz-Bacon, Karin; DiTirro, Danielle N; Ly, Tai Wei; Bacon, Kevin B

2016-01-01

Idiopathic pulmonary fibrosis (IPF) is a progressive, debilitating disease for which two medications, pirfenidone and nintedanib, have only recently been approved for treatment. The cytokine TGF-β has been shown to be a central mediator in the disease process. We investigated the role of a novel kinase, MAP3K19, upregulated in IPF tissue, in TGF-β-induced signal transduction and in bleomycin-induced pulmonary fibrosis. MAP3K19 has a very limited tissue expression, restricted primarily to the lungs and trachea. In pulmonary tissue, expression was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. MAP3K19 was also found to be overexpressed in bronchoalveolar lavage macrophages from IPF patients compared to normal patients. Treatment of A549 or THP-1 cells with either MAP3K19 siRNA or a highly potent and specific inhibitor reduced phospho-Smad2 & 3 nuclear translocation following TGF-β stimulation. TGF-β-induced gene transcription was also strongly inhibited by both the MAP3K19 inhibitor and nintedanib, whereas pirfenidone had a much less pronounced effect. In combination, the MAP3K19 inhibitor appeared to act synergistically with either pirfenidone or nintedanib, at the level of target gene transcription or protein production. Finally, in an animal model of IPF, inhibition of MAP3K19 strongly attenuated bleomycin-induced pulmonary fibrosis when administered either prophylactically ortherapeutically. In summary, these results strongly suggest that inhibition of MAP3K19 may have a beneficial therapeutic effect in the treatment of IPF and represents a novel strategy to target this disease.

Preparation, distribution, stability and tumor imaging properties of [62Zn] Bleomycin complex in normal and tumor-bearing mice

International Nuclear Information System (INIS)

Jalilian, A.R.; Fateh, B.; Ghergherehchi, M.; Karimian, A.; Matloobi, M.; Moradkhani, S.; Kamalidehghan, M.; Tabeie, F.

2003-01-01

Backgrounds: Bleomycin (BLM) has been labeled with radioisotopes and widely used in therapy and diagnosis. In this study BLM was labeled with [ 62 Zn] zinc chloride for oncologic PET studies. Materials and methods: The complex was obtained at the P H=2 normal saline at 90 d eg C in 60 min. Radio-TLC showed on overall radiochemical yield of 95-97% (radiochemical purity>97%). Stability of complex was checked in vitro in mice and human plasma/urine. Results: Preliminary in vitro studies performed to determined complex stability and distribution of [ 62 Zn] BLM in normal and fibrosarcoma tumors in mice according to bio-distribution/imaging studies. Conclusion: [ 62 Zn] BLM can be used in PET oncology studies due to its suitable physico-chemical propertied as a diagnostic complex behavior in higher animals

The effects of combined treatment with radiation and bleomycin on the oral carcinoma involving the mandible

International Nuclear Information System (INIS)

Okamoto, Manabu; Ozeki, Satoru; Higuchi, Yoshinori; Tashiro, Hideo

1988-01-01

The effect of concurrent combined treatment with 22.5 Gy of radiation and 110 mg of bleomycin or 55 mg of peplomycin on oral carcinoma involving the mandible was examined histologically. In 14 of 18 patients who had mandibles resected after this combined treatment, bone invasion by carcinoma was observed histologically. According to Shimosato's classification of histological effects, 3 belonged to Grade III/IV, 4 to IIb, 3 to IIa and 4 to I. The formation of new bone that was considered to be reparable was observed in the marked effective patients. In 4 patients the Grade IIb, residual surviving cancer cells were observed in the mandible. Accordingly, excision was needed in the area of radiologic features of mandibular infiltration. But it is considered that although the excision scope for the patient who has received the preoperative treatment is the same as that for the patient who has not, it is advantageous for the former patient that a wider safety region is obtained. (author)

Induction of complete and incomplete chromosome aberrations by bleomycin in human lymphocytes

International Nuclear Information System (INIS)

Benkhaled, L.; Xuncla, M.; Caballin, M.R.; Barrios, L.; Barquinero, J.F.

2008-01-01

Bleomycin (BLM) is a clastogenic compound, which due to the overdispersion in the cell distribution of induced dicentrics has been compared to the effect of high-LET radiation. Recently, it has been described that in fibroblast derived cell lines BLM induces incomplete chromosome elements more efficiently than any type of ionizing radiation. The objective of the present study was to evaluate in human lymphocytes the induction of dicentrics and incomplete chromosome elements by BLM. Peripheral blood samples have been treated with different concentrations of BLM. Two cytogenetic techniques were applied, fluorescence plus Giemsa (FPG) and FISH using pan-centromeric and pan-telomeric probes. The observed frequency of dicentric equivalents increases linearly with the BLM concentration, and for all BLM concentrations the distribution of dicentric equivalents was overdispersed. In the FISH study the ratio between total incomplete elements and multicentrics was 0.27. The overdispersion in the dicentric cell distribution, and the linear BLM-concentration dependence of dicentrics can be compared to the effect of high-LET radiation, on the contrary the ratio of incomplete elements and multicentrics is similar to the one induced by low-LET radiation (∼0.40). The elevated proportion of interstitial deletions in relation to total acentric fragments, higher than any type of ionizing radiation could be a characteristic signature of the clastogenic effect of BLM

Intermittent Hypoxia Increases the Severity of Bleomycin-Induced Lung Injury in Mice

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Thomas Gille

2018-01-01

Full Text Available Background. Severe obstructive sleep apnea (OSA with chronic intermittent hypoxia (IH is common in idiopathic pulmonary fibrosis (IPF. Here, we evaluated the impact of IH on bleomycin- (BLM- induced pulmonary fibrosis in mice. Methods. C57BL/6J mice received intratracheal BLM or saline and were exposed to IH (40 cycles/hour; FiO2 nadir: 6%; 8 hours/day or intermittent air (IA. In the four experimental groups, we evaluated (i survival; (ii alveolar inflammation, pulmonary edema, lung oxidative stress, and antioxidant enzymes; (iii lung cell apoptosis; and (iv pulmonary fibrosis. Results. Survival at day 21 was lower in the BLM-IH group (p<0.05. Pulmonary fibrosis was more severe at day 21 in BLM-IH mice, as assessed by lung collagen content (p=0.02 and histology. At day 4, BLM-IH mice developed a more severe neutrophilic alveolitis, (p<0.001. Lung oxidative stress was observed, and superoxide dismutase and glutathione peroxidase expression was decreased in BLM-IH mice (p<0.05 versus BLM-IA group. At day 8, pulmonary edema was observed and lung cell apoptosis was increased in the BLM-IH group. Conclusion. These results show that exposure to chronic IH increases mortality, lung inflammation, and lung fibrosis in BLM-treated mice. This study raises the question of the worsening impact of severe OSA in IPF patients.

Preparation of sup(99m)Tc-bleomycin with electrogenerated tin(II) ions

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Pihlar, B; Marsel, J; Tasic, D [Ljubljana Univ. (Yugoslavia); Erjavec, M [Institute of Oncology, Ljubljana (Yugoslavia)

1978-01-01

Some parameters influencing the efficiency of labelling bleomycin (BLM) with sup(99m)Tc using tin electrodes for electrolytic production of tin(II) ions were investigated. The results showed clearly the superiority of tin electrodes for labelling BLM with sup(99m)Tc in comparison with Zn electrodes. The alteration of the primary properties of BLM is negligible. The optimal procedure for the labelling of BLM is as follows. Into a vessel (15-20 cm/sup 3/) containing the corresponding amount of BLM in saline, and the desired amount of sup(99m)TcO/sub 4//sup -/ eluate in 0.9% NaCl, 0.5 ml 0.5 M HCl is added and diluted with saline to 10 ml. The electrolysis is performed using tin electrodes with a current density of about 6 mA/cm/sup 2/ for 10 to 20 s with stirring, which is prolonged after electrolysis for a few minutes. After filtration through a 0.22 ..mu..m Millipore filter, the labelled compound can be used for clinical applications. For analytical control of labelled BLM, gel filtration on Sephadex G-25 with UV and radioactivity detection can be recommended. From the results obtained, it has been concluded that gel filtration on Sephadex G-25 can give applicable information about the quality of this radiopharmaceutical.

Successful treatment of multiple basaliomas with bleomycin-based electrochemotherapy: a case series of three patients with Gorlin-Goltz syndrome.

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Kis, Erika; Baltás, Eszter; Kinyó, Agnes; Varga, Erika; Nagy, Nikoletta; Gyulai, Rolland; Kemény, Lajos; Oláh, Judit

2012-11-01

Gorlin-Goltz syndrome is a rare multisystemic disease, characterized by numerous basal cell carcinomas. The ideal approach for patients with the syndrome would be a treatment with a high cure rate, minimal scarring, short healing time and mild side-effects. Electrochemo-therapy is a novel therapeutic option that ablates tumours with electrical current and simultaneously administered anticancer drugs. Three patients with Gorlin-Goltz syndrome were treated with electrochemotherapy using intravenous bleomycin. Clinical response was obtained in 98 (99%) of the lesions, 86 (87%) of them showed complete response. In 2 tumours, regression was confirmed with histological examination. Long-term cosmetic results were excellent. We consider electrochemotherapy to be an additional tool in the therapeutic armamentarium for Gorlin-Goltz syndrome, and suggest using it as early as possible in selected patients to avoid disfiguring scarring.

Selective tumor cell targeting by the disaccharide moiety of bleomycin.

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Yu, Zhiqiang; Schmaltz, Ryan M; Bozeman, Trevor C; Paul, Rakesh; Rishel, Michael J; Tsosie, Krystal S; Hecht, Sidney M

2013-02-27

In a recent study, the well-documented tumor targeting properties of the antitumor agent bleomycin (BLM) were studied in cell culture using microbubbles that had been derivatized with multiple copies of BLM. It was shown that BLM selectively targeted MCF-7 human breast carcinoma cells but not the "normal" breast cell line MCF-10A. Furthermore, it was found that the BLM analogue deglycobleomycin, which lacks the disaccharide moiety of BLM, did not target either cell line, indicating that the BLM disaccharide moiety is necessary for tumor selectivity. Not resolved in the earlier study were the issues of whether the BLM disaccharide moiety alone is sufficient for tumor cell targeting and the possible cellular uptake of the disaccharide. In the present study, we conjugated BLM, deglycoBLM, and BLM disaccharide to the cyanine dye Cy5**. It was found that the BLM and BLM disaccharide conjugates, but not the deglycoBLM conjugate, bound selectively to MCF-7 cells and were internalized. The same was also true for the prostate cancer cell line DU-145 (but not for normal PZ-HPV-7 prostate cells) and for the pancreatic cancer cell line BxPC-3 (but not for normal SVR A221a pancreas cells). The targeting efficiency of the disaccharide was only slightly less than that of BLM in MCF-7 and DU-145 cells and comparable to that of BLM in BxPC-3 cells. These results establish that the BLM disaccharide is both necessary and sufficient for tumor cell targeting, a finding with obvious implications for the design of novel tumor imaging and therapeutic agents.

Endogenous annexin A1 counter-regulates bleomycin-induced lung fibrosis

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Flower Roderick J

2011-10-01

Full Text Available Abstract Background The balancing functions of pro/anti-inflammatory mediators of the complex innate responses have been investigated in a variety of experimental inflammatory settings. Annexin-A1 (AnxA1 is one mediator of endogenous anti-inflammation, affording regulation of leukocyte trafficking and activation in many contexts, yet its role in lung pathologies has been scarcely investigated, despite being highly expressed in lung cells. Here we have applied the bleomycin lung fibrosis model to AnxA1 null mice over a 21-day time-course, to monitor potential impact of this mediator on the control of the inflammatory and fibrotic phases. Results Analyses in wild-type mice revealed strict spatial and temporal regulation of the Anxa1 gene, e.g. up-regulation in epithelial cells and infiltrated granulocytes at day 7, followed by augmented protein levels in alveolar macrophages by day 21. Absence of AnxA1 caused increases in: i the degree of inflammation at day 7; and ii indexes of fibrosis (assessed by deposition of hydroxyproline in the lung at day 7 and 21. These alterations in AnxA1 null mice were paralleled by augmented TGF-β1, IFN-γ and TNF-α generation compared to wild-type mice. Finally, treatment of wild type animals with an AnxA1 peptido-mimetic, given prophylactically (from day 0 to 21 or therapeutically (from day 14 onward, ameliorated both signs of inflammation and fibrosis. Conclusion Collectively these data reveal a pathophysiological relevance for endogenous AnxA1 in lung inflammation and, more importantly, fibrosis, and may open new insights for the pharmacological treatment of lung fibrosis.

Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

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Ken Murakami

Full Text Available Sphingosine-1-phosphate (S1P is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein-coupled receptors (S1P1-5. Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1 or transforming growth factor β1 (TGF-β1 levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.

Bleomycin-Loaded pH-Sensitive Polymer–Lipid-Incorporated Liposomes for Cancer Chemotherapy

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Eiji Yuba

2018-01-01

Full Text Available Cancer chemotherapeutic systems with high antitumor effects and less adverse effects are eagerly desired. Here, a pH-sensitive delivery system for bleomycin (BLM was developed using egg yolk phosphatidylcholine liposomes modified with poly(ethylene glycol-lipid (PEG-PE for long circulation in the bloodstream and 2-carboxycyclohexane-1-carboxylated polyglycidol-having distearoyl phosphatidylethanolamine (CHexPG-PE for pH sensitization. The PEG-PE/CHexPG-PE-introduced liposomes showed content release responding to pH decrease and were taken up by tumor cells at a rate 2.5 times higher than that of liposomes without CHexPG-PE. BLM-loaded PEG-PE/CHexPG-PE-introduced liposomes exhibited comparable cytotoxicity with that of the free drug. Intravenous administration of these liposomes suppressed tumor growth more effectively in tumor-bearing mice than did the free drug and liposomes without CHexPG-PE. However, at a high dosage of BLM, these liposomes showed severe toxicity to the spleen, liver, and lungs, indicating the trapping of liposomes by mononuclear phagocyte systems, probably because of recognition of the carboxylates on the liposomes. An increase in PEG molecular weight on the liposome surface significantly decreased toxicity to the liver and spleen, although toxicity to the lungs remained. Further improvements such as the optimization of PEG density and lipid composition and the introduction of targeting ligands to the liposomes are required to increase therapeutic effects and to reduce adverse effects.

The distribution of a new /sup 111/In-Bleomycin complex in tumor cells by autoradiography

International Nuclear Information System (INIS)

Hou, D.Y.; Maruyama, Y.

1987-01-01

A new radioactive form of Bleomycin (/sup 111/In-BLMC) was effective for tumor imaging and therapy in mouse glioma and human small cell lung cancer (SCLC) cells. The distribution of drug in tumor cells was investigated by autoradiography. Human small cell lung cancer (N417 and H526, NCI) were exposed to /sup 111/ InCl/sub 3/ and (25-150 μCi/ml) or /sup 111/In-BLMC (25-150 μCi) carried by 15-25 μg BLM/ml) in 37 0 C for 1 hr, 3 hr or 24 hr, washed with fresh medium, and spread. The slides were smeared with NTB/sub 2/ or NTB/sub 3/ emulsion by using wet-mounting or dry-mounting technique and developed 3-14 days. The /sup 111/In-BLMC localized on the cell nucleus (47.8%) and nuclear membrane (29.2%); /sup 111/InCl/sub 3/ located mainly in the cytoplasm (45.8%). This indicates that the mechanism of killing of tumor cells may be related to the drug uptake and distribution of /sup 111/In-BLMC. A nuclear and nuclear membrane localization would favor damage to chromosomes and DNA

Combined Cytogenotoxic Effects of Bee Venom and Bleomycin on Rat Lymphocytes: An In Vitro Study

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Yasmina M. Abd-Elhakim

2014-01-01

Full Text Available This study was carried out to determine the cytotoxic and genotoxic effects of bee venom (BV and/or the chemotherapeutic agent bleomycin (BLM on healthy isolated rat lymphocytes utilizing morphometric and molecular techniques. Using the Ficoll-Histopaque density gradient centrifugation technique, lymphocytes were isolated, divided into groups, and subjected to BV and/or BLM at incubation medium concentrations of 10 or 20 μg/mL respectively for 24 and 72 hrs. An MTT assay and fluorescent microscopy examinations were used to assess the cytotoxic effects. To determine the predominant type of BV and/or BLM-induced cell death, LDH release assay was employed beside quantitative expression analyses of the apoptosis-related genes (Caspase-3 and Bcl-2. The genotoxic effects of the tested compounds were evaluated via DNA fragmentation assay. The results of these assays demonstrated that BV potentiates BLM-induced cytotoxicity through increased LDH release and diminished cell viability. Nevertheless, BV significantly inhibited the BLM-induced DNA damage. The results verify that BV significantly attenuates the genotoxic effects of BLM on noncancerous isolated rat lymphocytes but does not diminish BLM cytotoxicity.

Disulfonated tetraphenyl chlorin (TPCS2a)-induced photochemical internalisation of bleomycin in patients with solid malignancies: a phase 1, dose-escalation, first-in-man trial.

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Sultan, Ahmed A; Jerjes, Waseem; Berg, Kristian; Høgset, Anders; Mosse, Charles A; Hamoudi, Rifat; Hamdoon, Zaid; Simeon, Celia; Carnell, Dawn; Forster, Martin; Hopper, Colin

2016-09-01

Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies. In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged ≥18 to internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin-photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1·0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1·5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1·0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred. TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0·25 mg/kg as the recommended treatment dose for future trials. PCI Biotech. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessment of cobalt 57 tagged bleomycin as a clinical aid in staging of head and neck carcinoma

International Nuclear Information System (INIS)

Cummings, C.W.; Larson, S.M.; Dobie, R.A.; Weymuller, E.A. Jr.; Rudd, T.G.; Merello, A.

1981-01-01

Critical assessment of head and neck cancer with respect to staging has, on occasion, been disappointingly ineffective. We have attempted to correlate the incidence of measureable uptake of cobalt 57 tagged bleomycin by primary squamous cell carcinoma and metastatic cervical lymph nodes. Forty-six cases have been evaluated with respect to histopathological confirmation of the suspected metastatic disease. We have found that this diagnostic measure increases our acumen in staging of head and neck cancer. The relevance of the Co-Bleo scans as a diagnostic aid is reported in 46 cases. Malignant tumors greater than 2 cm in size appear to demonstrate active uptake of the imaging agent. Small tumor size and excess background radioactivity contribute to the false-negatives (17%). Inflammatory conditions or benign tumors of the salivary apparatus may result in minimal uptake, thus, a false-positive result (10%). An increase in the radioactivity of the Co-Bleo may enhance the benefits of this procedure in the search for an undiagnosed primary, as well as undiagnosed local or distant metastases

Assessment of cobalt 57 tagged bleomycin as a clinical aid in staging of head and neck carcinoma

International Nuclear Information System (INIS)

Cummings, C.W.; Larson, S.M.; Dobie, R.A.; Weymuller, E.A. Jr.; Rudd, T.G.; Merello, A.

1981-01-01

Critical assessment of head and neck cancer with respect to staging has, on occasion, been disappointingly ineffective. The incidence of measurable uptake of cobalt 57 tagged bleomycin by primary squamous cell carcinoma and metastatic cervical lymph nodes has been correlated. Forty-six cases have been evaluated with respect to histopathological confirmation of the suspected metastatic disease. We have found that this diagnostic measure increases our acumen in staging of head and neck cancer. The relevance of the Co-Bleo scans as a diagnostic aid is reported in 46 cases. Malignant tumors greater than 2 cm in size appear to demonstrate active uptake of the imaging agent. Small tumor size and excess background radioactivity contribute to the false-negatives (17%). Inflammatory conditions or benign tumors of the salivary apparatus may result in minimal uptake, thus, a false-positive result (10%). An increase in the radioactivity of the Co-Bleo may enhance the benefits of this procedure in the search for an undiagnosed primary, as well as undiagnosed local or distant metastases

The effect of extremely low frequency electromagnetic fields on the chromosomal instability in bleomycin treated fibroblast cells

International Nuclear Information System (INIS)

Cho, Yoon Hee; Kim, Yang Jee; Lee, Joong Won; Kim, Gye Eun; Chung, Hai Won

2008-01-01

In order to determine the effect of Extremely Low Frequency ElectroMagnetic Fields (ELF-EMF) on the frequency of MicroNuclei (MN), aneuploidy and chromosomal rearrangement induced by BLeoMycin (BLM) in human fibroblast cells, a 60 Hz ELF-EMF of 0.8 mT field strength was applied either alone or with BLM throughout the culture period and a micronucleus-centromere assay was performed. Our results indicate that the frequencies of MN, aneuploidy and chromosomal rearrangement induced by BLM increased in a dose-dependent manner. The exposure of cells to 0.8 mT ELF-EMF followed by BLM exposure for 3 hours led to significant increases in the frequencies of MN and aneuploidy compared to BLM treatment for 3 hours alone (p<0.05), but no significant difference was observed between field exposed and sham exposed control cells. The obtained results suggest that low density ELF-EMF could act as enhancer of the initiation process of BLM rather than as an initiator of mutagenic effects in human fibroblast

Response of mouse tongue epithelium to single doses of bleomycin and radiation

International Nuclear Information System (INIS)

Dorr, W.; Hirler, E.; Honig, M.

1993-01-01

Both bleomycin (BLM) and local X-irradiation (25 kV) induce denudation in the tongue epithelium of the C3H-Neuherberg mouse in a dose-dependent manner. In the present study the effect of BLM alone and of combined single doses of drug and radiation were studied using the incidence of epithelial denudation as the end-point. In 'time-line' experiments, 8 mg/kg BLM were given before or after graded doses of X-rays. BLM treatment required a reduction of the radiation dose (ED 50 ) from 15 Gy to 5-7 Gy, independent of sequence or time interval. In contrast, the time course of the response was clearly dependent on the treatment interval. Latency decreased when the drug was injected less than 2 h before irradiation with minimum latency observed at 30 min. Isobologram analysis of experiments with varying combinations of X-rays and BLM demonstrated that small drug doses were relatively more effective than larger doses, suggesting an upward concavity of the BLM dose-effective curve in vivo, i.e. a 'negative shoulder' of the curve in the low dose region. In contrast to the response to X-rays alone, which has a constant latent time to ulcer of 10 days, the latency in combined treatment was clearly shortened with increasing drug dose and at high doses eventually approximated the epithelial turnover time of 5 days. The data suggest that BLM both as a single agent and in combination with X-rays reduced the probability of abortive divisions and through this effect shortened the latent time to epithelial denudation. (author)

Influência do biofármaco DNA-hsp65 na lesão pulmonar induzida por bleomicina Influence of a DNA-hsp65 vaccine on bleomycin-induced lung injury

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Adriana Ignacio de Padua

2008-11-01

receiving intratracheal (IT instillation of saline; SB, injected with saline (placebo and then receiving IT instillation of bleomycin; PB, treated with plasmid only, without bacterial genome, and then receiving IT instillation of bleomycin; and BB, treated with the vaccine and then receiving IT instillation of bleomycin. Bleomycin was instilled 15 days after the last immunization, and the animals were killed six weeks thereafter. The left and right lungs were removed, the former for morphological analysis and the latter for hydroxyproline measurements. RESULTS: The proportion of deaths within the first 48 h after the IT instillation (deaths attributed to the surgical procedure was higher in the SB group than in the SS group (57.7% vs. 11.1%. The mean area of pulmonary interstitial septa was greater in the SB and PB groups (53.1 ± 8.6% and 53.6±9.3%, respectively than in the SS and BB groups (32.9 ± 2.7% and 34.3 ± 6.1%, respectively. The mean area of interstitial septa stained by picrosirius was greater in the SB, PB and BB groups than in the SS group (8.2 ± 4.9%, 7.2 ± 4.2% and 6.6 ± 4.1%, respectively, vs. 2.0±1.4%. The total hydroxyproline content in the lung was significantly lower in the SS group (104.9 ± 20.9 pg/lung than in the other groups (SB: 160.4 ± 47.8 pg/lung; PB: 170.0 ± 72.0 pg/lung; and BB: 162.5 ± 39.7 pg/lung. CONCLUSIONS: Immunization with the DNA-hsp65 vaccine reduced the deposition of noncollagen matrix in a model of bleomycin-induced lung lesion.

Antifibrotic effects of curcumin are associated with overexpression of cathepsins K and L in bleomycin treated mice and human fibroblasts

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Zhang Dongwei

2011-11-01

Full Text Available Abstract Background Lung fibrosis is characterized by fibroblast proliferation and the deposition of collagens. Curcumin, a polyphenol antioxidant from the spice tumeric, has been shown to effectively counteract fibroblast proliferation and reducing inflammation and fibrotic progression in animal models of bleomycin-induced lung injury. However, there is little mechanistic insight in the biological activity of curcumin. Here, we study the effects of curcumin on the expression and activity of cathepsins which have been implicated in the development of fibrotic lung diseases. Methods We investigated the effects of curcumin administration to bleomycin stimulated C57BL/6 mice and human fetal lung fibroblasts (HFL-1 on the expression of cathepsins K and L which have been implicated in matrix degradation, TGF-β1 modulation, and apoptosis. Lung tissues were evaluated for their contents of cathepsins K and L, collagen, and TGF-β1. HFL-1 cells were used to investigate the effects of curcumin and cathepsin inhibition on cell proliferation, migration, apoptosis, and the expression of cathepsins K and L and TGF-β1. Results Collagen deposition in lungs was decreased by 17-28% after curcumin treatment which was accompanied by increased expression levels of cathepsins L (25%-39% and K (41%-76% and a 30% decrease in TGF-β1 expression. Moreover, Tunel staining of lung tissue revealed a 33-41% increase in apoptotic cells after curcumin treatment. These in vivo data correlated well with data obtained from the human fibroblast line, HFL-1. Here, cathepsin K and L expression increased 190% and 240%, respectively, in the presence of curcumin and the expression of TGF-β1 decreased by 34%. Furthermore, curcumin significantly decreased cell proliferation and migration and increased the expression of surrogate markers of apoptosis. In contrast, these curcumin effects were partly reversed by a potent cathepsin inhibitor. Conclusion This study demonstrates that

Amifostine Analog, DRDE-30, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

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Aastha Arora

2018-04-01

Full Text Available Bleomycin (BLM is an effective curative option in the management of several malignancies including pleural effusions; but pulmonary toxicity, comprising of pneumonitis and fibrosis, poses challenge in its use as a front-line chemotherapeutic. Although Amifostine has been found to protect lungs from the toxic effects of radiation and BLM, its application is limited due to associated toxicity and unfavorable route of administration. Therefore, there is a need for selective, potent, and safe anti-fibrotic drugs. The current study was undertaken to assess the protective effects of DRDE-30, an analog of Amifostine, on BLM-induced lung injury in C57BL/6 mice. Whole body micro- computed tomography (CT was used to non-invasively observe tissue damage, while broncheo-alveolar lavage fluid (BALF and lung tissues were assessed for oxidative damage, inflammation and fibrosis. Changes in the lung density revealed by micro-CT suggested protection against BLM-induced lung injury by DRDE-30, which correlated well with changes in lung morphology and histopathology. DRDE-30 significantly blunted BLM-induced oxidative stress, inflammation and fibrosis in the lungs evidenced by reduced oxidative damage, endothelial barrier dysfunction, Myeloperoxidase (MPO activity, pro-inflammatory cytokine release and protection of tissue architecture, that could be linked to enhanced anti-oxidant defense system and suppression of redox-sensitive pro-inflammatory signaling cascades. DRDE-30 decreased the BLM-induced augmentation in BALF TGF-β and lung hydroxyproline levels, as well as reduced the expression of the mesenchymal marker α-smooth muscle actin (α-SMA, suggesting the suppression of epithelial to mesenchymal transition (EMT as one of its anti-fibrotic effects. The results demonstrate that the Amifostine analog, DRDE-30, ameliorates the oxidative injury and lung fibrosis induced by BLM and strengthen its potential use as an adjuvant in alleviating the side effects of

Extensive deep vein thrombosis as a complication of testicular cancer treated with the BEP protocol (bleomycin, etoposide and cisplatin: case report

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Max Senna Mano

Full Text Available CONTEXT: There are no reports in the literature of massive deep venous thrombosis (DVT associated with cisplatin, bleomycin and etoposide (BEP cancer treatment. CASE REPORT: The patient was a 18-year-old adolescent with a nonseminomatous germ cell tumor of the right testicle, with the presence of pulmonary, liver, and massive retroperitoneal metastases. Following radical orchiectomy, the patient started chemotherapy according to the BEP protocol (without routine prophylaxis for DVT. On day 4 of the first cycle, massive DVT was diagnosed, extending from both popliteal veins up to the thoracic segment of the inferior vena cava. Thrombolytic therapy with streptokinase was immediately started. On day 2 of thrombolytic therapy, the patient developed acute renal failure, due to extension of the thrombosis to the renal veins. Streptokinase was continued for six days and the outcome was remarkably favorable.

Delivery of antifibroblast agents as adjuncts to filtration surgery. Part I--Periocular clearance of cobalt-57 bleomycin in experimental drug delivery: pilot study in the rabbit

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Kay, J.S.; Litin, B.S.; Woolfenden, J.M.; Chvapil, M.; Herschler, J.

1986-10-01

Antitumor and antifibroblast agents show promise as adjuncts after glaucoma filtration surgery in reducing postoperative scarring and failure. We used nuclear imaging in rabbits to investigate periocular clearance of one such agent (/sup 57/Co-bleomycin). Sub-Tenon injection was compared to other delivery techniques. Our results showed that a collagen sponge and a silastic disc implant with a microhole prolonged drug delivery when compared to sub-Tenon injection alone or injection with a viscosity enhancing agent (0.5% sodium hyaluronate). We theorize that if an antifibroblast agent can be delivered in small and sustained amounts after filtration surgery, this may prolong bleb longevity and avoid unnecessary drug toxicity.

Delivery of antifibroblast agents as adjuncts to filtration surgery. Part I--Periocular clearance of cobalt-57 bleomycin in experimental drug delivery: pilot study in the rabbit

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Kay, J.S.; Litin, B.S.; Woolfenden, J.M.; Chvapil, M.; Herschler, J.

1986-01-01

Antitumor and antifibroblast agents show promise as adjuncts after glaucoma filtration surgery in reducing postoperative scarring and failure. We used nuclear imaging in rabbits to investigate periocular clearance of one such agent ( 57 Co-bleomycin). Sub-Tenon injection was compared to other delivery techniques. Our results showed that a collagen sponge and a silastic disc implant with a microhole prolonged drug delivery when compared to sub-Tenon injection alone or injection with a viscosity enhancing agent (0.5% sodium hyaluronate). We theorize that if an antifibroblast agent can be delivered in small and sustained amounts after filtration surgery, this may prolong bleb longevity and avoid unnecessary drug toxicity

Effects of turmeric and its active principle, curcumin, on bleomycin-induced chromosome aberrations in Chinese hamster ovary cells

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Araújo Maria Cristina P.

1999-01-01

Full Text Available Naturally occurring antioxidants have been extensively studied for their capacity to protect organisms and cells from oxidative damage. Many plant constituents including turmeric and curcumin appear to be potent antimutagens and antioxidants. The effects of turmeric and curcumin on chromosomal aberration frequencies induced by the radiomimetic agent bleomycin (BLM were investigated in Chinese hamster ovary (CHO cells. Three concentrations of each drug, turmeric (100, 250 and 500 mg/ml and curcumin (2.5, 5 and 10 mg/ml, were combined with BLM (10 mg/ml in CHO cells treated during the G1/S, S or G2/S phases of the cell cycle. Neither turmeric nor curcumin prevented BLM-induced chromosomal damage in any phases of the cell cycle. Conversely, a potentiation of the clastogenicity of BLM by curcumin was clearly observed in cells treated during the S and G2/S phases. Curcumin was also clastogenic by itself at 10 µg/ml in two protocols used. However, the exact mechanism by which curcumin produced clastogenic and potentiating effects remains unknown.

Randomized Phase IIA Trial of Gemcitabine Compared With Bleomycin Plus Vincristine for Treatment of Kaposi’s Sarcoma in Patients on Combination Antiretroviral Therapy in Western Kenya

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Naftali W. Busakhala

2018-01-01

Full Text Available Purpose: Kaposi’s sarcoma (KS is a spindle cell tumor resulting from growth dysregulation in the setting of infection with human herpes virus-8 (also called KS herpes virus. Advanced KS is characterized by poor responses to antiretroviral therapy and some of the chemotherapy readily accessible to patients in low-resource areas. Gemcitabine induced partial and complete regression of AIDS-associated KS (AIDS-KS in 11 of 24 patients in a pilot study. The current study compares the antimetabolite gemcitabine with the standard care bleomycin and vincristine (BV in the treatment of chemotherapy-naïve patients with AIDS-KS in a resource-limited setting. Patients and Methods: Patients with persistent or progressive KS despite treatment with combined antiretroviral therapy were randomly assigned to receive gemcitabine 1,000 mg/m2 or bleomycin 15 IU/ m2 and vincristine 1.4 mg/m2 given twice weekly. The main end point was objective response by bidirectional measurement, adverse events, and quality of life after three cycles of chemotherapy. Results: Of 70 participants enrolled, 36 received gemcitabine and 34 received BV. Complete response was achieved in 12 patients (33.3% in the gemcitabine arm and six (17.6% in the BV arm (P = .175. The partial response rate was 52.8% (n = 19 in the gemcitabine arm and 58.8% (n = 20 in the BV arm. Both study arms reported similar neurologic and hematologic adverse events; there was statistically significant baseline to post-treatment improvement in health-related quality-of-life scores. Conclusion: The results of this randomized, phase IIA trial demonstrate gemcitabine activity in chemotherapy-naïve patients with AIDS-KS, on the basis of response rates, adverse events, and health-related quality-of-life scores.

Protective Effect of Onion Extract on Bleomycin-Induced Cytotoxicity and Genotoxicity in Human Lymphocytes

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Yoon Hee Cho

2016-02-01

Full Text Available Following one of the world’s largest nuclear accidents, occured at Fukushima, Japan in 2011, a significant scientific effort has focused on minimizing the potential adverse health effects due to radiation exposure. The use of natural dietary antioxidants to reduce the risk of radiation-induced oxidative DNA damage is a simple strategy for minimizing radiation-related cancer rates and improving overall health. The onion is among the richest sources of dietary flavonoids and is an important food for increasing their overall intake. Therefore, we examined the effect of an onion extract on cyto- and geno-toxicity in human lymphocytes treated with bleomycin (BLM, a radiomimetic agent. In addition, we measured the frequency of micronuclei (MN and DNA damage following treatment with BLM using a cytokinesis-blocked micronucleus assay and a single cell gel electrophoresis assay. We observed a significant increase in cell viability in lymphocytes treated with onion extract then exposed to BLM compared to cells treated with BLM alone. The frequency of BLM induced MN and DNA damage increased in a dose-dependent manner; however, when lymphocytes were pretreated with onion extract (10 and 20 μL/mL, the frequency of BLM-induced MN was decreased at all doses of BLM and DNA damage was decreased at 3 μg/mL of BLM. These results suggest that onion extract may have protective effects against BLM-induced cyto- and genotoxicity in human lymphocytes.

Very low dose and dose-rate X-ray induced adaptive response in human lymphocytes at various cell cycle stages against bleomycin induced chromatid aberrations

International Nuclear Information System (INIS)

Hossein Mozdarani; Moghadam, R.N.

2007-01-01

Complete text of publication follows. Objective: To study the adaptive response induced by very low doses of X-rays at very low dose rate in human lymphocytes at different cell cycle stages followed by a challenge dose of bleomycin sulphate at G2 phase. Materials and Methods: Human peripheral blood lymphocytes before (G0) and after PHA stimulation (G1 and G2) were exposed to 1 and 5 cGy X-rays generated by a fluoroscopy unit with a dose rate of 5.56 mGy/min and challenged with 5 μg/ml bleomycin sulphate (BLM) 48 hours after culture initiation. Mitotic cells were arrested at metaphase by addition of colcemid in cultures 1.5 h before harvesting. Harvesting and slide preparation was performed using standard method. 100 well spread metaphases were analyzed for the presence of chromatid type aberrations for each sample. Results: Results obtained indicate that there is a linear relationship between the dose of BLM and chromatid aberrations below 5 μg/ml (R=0.93, p<0.0001). The results also show that pretreatment of lymphocytes with low dose X-rays at G0, G1 and G2 phases of the cell cycle significantly reduced the sensitivity of lymphocytes to the clastogenic effects of BLM in G2. Much lower frequencies of chromatid aberrations were observed in X-ray irradiated lymphocytes following BLM treatment (p<0.05). The magnitudes of adaptation induced at different phases of the cell cycle were not significantly different. Furthermore, there was no a significant difference in the magnitude of adaptive response induced by either 1 or 5 cGy X-rays. Conclusion: These observations might indicate that resistance of pre-exposure of lymphocytes to very low doses of X-rays protects them from clastogenic effects of BLM. This effect might be due to initial DNA damage induced in these cells leading to provocation of an active DNA repair mechanism independent of cell cycle stage.

The preventive role of levosimendan against bleomycin-induced pulmonary fibrosis in rats.

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Gürbüzel, Mehmet; Sayar, Ilyas; Cankaya, Murat; Gürbüzel, Ahmet; Demirtas, Levent; Bakirci, Eftal Murat; Capoglu, Ilyas

2016-04-01

In this study, the effects of levosimendan used in the treatment of acute congestive heart failure upon pulmonary fibrosis in rats induced with bleomycin (BL) were analyzed. A total of 33 male Sprague-Dawley type rats were categorized into five groups randomly. About 2.5U/kg BL was intratracheally administered to the rats in the BL, BL+L1, BL+L2, and BL+L3 groups, and 0.9% saline was intratracheally administered at the same rate to the control group. 0.3, 1, and 3mg/kg levosimendan was intraperitoneally administered to the BL+L1, BL+L2, and BL+L3 groups, respectively. Blood and tissue samples were taken from the rats euthanized to determine the changes in erythrocyte enzyme activities and to conduct histopathological evaluations after 14 days. With values between 0 and 3, histopathological scoring damage was assessed by the presence of inflammation and fibrosis in a semiquantitative manner. Compared with those in the C group, glutathione reductase (GR) and Catalase (CAT) enzymes decreased in the BL group; compared with that in the BL group, GR increased in the BL+L1 and BL+L3 groups, 6-phosphogluconate dehydrogenase (6PGD) increased in the BL+L3 group, and CAT increased in the BL+L2 and BL+L3 groups (p<0.05). In the histopathological evaluation, fibrosis occurred in all rats in the BL group, and tissue damage was noticed to be generally less in the BL+L1, BL+L2, and BL+L3 groups (p<0.001). The results obtained from biochemical and histopathological evaluations indicate that levosimendan had an anti-fibrotic effect without a dose-dependent response on pulmonary fibrosis. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Therapeutic potential of bleomycin plus suicide or interferon-β gene transfer combination for spontaneous feline and canine melanoma

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Agnetti, Lucrecia; Fondello, Chiara; Villaverde, Marcela S.; Glikin, Gerardo C.; Finocchiaro, Liliana M. E.

2017-01-01

We originated and characterized melanoma cell lines derived from tumors of two feline and two canine veterinary patients. These lines reestablished the morphology, physiology and cell heterogeneity of their respective parental tumors. We evaluated the cytotoxicity of bleomycin (BLM) alone, or combined with interferon-β (IFN-β) or HSVtk/GCV suicide gene (SG) lipofection on these cells. Although the four animals presented stage III disease (WHO system), SG treated feline tumors displayed stable disease in vivo, while the canine ones exhibited partial response. Their derived cell lines reflected this behavior. Feline were significantly more sensitive than canine cells to IFN-β gene transfer. BLM improved the antitumor effects of both genes. The higher levels of reactive oxygen species (ROS) significantly correlated with membrane and DNA damages, emphasizing ROS intervention in apoptotic and necrotic cell death. After 3 days of BLM alone or combined with gene treatments, the colony forming capacity of two canine and one feline treatments survivor cells almost disappeared. Taken together, these results suggest that the treatments eradicated tumor initiating cells and support the clinical potential of the tested combinations. PMID:29344558

Experimental studies on the radiation-modifying effect of bleomycin in malignant and normal mouse tissue in vivo

International Nuclear Information System (INIS)

Molin, J.; Sogaard, P.E.; Overgaard, J.

1981-01-01

The interaction between bleomycin (BLM) and radiation was studied in a C3H mammary carcinoma and its surrounding normal skin. In the skin, single and fractionated doses of sequential treatment with BLM (25 mg/kg) 24 hours prior to radiation therapy did not influence the response to irradiation, whereas simultaneous treatment with BLM given 15 minutes before radiation therapy enhanced the reaction to irradiation by a factor of 1.2 or 1.4 following treatment with one fraction or five fractions, respectively. The tumor response to irradiation was not influenced by a single sequential treatment, but five daily fractions of radiation therapy following five daily dose fractions of BLM increased the radiation dose needed to control 50% of the tumors, probably because the tumors continued to grow during the BLM treatment. Simultaneous treatment enhanced the response to irradiation by a factor of 1.2 after both single-dose and fractionated therapy. Based on these data it was concluded that none of the combined treatment schedules were able to produce a better therapeutic effect than radiation therapy alone. Furthermore, mortality due to lung fibrosis in mice treated with BLM indicated the marked toxicity of the drug. This toxicity was most pronounced after fractionated treatment and when radiation therapy and BLM were given simultaneously

Intratracheal Bleomycin Aerosolization: The Best Route of Administration for a Scalable and Homogeneous Pulmonary Fibrosis Rat Model?

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Alexandre Robbe

2015-01-01

Full Text Available Idiopathic pulmonary fibrosis (IPF is a chronic disease with a poor prognosis and is characterized by the accumulation of fibrotic tissue in lungs resulting from a dysfunction in the healing process. In humans, the pathological process is patchy and temporally heterogeneous and the exact mechanisms remain poorly understood. Different animal models were thus developed. Among these, intratracheal administration of bleomycin (BML is one of the most frequently used methods to induce lung fibrosis in rodents. In the present study, we first characterized histologically the time-course of lung alteration in rats submitted to BLM instillation. Heterogeneous damages were observed among lungs, consisting in an inflammatory phase at early time-points. It was followed by a transition to a fibrotic state characterized by an increased myofibroblast number and collagen accumulation. We then compared instillation and aerosolization routes of BLM administration. The fibrotic process was studied in each pulmonary lobe using a modified Ashcroft scale. The two quantification methods were confronted and the interobserver variability evaluated. Both methods induced fibrosis development as demonstrated by a similar progression of the highest modified Ashcroft score. However, we highlighted that aerosolization allows a more homogeneous distribution of lesions among lungs, with a persistence of higher grade damages upon time.

MSCs with ACE II gene affect apoptosis pathway of acute lung injury induced by bleomycin.

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Zhang, Xiaomiao; Gao, Fengying; Li, Qian; Dong, Zhixia; Sun, Bo; Hou, Lili; Li, Zhuozhe; Liu, Zhenwei

2015-02-01

The aim of this study was to evaluate the effect and related mechanisms of Mesenchymal stem cells (MSCs) and Angiotensin converting enzyme II (ACE II) on acute lung injury (ALI). MSCs were separated from umbilical cord cells, and the changes of phenotype before and after ACE II silence were observed using Flow Cytometer. ALI model was induced by 10 mg/mL bleomycin in 60 Balb/c mice, and the rest 8 mice were regarded as the baseline group. The mice were randomly divided into four groups (n = 15): control, ACE II, stem, and stem + ACE II. The apoptotic index (AI) was calculated using TUNEL, and the detection of protein and mRNA of Bax, Bak and p53, Bcl-2, Grp78, CHOP and Caspase 12 were used by western-blot and RT-PCR, respectively. The umbilical cord cells differentiated into stable MSCs about 14 days, and ACE II transfection reached a peak at the 5th day after transfection. ACE II silence did not affect the phenotype of MSCs. All the proteins and mRNAs expression except Bcl-2 in the stem and stem + ACE II were significantly lower than those in control from 8 h (p ACE II performed a better effect than single stem in most indexes, including AI (p ACE II can significantly suppress apoptosis in ALI mice, and may be an effective clinical treatment for ALI.

Combined effects of x-irradiation and bleomycin on the proliferation of isoproterenol-stimulated mouse parotid glands

International Nuclear Information System (INIS)

Shoju, Masumi

1977-01-01

Effects of x-irradiation and bleomycin (BLM) on DNA synthesis in isoproterenol (IPR)-stimulated mouse parotid glands were investigated. The incorporation of thymidine- 3 H into DNA in parotid glands increased remarkably in 16 hours with a peak at 22 hours after the injection of IPR. When x-irradiation (250 rads) was given at 1 hour after IPR (early G 1 phase), the stimulation of DNA synthesis was inhibited by about 50%, and the beginning of DNA synthesis was delayed nearly 6 hours. BLM injected in the early G 1 phase was also effective in inhibiting DNA synthesis. However, the injection of BLM in the late G 1 or S phase did not interfere with DNA synthesis. Combined x-irradiation and BLM inhibited DNA synthesis and delayed the beginning of the S phase far more strikingly than did x-irradiation alone. When BLM was injected at various intervals before and after x-irradiation, the greatest inhibition was found just after irradiation. Therefore, a longer interval between x-irradiation and BLM injection had a tendency to decrease the rate of inhibiting DNA synthesis. These findings were confirmed by measuring the labeling index and the mitotic index in the acinar cells of the mouse parotid gland. These results suggest that simultaneous application of x-irradiation and BLM has the greatest effect. (Evans, J.)

Longitudinal Changes in Serum Levels of Testosterone and Luteinizing Hormone in Testicular Cancer Patients after Orchiectomy Alone or Bleomycin, Etoposide, and Cisplatin

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Bandak, Mikkel; Jørgensen, Niels; Juul, Anders

2017-01-01

) or combination chemotherapy with bleomycin, etoposide, and cisplatin (BEP). DESIGN, SETTINGS, AND PARTICIPANTS: Changes in TT and LH were investigated during 5-yr follow-up (Stage I: n=75, BEP: n=81). A selected group of TC patients with mild Leydig cell dysfunction (LH ≥ 8 IU/l) were followed for a longer...... period (Stage I: n=20, BEP: n=23). An age-matched control group of 839 healthy men served as controls for TT and LH levels. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Changes in age-adjusted TT and LH were evaluated separately in each treatment group with univariate linear regression analysis....... The proportion of patients initiating testosterone substitution during follow-up was calculated. RESULTS AND LIMITATIONS: In the 75 Stage I patients there were no significant changes in LH and TT, while in the 81 BEP treated patients there was a significant decline in LH during follow-up (-24.2 percentage point...

Dynamics of bleomycin interaction with a strongly bound hairpin DNA substrate, and implications for cleavage of the bound DNA.

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Bozeman, Trevor C; Nanjunda, Rupesh; Tang, Chenhong; Liu, Yang; Segerman, Zachary J; Zaleski, Paul A; Wilson, W David; Hecht, Sidney M

2012-10-31

Recent studies involving DNAs bound strongly by bleomycins have documented that such DNAs are degraded by the antitumor antibiotic with characteristics different from those observed when studying the cleavage of randomly chosen DNAs in the presence of excess Fe·BLM. In the present study, surface plasmon resonance has been used to characterize the dynamics of BLM B(2) binding to a strongly bound hairpin DNA, to define the effects of Fe(3+), salt, and temperature on BLM-DNA interaction. One strong primary DNA binding site, and at least one much weaker site, were documented. In contrast, more than one strong cleavage site was found, an observation also made for two other hairpin DNAs. Evidence is presented for BLM equilibration between the stronger and weaker binding sites in a way that renders BLM unavailable to other, less strongly bound DNAs. Thus, enhanced binding to a given site does not necessarily result in increased DNA degradation at that site; i.e., for strongly bound DNAs, the facility of DNA cleavage must involve other parameters in addition to the intrinsic rate of C-4' H atom abstraction from DNA sugars.

The effect of dose loading and of double labelling with 57Co and 125I on the tissue distribution in animals

International Nuclear Information System (INIS)

Vos, C.M.; Westera, G.; Jagt, P.J. van der; Zanten, B. van; Vrije Universiteit, Amsterdam

1979-01-01

Dose loading effects upon the performance of 57 Co-bleomycin as a tumor localizing agent have been investigated in Rhabdomyosarcoma bearing Wag/Ry rats. The addition of non-radioactively labelled Co-bleomycin increased the relative uptake of 57 Co-bleomycin in rapid growing tumors, but the addition of non-chelated bleomycin had no influence at all. In our experimental system, iodinated bleomycin generally labelled by reaction with ICl, was found to be an unsatisfactory tumor localizing agent. In order to combine the useful localizing properties of Co-bleomycin with the qualified detection properties of some iodine isotopes, we attempted to prepare bleomycin doubly labelled with Co and I. However, we were unable to prepare 57 Co- 125 I-bleomycin by general labelling with ICl. This result indicates that both labels need the imidazole ring for the formation of a stable, labelled bleomycin. (orig.) [de

Vanillin as a modulator agent in SMART test: inhibition in the steps that precede N-methyl-N-nitrosourea-, N-ethyl-N-nitrosourea-, ethylmethanesulphonate- and bleomycin-genotoxicity.

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Sinigaglia, Marialva; Lehmann, Maurício; Baumgardt, Paula; do Amaral, Viviane Souza; Dihl, Rafael Rodrigues; Reguly, Maria Luíza; de Andrade, Heloísa Helena Rodrigues

2006-09-05

Vanillin (VA), the world's major flavoring compound used in food industry and confectionery products - that has antimutagenic and anticarcinogenic activity against a variety of mutagenic/carcinogenic agents - was tested for the interval between the formation of premutational lesion and it is finalization as a DNA lesion. The overall findings using co-treatment protocols in SMART test suggest that VA can lead to a significant protection against the general genotoxicity of ethylmethanesulphonate (EMS), N-ethyl-N-nitrosourea (ENU), N-methyl-N-nitrosourea (MNU) and bleomycin sulphate (BLEO). Considering MNU, ENU and EMS the desmutagenic activity observed could result from VA-stimulation of detoxification, via induction of glutathione S-transferase. However, the protector effect related to BLEO could be attributed to its powerful scavenger ability, which has the potential to prevent oxidative damage induced by BLEO.

Creation of lung-targeted dexamethasone immunoliposome and its therapeutic effect on bleomycin-induced lung injury in rats.

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Xue-Yuan Chen

Full Text Available OBJECTIVE: Acute lung injury (ALI, is a major cause of morbidity and mortality, which is routinely treated with the administration of systemic glucocorticoids. The current study investigated the distribution and therapeutic effect of a dexamethasone(DXM-loaded immunoliposome (NLP functionalized with pulmonary surfactant protein A (SP-A antibody (SPA-DXM-NLP in an animal model. METHODS: DXM-NLP was prepared using film dispersion combined with extrusion techniques. SP-A antibody was used as the lung targeting agent. Tissue distribution of SPA-DXM-NLP was investigated in liver, spleen, kidney and lung tissue. The efficacy of SPA-DXM-NLP against lung injury was assessed in a rat model of bleomycin-induced acute lung injury. RESULTS: The SPA-DXM-NLP complex was successfully synthesized and the particles were stable at 4°C. Pulmonary dexamethasone levels were 40 times higher with SPA-DXM-NLP than conventional dexamethasone injection. Administration of SPA-DXM-NLP significantly attenuated lung injury and inflammation, decreased incidence of infection, and increased survival in animal models. CONCLUSIONS: The administration of SPA-DXM-NLP to animal models resulted in increased levels of DXM in the lungs, indicating active targeting. The efficacy against ALI of the immunoliposomes was shown to be superior to conventional dexamethasone administration. These results demonstrate the potential of actively targeted glucocorticoid therapy in the treatment of lung disease in clinical practice.

In vivo biodistribution of 131I labeled bleomycin (BLM) and isomers (A2 and B2) on experimental animal models

International Nuclear Information System (INIS)

Avcibasi, U.; Demiroglu, H.; Uenak, P.; Mueftueler, F.Z.B.; Ichedef, C.A.; Guemueser, F.G.

2010-01-01

Bleomycins (BLMs; BLM, A2, and B2) were labeled with 131 I and radiopharmaceutical potentials were investigated using animal models in this study. Quality control procedures were carried out using thin layer radiochromatography (TLRC), high performance liquid chromatography (HPLC), and liquid chromatography (LC/MS/MS). Labeling yields of radiolabeled BLMs were found to be 90, 68, and 71%, respectively. HPLC chromatograms were taken for BLM and cold iodinated BLM ( 127 I-BLM). Five peaks were detected for BLM and three peaks for 127 I-BLM in the HPLC studies. Two peaks belong to isomers of BLM. The isomers of BLM were purified with using HPLC. Biological activity of BLM was determined on male Albino Wistar rats by biodistribution and scintigraphic studies were performed for BLMs by using New Zealand rabbits. The biodistribution results of 131 I-BLM showed high uptake in the stomach, the bladder, the prostate, the testicle, and the spinal cord in rats. Scintigraphic results on rabbits agrees with that of biodistributional studies on rats. The scintigraphy of radiolabeled isomers ( 131 I-A2 and 131 I-B2) are similarly found with that of 131 I-BLM. (author)

Ultrastructural changes of human esophageal carcinoma induced by preoperative treatments with bleomycin and/or radiation

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Kohro, T. (Niigata Univ. (Japan). School of Medicine)

1982-01-01

In the present study, 44 cases of esophageal carcinoma were electron-microscopically examined. Nuclear bodies of various types observed in carcinoma cells or in normal mucosa of the esophagus treated by bleomycin and radiation, single or combined (BLM/R), were classified into seven types. Types A and B were observed in carcinoma cells of both conditions of untreated or treated with BLM/R. Types C, D and E were specific findings in squamous carcinoma cells after BLM/R treatment. Types F and G were considered to be far advanced in terms of other nuclear bodies and were observed in strongly affected carcinoma cells. These nucleolar changes were considered to be specific alterations induced by BLM in esophageal carcinoma cells. The appearance of various nuclear bodies and a series of nucleolar segregation after BLM/R treatments were confirmed as well in metastatic lesions of abdominal lymph nodes that may be affected only with minimal or disregardable scattered radiation, if any, giving no sifnificant influence to cell activity. This fact has suggested that types C, D and E nuclear bodies and nucleolar segregation are changes specific to BLM/R treatments, some solely to BLM. Other nuclear changes consisted in the appearance of fibrillar structures of three different types that were considered to have been produced by disturbed ribosomal activity in the nuclei. On the basis of results in the present study, BLM apparently showed serious evidence of remarkable influences or effects, although not constantly and generally available, on certain squamous carcinoma cells of the esophagus. Some of the evidence was represented by nucleolar segregation and characteristic nuclear bodies of different types, particularly of types C, D and E.

Comparison of computed tomography and 57Co-bleomycin scintigraphy in staging the mediastinal lymph nodes of patients with non-small-cell lung cancer

International Nuclear Information System (INIS)

Laan, J.G. van der; Brink, A. van den; Boer, W.J. de; Piers, D.A.; Beekhuis, H.; Kengen, R.A.

1990-01-01

The value of computed tomography (CT) and of 57 Co-bleomycin scintigraphy ( 57 Co-BLM) in staging the mediastinal lymph nodes was compared in 28 patients suffering from non-small-cell lung cancer. The results were assessed against the pathological findings obtained during thoracotomy or mediastinoscopy. CT staging of the mediastinum had a sensitivity of 75%, a specificity of 80%, an accuracy of 79%, a positive predictive index of 60% and a negative predictive index of 89%. 57 Co-BLM scintigraphic staging had a sensitivity of 43%, a specificity of 94%, and accuracy of 80%, a positive predictive index of 75% and a negative predictive index of 81%. In this small series these differences were not statistically significant; it thus appears that CT and 57 Co-BLM are of equal value in staging the mediastinum. Mediastinoscopy is not contributory in case of a negative CT or 57 Co-BLM. A positive CT or 57 Co-BLM, however, indicates the need for histological verification of the mediastinal findings. (orig.) [de

Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis.

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Grabarz, Felipe; Aguiar, Cristhiane Favero; Correa-Costa, Matheus; Braga, Tárcio Teodoro; Hyane, Meire I; Andrade-Oliveira, Vinícius; Landgraf, Maristella Almeida; Câmara, Niels Olsen Saraiva

2018-04-01

Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18 -/- ) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists α-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in Jα18 -/- mice and in wild-type α-galactosylceramide-sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-β and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.

Oligosaccharide modification by N-acetylglucosaminyltransferase-V in macrophages are involved in pathogenesis of bleomycin-induced scleroderma.

Science.gov (United States)

Kato, Arisa; Yutani, Mizuki; Terao, Mika; Kimura, Akihiro; Itoi, Saori; Murota, Hiroyuki; Miyoshi, Eiji; Katayama, Ichiro

2015-08-01

Oligosaccharide modification by N-acetylglucosaminyltransferase-V (GnT-V), which catalyses the formation of β1,6 GlcNAc (N-acetylglucosamine) branches on N-glycans, is associated with various pathologies, such as cancer metastasis, multiple sclerosis and liver fibrosis. In this study, we demonstrated the involvement of GnT-V in the pathophysiology of scleroderma. High expression of GnT-V was observed in infiltrating cells in skin section samples from systemic and localized patients with scleroderma. Most of the infiltrating cells were T cells and macrophages, most of which were CD163(+) M2 macrophages. To determine the role of GnT-V in scleroderma, we next investigated skin sclerosis in GnT-V knockout (MGAT5(-/-) ) mice. Expression of GnT-V was also elevated in bleomycin (BLM)-injected sclerotic skin, and MGAT5(-/-) mice were resistant to BLM-induced skin sclerosis with reduced collagen type 1 α1 content, suggesting the biological significance of GnT-V in skin sclerosis. Furthermore, the number of CD163(+) M2 macrophages and CD3-positive T cells in BLM-induced skin sclerosis was significantly fewer in MGAT5(-/-) mice. In bone marrow-derived macrophages (BMDMs), IL-4-induced expressions of Fizz1 and Ym1 were significantly reduced in MGAT5(-/-) mice-derived BMDMs. Taken together, these results suggest the induction of GnT-V in skin sclerosis progression is possibly dependent on increased numbers of M2 macrophages in the skin, which are important for tissue fibrosis and remodelling. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Analysis of spontaneous and bleomycin-induced chromosome damage in peripheral lymphocytes of long-haul aircrew members from Argentina

International Nuclear Information System (INIS)

Bolzan, Alejandro D.; Bianchi, Martha S.; Gimenez, Esteban M.; Flaque, Maria C. Diaz; Ciancio, Vicente R.

2008-01-01

Spontaneous and bleomycin (BLM)-induced chromosomal aberrations in G0 and G2 stages of the cell cycle have been analyzed in peripheral lymphocytes of 21 long-haul aircrew members from Argentina in order to assess BLM-induced clastogenesis as a first approach to determine the DNA repair capacity and thereby the susceptibility to environmental cancers in aircrew. The possibility that occupational exposure of flight personnel to cosmic radiation can induce an adaptive response in their peripheral lymphocytes that can be detected by a subsequent in vitro treatment with BLM was also investigated. For comparison, aberrations were also scored in the lymphocytes of 15 healthy volunteers matched by age, health, sex, drinking and smoking habits to the flight personnel group. Aircrew exhibited a higher frequency of spontaneous dicentrics and ring chromosomes than the control population (p 0.05). However, the aircrew sampled population was almost two times more sensitive to BLM G0 clastogenic effects than controls (p < 0.05). Therefore, our data suggest that chronic exposure of aircrew to cosmic radiation increases the in vitro chromosomal sensitivity of their peripheral lymphocytes to BLM (at least in the G0 stage of the cell cycle), and that occupational exposure of flight personnel to cosmic radiation does not induce an adaptive response to this radiomimetic compound. Our results justify further studies aimed at determine if those aircrew members hypersensitive to BLM are more prone to develop environmental cancer than BLM-insensitive individuals

Pretreatment with UV light renders the chromatin in human fibroblasts more susceptible to the DNA-damaging agents bleomycin, gamma radiation and 8-methoxypsoralen

International Nuclear Information System (INIS)

Ljungman, Mats

1989-01-01

Confluent human fibroblast cultures were pretreated with either 254 nm UV light (UV) or methyl methanesulphonate (MMS), incubated at 37 0 C and subsequently challenged on ice with bleomycin (BLM), gamma-radiation or 8-methoxy-psoralen (MOP). The resulting number of challenge-induced DNA damages (measured as DNA strand breaks or cross-links) were compared with the numbers induced in similarly challenged but non-pretreated control cells. It was found that the timing of the subsequent challenge of cells pretreated with UV did significantly affect the amount of induced DNA damage. When the challenging agents were administered after a 10-20 min incubation period following UV pretreatment, the amount of induced DNA damage was increased 50% over control cells. In contrast, the timing of the subsequent challenge of cells pretreated with MMS has no influence on the level of challenge-induced damage. It is hypothesized that UV-irradiated chromatin undergoes a time-dependent decondensation that renders it more susceptible to the induction of strand breaks and cross-links by BLM, gamma-radiation and MOP. A possible role for chromatin decondensation in UV-induced excision repair is discussed. (author)

Chromatin condensation and differential sensitivity of mammalian and insect cells to DNA strand breaks induced by bleomycin

International Nuclear Information System (INIS)

Lopez-Larraza, Daniel M.; Padron, Juan; Ronci, Natalia E.; Vidal Rioja, Lidia A.

2006-01-01

Bleomycin (BLM) induces DNA damage in living cells. In this report we analyzed the role of chromatin compactness in the differential response of mosquito (ATC-15) and mammalian (CHO) cells to DNA strand breaks induced by BLM. We used cells unexposed and exposed to sodium butyrate (NaB), which induces chromatin decondensation. By nucleoid sedimentation assay and digestions of nuclei with DNAse I, untreated mosquito cells (no BLM; no NaB) were shown to have more chromatin condensation than untreated CHO cells. By alkaline unwinding ATC-15 cells treated with NaB showed more BLM-induced DNA strand breaks than NaB-untreated CHO cells. The time-course of BLM-induced DNA damage to nuclear DNA was similar for NaB-untreated mammalian and insect cells, but with mosquito cells showing less DNA strand breaks, both at physiological temperatures and at 4 o C. However, when DNA repair was inhibited by low temperatures and chromatin was decondensed by NaB treatments, differences in BLM-induced DNA damage between these cells lines were no longer observed. In both cell lines, NaB did not affect BLM action on cell growth and viability. On the other hand, the low sensitivity of ATC-15 cells to BLM was reflected in their better growth efficiency. These cells exhibited a satisfactory growth at BLM doses that produced a permanent arrest of growth in CHO cells. The data suggest that mosquito cells might have linker DNAs shorter than those of mammalian cells, which would result in the observed both greater chromatin condensation and greater resistance to DNA damage induced by BLM as compared to CHO cells

Chromatin condensation and differential sensitivity of mammalian and insect cells to DNA strand breaks induced by bleomycin

Energy Technology Data Exchange (ETDEWEB)

Lopez-Larraza, Daniel M. [IMBICE, C.C. 403, 1900 La Plata (Argentina)]. E-mail: danielop@imbice.org.ar; Padron, Juan [IMBICE, C.C. 403, 1900 La Plata (Argentina); Ronci, Natalia E. [IMBICE, C.C. 403, 1900 La Plata (Argentina); Vidal Rioja, Lidia A. [IMBICE, C.C. 403, 1900 La Plata (Argentina)

2006-08-30

Bleomycin (BLM) induces DNA damage in living cells. In this report we analyzed the role of chromatin compactness in the differential response of mosquito (ATC-15) and mammalian (CHO) cells to DNA strand breaks induced by BLM. We used cells unexposed and exposed to sodium butyrate (NaB), which induces chromatin decondensation. By nucleoid sedimentation assay and digestions of nuclei with DNAse I, untreated mosquito cells (no BLM; no NaB) were shown to have more chromatin condensation than untreated CHO cells. By alkaline unwinding ATC-15 cells treated with NaB showed more BLM-induced DNA strand breaks than NaB-untreated CHO cells. The time-course of BLM-induced DNA damage to nuclear DNA was similar for NaB-untreated mammalian and insect cells, but with mosquito cells showing less DNA strand breaks, both at physiological temperatures and at 4 {sup o}C. However, when DNA repair was inhibited by low temperatures and chromatin was decondensed by NaB treatments, differences in BLM-induced DNA damage between these cells lines were no longer observed. In both cell lines, NaB did not affect BLM action on cell growth and viability. On the other hand, the low sensitivity of ATC-15 cells to BLM was reflected in their better growth efficiency. These cells exhibited a satisfactory growth at BLM doses that produced a permanent arrest of growth in CHO cells. The data suggest that mosquito cells might have linker DNAs shorter than those of mammalian cells, which would result in the observed both greater chromatin condensation and greater resistance to DNA damage induced by BLM as compared to CHO cells.

111Indium-labeled neutrophil migration into the lungs of bleomycin-treated rabbits assessed noninvasively by external scintigraphy

International Nuclear Information System (INIS)

Haslett, C.; Shen, A.S.; Feldsien, D.C.; Allen, D.; Henson, P.M.; Cherniack, R.M.

1989-01-01

Factors controlling neutrophil migration into the lung are poorly understood, but their identification is important for our understanding of the pathogenesis of inflammatory lung diseases. Pulmonary inflammation is difficult to quantify, and neutrophils in tissues and BAL may not accurately represent cell migration. In this study, intravenously delivered pulses of rabbit neutrophils labeled with Indium-111 (111In-neutrophils) were used to monitor neutrophil migration into the lungs. Radioactivity quantified in the lung region of interest (ROI) of external gamma camera scintigrams recorded 24 h after intravenous 111In-neutrophil injection accurately reflected the actual neutrophil-associated lung tissue radioactivity. ROI radioactivity at 24 h also correlated closely with the percent of 111In-neutrophils that had migrated into lavageable air spaces, and this parameter therefore provided an index of total lung 111In-neutrophil migration. Using 24-h ROI radioactivity and percent of injected 111In-neutrophils recovered in BAL at 24 h as indices of neutrophil migration into the lung, it was found that intratracheal saline caused only a transient neutrophil migration, whereas 10 U/kg intratracheal bleomycin induced migration that persisted for as long as 3 wk. 111In-neutrophil migration into the lung, assessed by external scintigraphy, correlated with total neutrophils quantified in histologic sections (r = 0.71, p = 0.006). The data suggest that this approach will be valuable in investigating mechanisms controlling neutrophil migration in lung inflammation, and that 111In-neutrophil scintigraphy may provide a noninvasive index of total lung neutrophil load that might be useful in staging inflammation in patchy diseases such as idiopathic pulmonary fibrosis

Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis.

Science.gov (United States)

Henry, Eric; Cores, Jhon; Hensley, M Taylor; Anthony, Shirena; Vandergriff, Adam; de Andrade, James B M; Allen, Tyler; Caranasos, Thomas G; Lobo, Leonard J; Cheng, Ke

2015-11-01

Lung diseases are devastating conditions and ranked as one of the top five causes of mortality worldwide according to the World Health Organization. Stem cell therapy is a promising strategy for lung regeneration. Previous animal and clinical studies have focused on the use of mesenchymal stem cells (from other parts of the body) for lung regenerative therapies. We report a rapid and robust method to generate therapeutic resident lung progenitors from adult lung tissues. Outgrowth cells from healthy lung tissue explants are self-aggregated into three-dimensional lung spheroids in a suspension culture. Without antigenic sorting, the lung spheroids recapitulate the stem cell niche and contain a natural mixture of lung stem cells and supporting cells. In vitro, lung spheroid cells can be expanded to a large quantity and can form alveoli-like structures and acquire mature lung epithelial phenotypes. In severe combined immunodeficiency mice with bleomycin-induced pulmonary fibrosis, intravenous injection of human lung spheroid cells inhibited apoptosis, fibrosis, and infiltration but promoted angiogenesis. In a syngeneic rat model of pulmonary fibrosis, lung spheroid cells outperformed adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration. Previously, lung spheroid cells (the spheroid model) had only been used to study lung cancer cells. Our data suggest that lung spheroids and lung spheroid cells from healthy lung tissues are excellent sources of regenerative lung cells for therapeutic lung regeneration. The results from the present study will lead to future human clinical trials using lung stem cell therapies to treat various incurable lung diseases, including pulmonary fibrosis. The data presented here also provide fundamental knowledge regarding how injected stem cells mediate lung repair in pulmonary fibrosis. ©AlphaMed Press.

14-3-3ε boosts bleomycin-induced DNA damage response by inhibiting the drug-resistant activity of MVP.

Science.gov (United States)

Tang, Siwei; Bai, Chen; Yang, Pengyuan; Chen, Xian

2013-06-07

Major vault protein (MVP) is the predominant constituent of the vault particle, the largest known ribonuclear protein complex. Although emerging evidence have been establishing the links between MVP (vault) and multidrug resistance (MDR), little is known regarding exactly how the MDR activity of MVP is modulated during cellular response to drug-induced DNA damage (DDR). Bleomycin (BLM), an anticancer drug, induces DNA double-stranded breaks (DSBs) and consequently triggers the cellular DDR. Due to its physiological implications in hepatocellular carcinoma (HCC) and cell fate decision, 14-3-3ε was chosen as the pathway-specific bait protein to identify the critical target(s) responsible for HCC MDR. By using an LC-MS/MS-based proteomic approach, MVP was first identified in the BLM-induced 14-3-3ε interactome formed in HCC cells. Biological characterization revealed that MVP possesses specific activity to promote the resistance to the BLM-induced DDR. On the other hand, 14-3-3ε enhances BLM-induced DDR by interacting with MVP. Mechanistic investigation further revealed that 14-3-3ε, in a phosphorylation-dependent manner, binds to the phosphorylated sites at both Thr52 and Ser864 of the monomer of MVP. Consequently, the phosphorylation-dependent binding between 14-3-3ε and MVP inhibits the drug-resistant activity of MVP for an enhanced DDR to BLM treatment. Our findings provide an insight into the mechanism underlying how the BLM-induced interaction between 14-3-3ε and MVP modulates MDR, implicating novel strategy to overcome the chemotherapeutic resistance through interfering specific protein-protein interactions.

Regeneration of alveolar type I and II cells from Scgb1a1-expressing cells following severe pulmonary damage induced by bleomycin and influenza.

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Dahai Zheng

Full Text Available The lung comprises an extensive surface of epithelia constantly exposed to environmental insults. Maintaining the integrity of the alveolar epithelia is critical for lung function and gaseous exchange. However, following severe pulmonary damage, what progenitor cells give rise to alveolar type I and II cells during the regeneration of alveolar epithelia has not been fully determined. In this study, we have investigated this issue by using transgenic mice in which Scgb1a1-expressing cells and their progeny can be genetically labeled with EGFP. We show that following severe alveolar damage induced either by bleomycin or by infection with influenza virus, the majority of the newly generated alveolar type II cells in the damaged parenchyma were labeled with EGFP. A large proportion of EGFP-expressing type I cells were also observed among the type II cells. These findings strongly suggest that Scgb1a1-expressing cells, most likely Clara cells, are a major cell type that gives rise to alveolar type I and II cells during the regeneration of alveolar epithelia in response to severe pulmonary damage in mice.

Study on combined effects of radiation and bleomycin on carcinoma of tongue iduced by DMBA in hamster

International Nuclear Information System (INIS)

Kitamura, Nobuyasu

1979-01-01

Carcinoma of the tongue (Mostly squamous cell carcinoma) was induced in hamsters by 9,10-dimethyl-1, 2-benzanthracene (DMBA). The amount of various kinds of free radicals, which increased due to radioactive radiation and administration of bleomycin (BLM) in tongue and liver tissues, was determined by an electron spin resonance method. The hamsters were separated into seven groups: BLM administration only (group A 1 ), 60 Co-γ-ray irradiation only (A 2 ), 60 Co-γ-ray irradiation 30 min after BLM administration (A 3 ), BLM administration 30 min after 60 Co-γ-ray irradiation (A 4 ), 60 Co-γ-ray irradiation 24 h after BLM administration (A 5 ), BLM administration 24 h after 60 Co-γ-ray irradiation (A 6 ), and the control (A 7 ). Mean free radicals in the groups were compared, using samples fixed 5 min after treatment. The ratio of mean free radicals of carcinoma of the tongue were 2.6, 2.9, 3.7, 3.9, 3.0, 3.2, and 1 in A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , and A 7 . The ratio of mean free radicals of the liver under the same condition were 1.5, 1.6, 3.3, 3.8, 2.2, 2.6, and 1. A combination of BLM and radioactive radiation increased the amount of free radicals in carcinoma of the tongue and in the liver. Especially BLM administration 30 min after 60 Co-γ-ray irradiation showed a synergistic effect. Judging from the amount of free radicals determined, the effect of radioactive irradiation increased when combined with BLM administration. BLM was most effective when it was administered 5 min after radioactive irradiation. (Tsunoda, M.)

Analysis of spontaneous and bleomycin-induced chromosome damage in peripheral lymphocytes of long-haul aircrew members from Argentina

Energy Technology Data Exchange (ETDEWEB)

Bolzan, Alejandro D. [Laboratorio de Citogenetica y Mutagenesis, Instituto Multidisciplinario de Biologia Celular (IMBICE), C.C. 403, 1900 La Plata (Argentina); Miembro de la Carrera del Investigador Cientifico del CONICET (Argentina)], E-mail: abolzan@imbice.org.ar; Bianchi, Martha S. [Laboratorio de Citogenetica y Mutagenesis, Instituto Multidisciplinario de Biologia Celular (IMBICE), C.C. 403, 1900 La Plata (Argentina); Miembro de la Carrera del Investigador Cientifico del CONICET (Argentina); Gimenez, Esteban M.; Flaque, Maria C. Diaz [Laboratorio de Citogenetica y Mutagenesis, Instituto Multidisciplinario de Biologia Celular (IMBICE), C.C. 403, 1900 La Plata (Argentina); Ciancio, Vicente R. [Universidad Nacional de La Plata, Facultad de Ciencias Medicas, 120 y 60, 1900 La Plata (Argentina)

2008-03-01

Spontaneous and bleomycin (BLM)-induced chromosomal aberrations in G0 and G2 stages of the cell cycle have been analyzed in peripheral lymphocytes of 21 long-haul aircrew members from Argentina in order to assess BLM-induced clastogenesis as a first approach to determine the DNA repair capacity and thereby the susceptibility to environmental cancers in aircrew. The possibility that occupational exposure of flight personnel to cosmic radiation can induce an adaptive response in their peripheral lymphocytes that can be detected by a subsequent in vitro treatment with BLM was also investigated. For comparison, aberrations were also scored in the lymphocytes of 15 healthy volunteers matched by age, health, sex, drinking and smoking habits to the flight personnel group. Aircrew exhibited a higher frequency of spontaneous dicentrics and ring chromosomes than the control population (p < 0.05). BLM sensitivity test showed that aircrew and controls are equally sensitive to BLM G2 clastogenic effects, since both groups exhibited a similar frequency of chromatid breaks per cell (p > 0.05). However, the aircrew sampled population was almost two times more sensitive to BLM G0 clastogenic effects than controls (p < 0.05). Therefore, our data suggest that chronic exposure of aircrew to cosmic radiation increases the in vitro chromosomal sensitivity of their peripheral lymphocytes to BLM (at least in the G0 stage of the cell cycle), and that occupational exposure of flight personnel to cosmic radiation does not induce an adaptive response to this radiomimetic compound. Our results justify further studies aimed at determine if those aircrew members hypersensitive to BLM are more prone to develop environmental cancer than BLM-insensitive individuals.

Clastogenic adaption of Vicia faba root tip meristem cells after consecutive treatments with S-phase dependent and S-phase independent agents

International Nuclear Information System (INIS)

Heindorff, K.; Schubert, I.; Rieger, R.; Michaelis, A.

1987-01-01

Pretreatment of Vicia faba root tip meristems with low doses of S-phase independent clastogens, such as X-rays or bleomycin, prior to a high (challenge) dose of S-phase dependent clastogens, such as alkylating agents (TEM, Trenimon) or the pyridazine derivative MH, led to decreased challenge treatment-induced aberration frequencies, i.e., clastogenic adaptation. Using the inverse treatment sequence bleomycin and MH proved to be able to substitute for each other in provoking clastogenic (cross) adaptation while bleomycin and alkylating agents were unable to do so. The data support the assumption of inducible cellular functions that become triggered by low clastogen doses and additionally describe some particular properties of bleomycin when used for conditioning. Bleomycin proved to be capable to exert protection independent of the agent used for challenge treatment. (author)

Accurate and rapid modeling of iron-bleomycin-induced DNA damage using tethered duplex oligonucleotides and electrospray ionization ion trap mass spectrometric analysis.

Science.gov (United States)

Harsch, A; Marzilli, L A; Bunt, R C; Stubbe, J; Vouros, P

2000-05-01

Bleomycin B(2)(BLM) in the presence of iron [Fe(II)] and O(2)catalyzes single-stranded (ss) and double-stranded (ds) cleavage of DNA. Electrospray ionization ion trap mass spectrometry was used to monitor these cleavage processes. Two duplex oligonucleotides containing an ethylene oxide tether between both strands were used in this investigation, allowing facile monitoring of all ss and ds cleavage events. A sequence for site-specific binding and cleavage by Fe-BLM was incorporated into each analyte. One of these core sequences, GTAC, is a known hot-spot for ds cleavage, while the other sequence, GGCC, is a hot-spot for ss cleavage. Incubation of each oligo-nucleotide under anaerobic conditions with Fe(II)-BLM allowed detection of the non-covalent ternary Fe-BLM/oligonucleotide complex in the gas phase. Cleavage studies were then performed utilizing O(2)-activated Fe(II)-BLM. No work-up or separation steps were required and direct MS and MS/MS analyses of the crude reaction mixtures confirmed sequence-specific Fe-BLM-induced cleavage. Comparison of the cleavage patterns for both oligonucleotides revealed sequence-dependent preferences for ss and ds cleavages in accordance with previously established gel electrophoresis analysis of hairpin oligonucleotides. This novel methodology allowed direct, rapid and accurate determination of cleavage profiles of model duplex oligonucleotides after exposure to activated Fe-BLM.

Mycobacterium tuberculosis Ku can bind to nuclear DNA damage and sensitize mammalian cells to bleomycin sulfate.

Science.gov (United States)

Castore, Reneau; Hughes, Cameron; Debeaux, Austin; Sun, Jingxin; Zeng, Cailing; Wang, Shih-Ya; Tatchell, Kelly; Shi, Runhua; Lee, Kyung-Jong; Chen, David J; Harrison, Lynn

2011-11-01

Radiotherapy and chemotherapy are effective cancer treatments due to their ability to generate DNA damage. The major lethal lesion is the DNA double-strand break (DSB). Human cells predominantly repair DSBs by non-homologous end joining (NHEJ), which requires Ku70, Ku80, DNA-PKcs, DNA ligase IV and accessory proteins. Repair is initiated by the binding of the Ku heterodimer at the ends of the DSB and this recruits DNA-PKcs, which initiates damage signaling and functions in repair. NHEJ also exists in certain types of bacteria that have dormant phases in their life cycle. The Mycobacterium tuberculosis Ku (Mt-Ku) resembles the DNA-binding domain of human Ku but does not have the N- and C-terminal domains of Ku70/80 that have been implicated in binding mammalian NHEJ repair proteins. The aim of this work was to determine whether Mt-Ku could be used as a tool to bind DSBs in mammalian cells and sensitize cells to DNA damage. We generated a fusion protein (KuEnls) of Mt-Ku, EGFP and a nuclear localization signal that is able to perform bacterial NHEJ and hence bind DSBs. Using transient transfection, we demonstrated that KuEnls is able to bind laser damage in the nucleus of Ku80-deficient cells within 10 sec and remains bound for up to 2 h. The Mt-Ku fusion protein was over-expressed in U2OS cells and this increased the sensitivity of the cells to bleomycin sulfate. Hydrogen peroxide and UV radiation do not predominantly produce DSBs and there was little or no change in sensitivity to these agents. Since in vitro studies were unable to detect binding of Mt-Ku to DNA-PKcs or human Ku70/80, this work suggests that KuEnls sensitizes cells by binding DSBs, preventing human NHEJ. This study indicates that blocking or decreasing the binding of human Ku to DSBs could be a method for enhancing existing cancer treatments.

Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4 Induced Hepatic Fibrosis in Mice.

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Leola N Chow

Full Text Available Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM-induced pulmonary fibrosis and carbon tetrachloride (CCl4-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC, the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis.

ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis.

Science.gov (United States)

Martins, Vanessa; Valença, Samuel S; Farias-Filho, Francisco A; Molinaro, Raphael; Simões, Rafael L; Ferreira, Tatiana P T; e Silva, Patrícia M R; Hogaboam, Cory M; Kunkel, Steven L; Fierro, Iolanda M; Canetti, Claudio; Benjamim, Claudia F

2009-05-01

Despite an increase in the knowledge of mechanisms and mediators involved in pulmonary fibrosis, there are no successful therapeutics available. Lipoxins (LX) and their 15-epimers, aspirin-triggered LX (ATL), are endogenously produced eicosanoids with potent anti-inflammatory and proresolution effects. To date, few studies have been performed regarding their effect on pulmonary fibrosis. In the present study, using C57BL/6 mice, we report that bleomycin (BLM)-induced lung fibrosis was prevented by the concomitant treatment with an ATL synthetic analog, ATLa, which reduced inflammation and matrix deposition. ATLa inhibited BLM-induced leukocyte accumulation and alveolar collapse as evaluated by histology and morphometrical analysis. Moreover, Sirius red staining and lung hydroxyproline content showed an increased collagen deposition in mice receiving BLM alone that was decreased upon treatment with the analog. These effects resulted in benefits to pulmonary mechanics, as ATLa brought to normal levels both lung resistance and compliance. Furthermore, the analog improved mouse survival, suggesting an important role for the LX pathway in the control of disease establishment and progression. One possible mechanism by which ATLa restrained fibrosis was suggested by the finding that BLM-induced myofibroblast accumulation/differentiation in the lung parenchyma was also reduced by both simultaneous and posttreatment with the analog (alpha-actin immunohistochemistry). Interestingly, ATLa posttreatment (4 days after BLM) showed similar inhibitory effects on inflammation and matrix deposition, besides the TGF-beta level reduction in the lung, reinforcing an antifibrotic effect. In conclusion, our findings show that LX and ATL can be considered as promising therapeutic approaches to lung fibrotic diseases.

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

Directory of Open Access Journals (Sweden)

Hong-Mei Yang

2017-02-01

Full Text Available Bleomycin (BLM, a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22 tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

Changes in expression of cytokines in polyhexamethylene guanidine-induced lung fibrosis in mice: Comparison of bleomycin-induced lung fibrosis.

Science.gov (United States)

Kim, Min-Seok; Kim, Sung-Hwan; Jeon, Doin; Kim, Hyeon-Young; Lee, Kyuhong

2018-01-15

Inhalation of polyhexamethylene guanidine (PHMG) causes irreversible pulmonary injury, such as pulmonary fibrosis. However, the mechanism underlying PHMG-induced lung injury is unclear. In this study, we compared the difference in time-dependent lung injury between PHMG- and bleomycin (BLM)-treated mice and determined cytokines involved in inducing lung injury by performing cytokine antibody array analysis. Mice were treated once with 1.8mg/kg BLM or 1.2mg/kg PHMG through intratracheal instillation and were sacrificed on days 7 and 28. Bronchoalveolar lavage fluid (BALF) analysis showed that the number of neutrophils was significantly higher in PHMG-treated mice than in BLM-treated mice on day 7. Histopathological analysis showed inflammatory cell infiltration and fibrosis mainly in the terminal bronchioles and alveoli in the lungs of PHMG- and BLM-treated mice. However, continuous macrophage infiltration in the alveolar space and bronchioloalveolar epithelial hyperplasia (BEH) were only observed in PHMG-treated mice. Cytokine antibody array analysis showed that 15 and eight cytokines were upregulated in PHMG- and BLM-treated mice, respectively, on day 7. On day 28, 13 and five cytokines were upregulated in PHMG and BLM-treated mice, respectively. In addition, the expressed cytokines between days 7 and 28 in BLM-treated mice were clearly different, but were similar in PHMG-treated mice. Consequently, between PHMG- and BLM-treated mice, we observed differences in the expression patterns and types of cytokines. These differences are considered to be a result of the inflammatory processes induced by both substances, which may mainly involve macrophage infiltration. Therefore, continuous induction of the inflammatory response by PHMG may play an important role in the development of pulmonary fibrosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Modulation of the genotoxicity of bleomycin by amines through noncovalent DNA interactions and alteration of physiological conditions in yeast

International Nuclear Information System (INIS)

Hoffmann, George R.; Gessner, Gabrielle S.; Hughes, Jennifer F.; Ronan, Matthew V.; Sylvia, Katelyn E.; Willett, Christine J.

2007-01-01

The effects of amines on the induction of mitotic gene conversion by bleomycin (BLM) were studied at the trp5 locus in Saccharomyces cerevisiae strain D7. BLM induces double-strand breaks in DNA and is a potent recombinagen in this assay. The polyamine spermidine causes concentration-dependent protection against the genotoxicity of BLM, reducing the convertant frequency by over 90% under the most protective conditions. Spermine, diethylenetriamine, ethylenediamine, putrescine, and ethylamine were also antigenotoxic in combined treatments with BLM. There was a general correspondence between the protective effect and the number of amino groups, suggesting that more strongly cationic amines tend to be stronger antirecombinagens. Electrostatic association of the amines with DNA probably hinders BLM access to the 4' position of deoxyribose where it generates a free radical. Other amines interact with BLM differently from these unbranched aliphatic amines. The aminothiol cysteamine inhibits the genotoxicity of BLM under hypoxic conditions but increases it under euoxic conditions. In contrast, pargyline potentiates the genotoxicity of BLM under hypoxic conditions but not under euoxic conditions. The antirecombinagenic effect of cysteamine apparently involves DNA binding and depletion of oxygen needed for BLM activity, whereas its potentiation of BLM entails its serving as an electron source for the activation of BLM. Pargyline may enhance BLM indirectly by preventing the depletion of oxygen by monoamine and polyamine oxidase. The planar 9-aminoacridine weakly induces gene conversion in strain D7, but it is strongly synergistic with BLM. Enhancement of BLM activity by this compound and by the related nitroacridine Entozon is apparently mediated by intercalation of the acridine ring system into DNA. Thus, the influence of amines on the genotoxicity of BLM in yeast encompasses antigenotoxic, potentiating, and synergistic interactions. The underlying mechanisms involve

Modulation of the genotoxicity of bleomycin by amines through noncovalent DNA interactions and alteration of physiological conditions in yeast

Energy Technology Data Exchange (ETDEWEB)

Hoffmann, George R. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States)], E-mail: ghoffmann@holycross.edu; Gessner, Gabrielle S.; Hughes, Jennifer F.; Ronan, Matthew V.; Sylvia, Katelyn E.; Willett, Christine J. [Department of Biology, College of the Holy Cross, One College Street, Worcester, MA 01610-2395 (United States)

2007-10-01

The effects of amines on the induction of mitotic gene conversion by bleomycin (BLM) were studied at the trp5 locus in Saccharomyces cerevisiae strain D7. BLM induces double-strand breaks in DNA and is a potent recombinagen in this assay. The polyamine spermidine causes concentration-dependent protection against the genotoxicity of BLM, reducing the convertant frequency by over 90% under the most protective conditions. Spermine, diethylenetriamine, ethylenediamine, putrescine, and ethylamine were also antigenotoxic in combined treatments with BLM. There was a general correspondence between the protective effect and the number of amino groups, suggesting that more strongly cationic amines tend to be stronger antirecombinagens. Electrostatic association of the amines with DNA probably hinders BLM access to the 4' position of deoxyribose where it generates a free radical. Other amines interact with BLM differently from these unbranched aliphatic amines. The aminothiol cysteamine inhibits the genotoxicity of BLM under hypoxic conditions but increases it under euoxic conditions. In contrast, pargyline potentiates the genotoxicity of BLM under hypoxic conditions but not under euoxic conditions. The antirecombinagenic effect of cysteamine apparently involves DNA binding and depletion of oxygen needed for BLM activity, whereas its potentiation of BLM entails its serving as an electron source for the activation of BLM. Pargyline may enhance BLM indirectly by preventing the depletion of oxygen by monoamine and polyamine oxidase. The planar 9-aminoacridine weakly induces gene conversion in strain D7, but it is strongly synergistic with BLM. Enhancement of BLM activity by this compound and by the related nitroacridine Entozon is apparently mediated by intercalation of the acridine ring system into DNA. Thus, the influence of amines on the genotoxicity of BLM in yeast encompasses antigenotoxic, potentiating, and synergistic interactions. The underlying mechanisms involve

Synergistic effect of bolus exposure to zinc oxide nanoparticles on bleomycin-induced secretion of pro-fibrotic cytokines without lasting fibrotic changes in murine lungs.

Science.gov (United States)

Wu, Wenting; Ichihara, Gaku; Hashimoto, Naozumi; Hasegawa, Yoshinori; Hayashi, Yasuhiko; Tada-Oikawa, Saeko; Suzuki, Yuka; Chang, Jie; Kato, Masashi; D'Alessandro-Gabazza, Corina N; Gabazza, Esteban C; Ichihara, Sahoko

2014-12-30

Zinc oxide (ZnO) nanoparticles are widely used in various products, and the safety evaluation of this manufactured material is important. The present study investigated the inflammatory and fibrotic effects of pulmonary exposure to ZnO nanoparticles in a mouse model of pulmonary fibrosis. Pulmonary fibrosis was induced by constant subcutaneous infusion of bleomycin (BLM). Female C57BL/6Jcl mice were divided into BLM-treated and non-treated groups. In each treatment group, 0, 10, 20 or 30 µg of ZnO nanoparticles were delivered into the lungs through pharyngeal aspiration. Bronchoalveolar lavage fluid (BALF) and the lungs were sampled at Day 10 or 14 after administration. Pulmonary exposure by a single bolus of ZnO nanoparticles resulted in severe, but transient inflammatory infiltration and thickening of the alveolar septa in the lungs, along with the increase of total and differential cell counts in BLAF. The BALF level of interleukin (IL)-1β and transforming growth factor (TGF)-β was increased at Day 10 and 14, respectively. At Day 10, the synergistic effect of BLM and ZnO exposure was detected on IL-1β and monocyte chemotactic protein (MCP)-1 in BALF. The present study demonstrated the synergistic effect of pulmonary exposure to ZnO nanoparticles and subcutaneous infusion of BLM on the secretion of pro-fibrotic cytokines in the lungs.

A direct view by immunofluorescent comet assay (IFCA) of DNA damage induced by nicking and cutting enzymes, ionizing (137)Cs radiation, UV-A laser microbeam irradiation and the radiomimetic drug bleomycin.

Science.gov (United States)

Grigaravicius, Paulius; Rapp, Alexander; Greulich, Karl Otto

2009-03-01

In DNA repair research, DNA damage is induced by different agents, depending on the technical facilities of the investigating researchers. A quantitative comparison of different investigations is therefore often difficult. By using a modified variant of the neutral comet assay, where the histone H1 is detected by immunofluorescence [immunofluorescent comet assay (IFCA)], we achieve previously unprecedented resolution in the detection of fragmented chromatin and show that trillions of ultraviolet A photons (of a few eV), billions of bleomycin (BLM) molecules and thousands of gamma quanta (of 662 keV) generate, in first order, similar damage in the chromatin of HeLa cells. A somewhat more detailed inspection shows that the damage caused by 20 Gy ionizing radiation and by a single laser pulse of 10 microJ are comparable, while the damage caused by 12 microg/ml BLM depends highly on the individual cell. Taken together, this work provides a detailed view of DNA fragmentation induced by different treatments and allows comparing them to some extent, especially with respect to the neutral comet assay.

Antioxidants enhance the recovery of three cycles of bleomycin, etoposide, and cisplatin-induced testicular dysfunction, pituitary-testicular axis, and fertility in rats.

Science.gov (United States)

Kilarkaje, Narayana; Mousa, Alyaa M; Al-Bader, Maie M; Khan, Khalid M

2013-10-01

To investigate the effects of an antioxidant cocktail (AC) on bleomycin, etoposide, and cisplatin (BEP)-induced testicular dysfunction. In vivo study. Research laboratory. Adult male and female Sprague-Dawley rats. The rats were treated with three cycles of 21 days each of therapeutically relevant dose levels of BEP (0.75, 7.5, and 1.5 mg/kg) with or without the AC (a mixture of α-tocopherol, L-ascorbic acid, Zn, and Se). Sperm parameters, fertility, serum hormone levels (ELISA), testicular histopathology, and expression of proliferating cell nuclear antigen (PCNA), and transferrin (Western blotting and immunohistochemistry) were evaluated at the end of treatment and a 63-day recovery period. At the end of treatment, the AC improved BEP-induced decrease in sperm motility and increase in abnormality but had no effect on reduced sperm count, fertility, and tubular atrophy, although it up-regulated germ cell proliferation. The AC normalized reduced inhibin B levels, but had no effect on decreased transferrin and testosterone and elevated LH levels. At the end of the recovery period, the AC enhanced the expression of PCNA and transferrin, repopulation of germ cells, LH-testosterone axis, and fertility, but had no effect on reduced FSH and elevated inhibin B levels. The antioxidants protect and then enhance the recovery of testicular and reproductive endocrine functions when administered concomitantly with BEP therapy. The AC may be beneficial to regain testicular functions after chemotherapy. Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Bleomycin-induced epithelial–mesenchymal transition in sclerotic skin of mice: Possible role of oxidative stress in the pathogenesis

Energy Technology Data Exchange (ETDEWEB)

Zhou, Cheng-Fan, E-mail: zhouchengfan@sohu.com [Institute of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China); Zhou, Deng-Chuan [Department of Emergency Medicine and Critical Care Medicine, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Zhang, Jia-Xiang; Wang, Feng; Cha, Wan-Sheng [Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China); Wu, Chang-Hao [Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, University of Surrey (United Kingdom); Zhu, Qi-Xing, E-mail: zqxing@yeah.net [Institute of Dermatology, the First Affiliated Hospital, Anhui Medical University, Hefei, Anhui 230022 (China); Department of Occupational Health and Environmental Health, School of Public Health, Anhui Medical University, Hefei, Anhui 230032 (China)

2014-06-15

Epithelial–mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4 weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100 mg/kg body weight/day) injected daily for 3 weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice. - Highlights: • We provided the first evidence that EMT occurred in BLM-induced skin fibrosis. • Epithelial cells superficial to the BMZ underwent

Bleomycin-induced epithelial–mesenchymal transition in sclerotic skin of mice: Possible role of oxidative stress in the pathogenesis

International Nuclear Information System (INIS)

Zhou, Cheng-Fan; Zhou, Deng-Chuan; Zhang, Jia-Xiang; Wang, Feng; Cha, Wan-Sheng; Wu, Chang-Hao; Zhu, Qi-Xing

2014-01-01

Epithelial–mesenchymal transition (EMT) derived myofibroblasts are partly responsible for the increased collagen synthesis and deposition that occur in tissue fibrosis; however EMT occurrence in skin fibrosis and its mechanism remain unknown. The aim of this study was to investigate whether epithelial cells undergo EMT and determine the role of oxidative stress in this process. BALB/c mice were subcutaneously injected with bleomycin (BLM) or phosphate buffer saline (PBS) into the shaved back daily for 2, 3, and 4 weeks. Skin collagen deposition was evaluated by histopathology and Western blotting. EMT characteristics in the skin were determined by histopathology and immunofluorescent staining for E-cadherin and vimentin, which were further evaluated by Western blotting and reverse transcriptase polymerase chain reaction (RT-PCR). To investigate the role of oxidative stress in EMT, the antioxidant N-acetylcysteine (NAC) was intraperitoneally (100 mg/kg body weight/day) injected daily for 3 weeks. The epithelial suprabasal cells were detached from the basement membrane zone (BMZ) in the sclerotic skin treated with BLM. Immunofluorescent staining indicated vimentin-positive epithelial cells frequently occurring in the thickened epidermis of BLM-treated mice. Western blotting and RT-PCR showed that the expression of E-cadherin was significantly decreased but that of vimentin significantly increased in the skin treated with BLM. NAC attenuated BLM induced oxidative damage, changes in E-cadherin and vimentin expressions and collagen deposition in the sclerotic skin of mice. This study provides the first evidence that BLM induces the EMT of the epithelial cells superficial to the basement membrane zone in the skin fibrosis. Oxidative stress may contribute, at least in part, to BLM induced EMT and skin fibrosis in mice. - Highlights: • We provided the first evidence that EMT occurred in BLM-induced skin fibrosis. • Epithelial cells superficial to the BMZ underwent

Chemical Composition of Pinus roxburghii Bark Volatile Oil and Validation of Its Anti-Inflammatory Activity Using Molecular Modelling and Bleomycin-Induced Inflammation in Albino Mice

Directory of Open Access Journals (Sweden)

Rola M. Labib

2017-08-01

Full Text Available The chemical composition of Pinus roxburghii bark essential oil (PRO was qualitatively and quantitatively determined using GC/FID and GC/MS. The anti-inflammatory activity was assessed in vitro by evaluating the binding percentages on the cannabinoids and opioids receptors. Bleomycin (BLM-induced pulmonary inflammation in albino mice was adopted to assess PRO anti-inflammatory efficacy in vivo. In silico molecular modelling of its major components was performed on human glucocorticoids receptor (GR. Seventy-five components were identified in which longifolene (33.13% and palmitic acid (9.34% constituted the predominant components. No binding was observed on cannabinoid receptor type 1 (CB1, whereas mild binding was observed on cannabinoid receptor type 2 (CB2, delta, kappa, and mu receptors accounting for 2.9%, 6.9%, 10.9% and 22% binding. A significant in vivo activity was evidenced by reduction of the elevated malondialdehyde (MDA, nitric oxide (NO, myeloperoxidase (MPO, interleukin-6 (IL-6, and tumor necrosis factor-α (TNF-α levels by 55.56%, 55.66%, 64.64%, 58.85% and 77.78% with concomitant elevation of superoxide dismutase (SOD and catalase (CAT activities comparable to BLM-treated group at 100 mg/kg body weight. In silico studies showed that palmitic acid exerted the fittest binding. PRO could serve as a potent anti-inflammatory natural candidate that should be supported by further clinical trials.

The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways.

Science.gov (United States)

del Río, Carmen; Navarrete, Carmen; Collado, Juan A; Bellido, M Luz; Gómez-Cañas, María; Pazos, M Ruth; Fernández-Ruiz, Javier; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A; Cantarero, Irene; Muñoz, Eduardo

2016-02-18

Scleroderma is a group of rare diseases associated with early and transient inflammation and vascular injury, followed by fibrosis affecting the skin and multiple internal organs. Fibroblast activation is the hallmark of scleroderma, and disrupting the intracellular TGFβ signaling may provide a novel approach to controlling fibrosis. Because of its potential role in modulating inflammatory and fibrotic responses, both PPARγ and CB2 receptors represent attractive targets for the development of cannabinoid-based therapies. We have developed a non-thiophilic and chemically stable derivative of the CBD quinol (VCE-004.8) that behaves as a dual agonist of PPARγ and CB2 receptors, VCE-004.8 inhibited TGFβ-induced Col1A2 gene transcription and collagen synthesis. Moreover, VCE-004.8 inhibited TGFβ-mediated myofibroblast differentiation and impaired wound-healing activity. The anti-fibrotic efficacy in vivo was investigated in a murine model of dermal fibrosis induced by bleomycin. VCE-004.8 reduced dermal thickness, blood vessels collagen accumulation and prevented mast cell degranulation and macrophage infiltration in the skin. These effects were impaired by the PPARγ antagonist T0070907 and the CB2 antagonist AM630. In addition, VCE-004.8 downregulated the expression of several key genes associated with fibrosis, qualifying this semi-synthetic cannabinoid as a novel compound for the management of scleroderma and, potentially, other fibrotic diseases.

Chemical Composition of Pinus roxburghii Bark Volatile Oil and Validation of Its Anti-Inflammatory Activity Using Molecular Modelling and Bleomycin-Induced Inflammation in Albino Mice.

Science.gov (United States)

Labib, Rola M; Youssef, Fadia S; Ashour, Mohamed L; Abdel-Daim, Mohamed M; Ross, Samir A

2017-08-29

The chemical composition of Pinus roxburghii bark essential oil (PRO) was qualitatively and quantitatively determined using GC/FID and GC/MS. The anti-inflammatory activity was assessed in vitro by evaluating the binding percentages on the cannabinoids and opioids receptors. Bleomycin (BLM)-induced pulmonary inflammation in albino mice was adopted to assess PRO anti-inflammatory efficacy in vivo. In silico molecular modelling of its major components was performed on human glucocorticoids receptor (GR). Seventy-five components were identified in which longifolene (33.13%) and palmitic acid (9.34%) constituted the predominant components. No binding was observed on cannabinoid receptor type 1 (CB1), whereas mild binding was observed on cannabinoid receptor type 2 (CB2), delta , kappa , and mu receptors accounting for 2.9%, 6.9%, 10.9% and 22% binding. A significant in vivo activity was evidenced by reduction of the elevated malondialdehyde (MDA), nitric oxide (NO), myeloperoxidase (MPO), interleukin-6 (IL-6), and tumor necrosis factor- α (TNF- α ) levels by 55.56%, 55.66%, 64.64%, 58.85% and 77.78% with concomitant elevation of superoxide dismutase (SOD) and catalase (CAT) activities comparable to BLM-treated group at 100 mg/kg body weight. In silico studies showed that palmitic acid exerted the fittest binding. PRO could serve as a potent anti-inflammatory natural candidate that should be supported by further clinical trials.

Labelled antibiotics as tumour-localizing agents

International Nuclear Information System (INIS)

Taylor, D.M.; McCready, V.R.

1976-01-01

The published results of clinical and experimental studies of labelled bleomycins and tetracyclines are reviewed. None of the labelled antibiotics yet studied show anything approaching absolute tumour specificity. Clinical trials suggest that 57 Co-bleomycin is superior to either 111 In- or 99 Tcsup(m)-bleomycin and that it may possess some advantages over 67 Ga-citrate in respect of lower uptake in the abdomen and, possibly, lower uptakes in benign and inflammatory lesions. Radioiodine-labelled or 99 Tcsup(m)-labelled tetracyclines appear to be of little value in tumour localization. (author)

Acute fibrinous and organising pneumonia: a rare histopathological variant of chemotherapy-induced lung injury.

Science.gov (United States)

Gupta, Arjun; Sen, Shiraj; Naina, Harris

2016-04-06

Bleomycin-induced lung injury is the most common chemotherapy-associated lung disease, and is linked with several histopathological patterns. Acute fibrinous and organising pneumonia (AFOP) is a relatively new and rare histological pattern of diffuse lung injury. We report the first known case of bleomycin-induced AFOP. A 36-year-old man with metastatic testicular cancer received three cycles of bleomycin, etoposide and cisplatin, before being transitioned to paclitaxel, ifosfamide and cisplatin. He subsequently presented with exertional dyspnoea, cough and pleuritic chest pain. CT of the chest demonstrated bilateral ground glass opacities with peribronchovascular distribution and pulmonary function tests demonstrated a restrictive pattern of lung disease with impaired diffusion. Transbronchial biopsy revealed intra-alveolar fibrin deposits with organising pneumonia, consisting of intraluminal loose connective tissue consistent with AFOP. The patient received high-dose corticosteroids with symptomatic and radiographic improvement. AFOP should be recognised as a histopathological variant of bleomycin-induced lung injury. 2016 BMJ Publishing Group Ltd.

Managing AIDS-related Kaposi's sarcoma and pregnancy

African Journals Online (AJOL)

additional 14 cycles of chemotherapy, which was discontinued when her KS lesions demonstrated a good clinical response. She returned 6 months later with KS progression and was re-challenged with the ABV regime (doxorubicin, bleomycin and vincristine) for 6 cycles. She reached the tolerance dose of bleomycin, and ...

Tumor blood flow modifying effects of electrochemotherapy. A potential vascular targeted mechanism

International Nuclear Information System (INIS)

Sersa, G.; Cemazar, M.; Miklavcic, D.

2003-01-01

Background. The aim of this study was to determine the tumor blood flow modifying, and potential vascular targeted effect of electrochemotherapy with bleomycin or cisplatin. Materials and methods. Electrochemotherapy was performed by application of short intense electric pulses to the tumors after systemic administration of bleomycin or cisplatin. Evaluated were antitumor effectiveness of electrochemotherapy by tumor measurement, tumor blood flow modifying effect by Patent blue staining technique, and sensitivity of endothelial and tumor cells to the drugs and electrochemotherapy by clonogenicity assay. Results. Electrochemotherapy was effective in treatment of SA-1 tumors in A/J mice resulting in substantial tumor growth delay and also tumor cures. Tumor blood flow reduction following electrochemotherapy correlated well with its antitumor effectiveness. Virtually complete shut down of the tumor blood flow was observed already at 24 h after electrochemotherapy with bleomycin whereas only 50% reduction was observed after electrochemotherapy with cisplatin. Sensitivity of human endothelial HMEC-1 cells to electrochemotherapy suggests a vascular targeted effect for electrochemotherapy in vivo with bleomycin as well as with cisplatin. Conclusion. These results show that, in addition to direct electroporation of tumor cells, other vascular targeted mechanisms are involved in electrochemotherapy with bleomycin or cisplatin, potentially mediated by tumor blood flow reduction, and enhanced tumor cell death as a result of endothelial damage by electrochemotherapy. (author)

Clinical Investigation Program: Annual Progress Report

Science.gov (United States)

1992-09-30

Diamminedichloroplatinum (II), Methotrexate and Bleomycin in the Treatment of Advanced Epidermoid Carcinoma of the Penis , Phase II...II), Methotrexate and Bleomycin in the Treatment of Advanced Epidermoid Carcinoma of the Penis , Phase II (5) Start Date: (6) Est Compl Date: (7...Associate Investigators (11) Key Words: constitutional delay delayed puberty (12) Accumulative MEDCASE:* (13) Est Accum OKA Cost:* *Refer to Unit Summary

PET/CT with 18F-FDG- and 18F-FBEM-labeled leukocytes for metabolic activity and leukocyte recruitment monitoring in a mouse model of pulmonary fibrosis.

Science.gov (United States)

Bondue, Benjamin; Sherer, Félicie; Van Simaeys, Gaetan; Doumont, Gilles; Egrise, Dominique; Yakoub, Yousof; Huaux, François; Parmentier, Marc; Rorive, Sandrine; Sauvage, Sébastien; Lacroix, Simon; Vosters, Olivier; De Vuyst, Paul; Goldman, Serge

2015-01-01

Idiopathic pulmonary fibrosis is characterized by a progressive and irreversible respiratory failure. Validated noninvasive methods able to assess disease activity are essential for prognostic purposes as well as for the evaluation of emerging antifibrotic treatments. C57BL/6 mice were used in a murine model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin (control mice were instilled with a saline solution). At different times after instillation, PET/CT with (18)F-FDG- or (18)F-4-fluorobenzamido-N-ethylamino-maleimide ((18)F-FBEM)-labeled leukocytes was performed to assess metabolic activity and leukocyte recruitment, respectively. In bleomycin-treated mice, a higher metabolic activity was measured on (18)F-FDG PET/CT scans from day 7 to day 24 after instillation, with a peak of activity measured at day 14. Of note, lung mean standardized uptake values correlated with bleomycin doses, histologic score of fibrosis, lung hydroxyproline content, and weight loss. Moreover, during the inflammatory phase of the model (day 7), but not the fibrotic phase (day 23), bleomycin-treated mice presented with an enhanced leukocyte recruitment as assessed by (18)F-FBEM-labeled leukocyte PET/CT. Autoradiographic analysis of lung sections and CD45 immunostaining confirm the higher and early recruitment of leukocytes in bleomycin-treated mice, compared with control mice. (18)F-FDG- and (18)F-FBEM-labeled leukocyte PET/CT enable monitoring of metabolic activity and leukocyte recruitment in a mouse model of pulmonary fibrosis. Implications for preclinical evaluation of antifibrotic therapy are expected. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Combination therapies in oral squamous cell carcinomas

International Nuclear Information System (INIS)

Krishnamurthi, S.; Shanta, V.

1982-01-01

The clinical trials are reported involving combined radiotherapy and chemotherapy in oral squamous cell carcinomas. Bleomycin was the only drug that potentiated radiation response in buccal squamous cell carcinomas. The response of the primary tumors was consistent, predictable and reproducible. The following drugs or chemicals were used: synkavit, methotrexate, metronidazole, bleomycin, pepleomycin, and hyperbaric oxygen. The results and their comparison is given in tables

Effects of combined treatment of α-tocopherol, L-ascorbic acid, selenium and zinc on bleomycin, etoposide and cisplatin-induced alterations in testosterone synthesis pathway in rats.

Science.gov (United States)

Kilarkaje, Narayana

2014-12-01

To investigate the effects of therapeutically relevant dose levels of bleomycin, etoposide and cisplatin (BEP) on testicular steroidogenic enzymes, and possible protective effects of an antioxidant cocktail (AC). Adult Sprague-Dawley rats received BEP with or without the AC (α-tocopherol, L-ascorbic acid, selenium and zinc) for either (a) 4 days (short term; 1.5, 15 and 3 mg/kg), or (b) three cycles of 21 days each (0.75, 7.5 and 1.5 mg/kg), or (c) the three cycles with a 63-day recovery period. The expression of steroidogenic enzymes were measured in the testes by Western blotting and immunofluorescent labeling. The short-term BEP exposure resulted in a decrease in scavenger receptor class-B1 and an increase in luteinizing hormone receptor (LHR). The AC with or without BEP has increased the levels of LHR, 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-HSD, but without significant changes in testosterone levels. The three cycles of BEP up-regulated the expression of steroidogenic acute regulatory protein (StAR) and down-regulated that of cholesterol side chain cleavage enzyme (P450scc), cytochrome p450 17A1 (Cyp17A1, recovered by the AC) and 17β-HSD, associated with significant reduction in testosterone levels. The three cycles with the recovery time led to decreases in LHR, StAR, P450scc and Cyp17A1 and increases in 3β-HSD and 17β-HSD. The AC did not enhance the recovery of the enzyme levels. The three cycles of BEP treatment inhibit the testosterone synthesis pathway even after the recovery time. The AC recovers the effects of BEP chemotherapy on a few steroidogenic enzymes.

Induced pluripotent stem cells inhibit bleomycin-induced pulmonary fibrosis in mice through suppressing TGF-β1/Smad-mediated epithelial to mesenchymal transition

Directory of Open Access Journals (Sweden)

Yan Zhou

2016-11-01

Full Text Available Pulmonary fibrosis is a progressive and irreversible fibrotic lung disorder with high mortality and few treatment options. Recently, induced pluripotent stem (iPS cells have been considered as an ideal resource for stem cell-based therapy. Although an earlier study demonstrated the therapeutic effect of iPS cells on pulmonary fibrosis, the exact mechanisms remain obscure. The present study investigated the effects of iPS cells on inflammatory responses, transforming growth factor (TGF-β1 signaling pathway, and epithelial to mesenchymal transition (EMT during bleomycin (BLM-induced lung fibrosis. A single intratracheal instillation of BLM (5 mg/kg was performed to induce pulmonary fibrosis in C57BL/6 mice. Then, iPS cells (c-Myc-free were administrated intravenously at 24 h following BLM instillation. Three weeks after BLM administration, pulmonary fibrosis was evaluated. As expected, treatment with iPS cells significantly limited the pathological changes, edema, and collagen deposition in lung tissues of BLM-induced mice. Mechanically, treatment with iPS cells obviously repressed the expression ratios of matrix metalloproteinase-2 (MMP-2 to its tissue inhibitor -2 (TIMP-2 and MMP-9/TIMP-1 in BLM-induced pulmonary tissues. In addition, iPS cell administration remarkably suppressed BLM-induced up-regulation of pulmonary inflammatory mediators, including tumor necrosis factor-α, interleukin (IL-1β, IL-6, inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and prostaglandin E2. We further demonstrated that transplantation of iPS cells markedly inhibited BLM-mediated activation of TGF-β1/Mothers against decapentaplegic homolog 2/3 (Smad2/3 and EMT in lung tissues through up-regulating epithelial marker E-cadherin and down-regulating mesenchymal markers including fibronectin, vimentin and α-smooth muscle actin. Moreover, in vitro, iPS cell-conditioned medium (iPSC-CM profoundly inhibited TGF-β1-induced EMT signaling pathway in mouse

Histopathological Correlations between Mediastinal Fat-Associated Lymphoid Clusters and the Development of Lung Inflammation and Fibrosis following Bleomycin Administration in Mice.

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Elewa, Yaser Hosny Ali; Ichii, Osamu; Takada, Kensuke; Nakamura, Teppei; Masum, Md Abdul; Kon, Yasuhiro

2018-01-01

Bleomycin (BLM) has been reported to induce lung inflammation and fibrosis in human and mice and showed genetic susceptibility. Interestingly, the C57BL/6 (B6) mice had prominent mediastinal fat-associated lymphoid cluster (MFALCs) under healthy condition, and showed susceptibility to development of lung fibrosis following BLM administration. However, the pathogenesis of lung lesion progression, and their correlation with MFALC morphologies, remain to be clarified. To investigate the correlations between MFALC structures and lung injuries in B6 mice, histopathological examination of mediastinal fat tissues and lungs was examined at 7 and 21 days (d) following a single 50 μL intranasal (i.n.) instillation of either BLM sulfate (5 mg/kg) (BLM group) or phosphate-buffered saline (control group). The lung fibrosis was examined by Masson's trichrome (MT) stain of paraffin sections and mRNA expression levels of Col1a1, Col3a1, and Acta2 in different frozen lung samples. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1, BrdU, LYVE-1, and peripheral node addressin (PNAd) was performed to detect T- and B-cells, macrophages, granulocytes, proliferating cells, lymph vessels (LVs), and high endothelial venules (HEVs). We found that MFALCs were more abundant in the BLM group as compared to the control group. The lung of BLM group developed pneumonitis with severe cellular infiltrations at 7 days and significant collagen deposition (MT) and higher expression of Col1a1, and Col3a1 at 21 days post-administration. Numerous immune cells, proliferating cells, HEVs, and LVs were observed in both MFALCs and lungs of the BLM group. Interestingly, PNAd + HEVs were observed in the lungs of the BLM group, but not the control group. Moreover, numerous Gr1 + polymorphonuclear and mononuclear-like ring cells were found in the MFALCs and lungs of the BLM group. Interestingly, flow cytometric analysis revealed a significant increase of B-cell populations within the

Histopathological Correlations between Mediastinal Fat-Associated Lymphoid Clusters and the Development of Lung Inflammation and Fibrosis following Bleomycin Administration in Mice

Directory of Open Access Journals (Sweden)

Yaser Hosny Ali Elewa

2018-02-01

Full Text Available Bleomycin (BLM has been reported to induce lung inflammation and fibrosis in human and mice and showed genetic susceptibility. Interestingly, the C57BL/6 (B6 mice had prominent mediastinal fat-associated lymphoid cluster (MFALCs under healthy condition, and showed susceptibility to development of lung fibrosis following BLM administration. However, the pathogenesis of lung lesion progression, and their correlation with MFALC morphologies, remain to be clarified. To investigate the correlations between MFALC structures and lung injuries in B6 mice, histopathological examination of mediastinal fat tissues and lungs was examined at 7 and 21 days (d following a single 50 μL intranasal (i.n. instillation of either BLM sulfate (5 mg/kg (BLM group or phosphate-buffered saline (control group. The lung fibrosis was examined by Masson’s trichrome (MT stain of paraffin sections and mRNA expression levels of Col1a1, Col3a1, and Acta2 in different frozen lung samples. Furthermore, immunohistochemistry for CD3, B220, Iba1, Gr1, BrdU, LYVE-1, and peripheral node addressin (PNAd was performed to detect T- and B-cells, macrophages, granulocytes, proliferating cells, lymph vessels (LVs, and high endothelial venules (HEVs. We found that MFALCs were more abundant in the BLM group as compared to the control group. The lung of BLM group developed pneumonitis with severe cellular infiltrations at 7 days and significant collagen deposition (MT and higher expression of Col1a1, and Col3a1 at 21 days post-administration. Numerous immune cells, proliferating cells, HEVs, and LVs were observed in both MFALCs and lungs of the BLM group. Interestingly, PNAd + HEVs were observed in the lungs of the BLM group, but not the control group. Moreover, numerous Gr1 + polymorphonuclear and mononuclear-like ring cells were found in the MFALCs and lungs of the BLM group. Interestingly, flow cytometric analysis revealed a significant increase of B-cell populations

Carcinoma of the penis

International Nuclear Information System (INIS)

Modig, H.; Duchek, M.; Sjoedin, J.G.

1993-01-01

Forty-four patients with squamous cell carcinoma of the penis stage T1-T2, N0 were either treated surgically (n=19) or with a combination of irradiation and bleomycin (n=25). The overall actuarial survival rate was 80% at 3 years, 77% at 5 years and 60% at 10 years. The result of irradiation treatment combined with bleomycin was in stage N0 equivalent to that of surgical therapy. The non-surgical treatment had the advantage of preserved sexual ability. (orig.)

Clinical studies of 57Co-BLM for tumor detection

International Nuclear Information System (INIS)

Lee, Jhin Oh; Ryu, Yong Wun; Kim, Jang Hee

1986-12-01

Investigation with 57 Co-Bleomycin in patients with the various cancers and in tumor bearing animals are described. In the patients, 57 Co-Bleomycin appears to be one of the useful tumor-seeking radiopharmaceuticals, and worth applicable to clinical uses. Labelled yield of 57 Co-Bleo. was about 97% by thin layer chromatography. The pyrogen free tests were performed to meet U.S.P. critical ranges. In clinical studies with 57 Co-Bleo, 4 cases out of 5 patients with lung cancer, 2 cases among 3 thyroid cancer patients, and all 3 hepatoma patients showed positive tumor scans. The patients with stomach cancer, and the esophageal cancer showed false negative scintigraphy. A case with pulmonary tuberculosis showed a positive scan while liver abscess showed a negative picture. The merits of 57 Co-Bleomycin scintigraphy seems to be its relatively high affinity to tumors and low radiation hazard in spite of long physical half life. (Author)

Uptake of labelled tallysomycin by solid Ehrlich ascites tumors in mice

International Nuclear Information System (INIS)

Liniecki, J.; Rembelska, M.; Koniarek, B.

1983-01-01

Tumor and normal tissue uptake of 51 Cr- or 57 Co-labelled bleomycin (BLEO) and tallysomycin (TLM) was compared in female solid Ehrlich ascites tumor mice of Swiss strain. The complexes were administered intraperitoneally: 30-50 μg of each complex with an activity of 40-120 μCi. Activity distribution factors (ADF) and tumor/non-tumor ratios for blood, bone, skeletal muscles, kidneys and liver were determined. The ratios were generally higher for complexes labelled with 57 Co than for the 51 Cr-labelled ones; bleomycin appears equivalent or superior to tallysomycin. (orig.) [de

Expression of Telomere-Associated Proteins is Interdependent to Stabilize Native Telomere Structure and Telomere Dysfunction by G-Quadruplex Ligand Causes TERRA Upregulation.

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Sadhukhan, Ratan; Chowdhury, Priyanka; Ghosh, Sourav; Ghosh, Utpal

2018-06-01

Telomere DNA can form specialized nucleoprotein structure with telomere-associated proteins to hide free DNA ends or G-quadruplex structures under certain conditions especially in presence of G-quadruplex ligand. Telomere DNA is transcribed to form non-coding telomere repeat-containing RNA (TERRA) whose biogenesis and function is poorly understood. Our aim was to find the role of telomere-associated proteins and telomere structures in TERRA transcription. We silenced four [two shelterin (TRF1, TRF2) and two non-shelterin (PARP-1, SLX4)] telomere-associated genes using siRNA and verified depletion in protein level. Knocking down of one gene modulated expression of other telomere-associated genes and increased TERRA from 10q, 15q, XpYp and XqYq chromosomes in A549 cells. Telomere was destabilized or damaged by G-quadruplex ligand pyridostatin (PDS) and bleomycin. Telomere dysfunction-induced foci (TIFs) were observed for each case of depletion of proteins, treatment with PDS or bleomycin. TERRA level was elevated by PDS and bleomycin treatment alone or in combination with depletion of telomere-associated proteins.

Chemotherapy response as a prognosticator for survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy

International Nuclear Information System (INIS)

Eagan, R.T.; Fleming, T.R.; Lee, R.E.; Ingle, J.N.; Frytak, S.; Creagan, E.T.

1980-01-01

Twenty-two patients with limited unresectable squamous cell lung cancer were treated with 6 courses of combination chemotherapy consisting of cyclophosphamide, adriamycin, cisplatin, and bleomycin (CAP-Bleo) and short-course thoracic irradiation started after the first 4 weeks of chemotherapy. Of 20 patients with visible tumor who were treated with 4 weeks of chemotherapy alone, 10 (50%) had a tumor regression in that 4 week period and 10 did not. Those patients with tumor regression had significantly better progression free and overall survivals than did patients with no chemotherapy regressions (medians of 258 days vs. 136 days and 356 days vs. 150 days respectively). The original bleomycin dose had to be reduced by 50% primarily because of excessive radiation esophagitis that has not been reported with use of either the CAP regimen or bleomycin along in conjunction with thoracic irradiation. An initial chemotherapy regression seems to be a good prognosticator for progression-free and overall survival in patients with limited squamous cell lung cancer treated with combined chemotherapy and radiotherapy

Use of toxicogenomics for identifying genetic markers of pulmonary oedema

International Nuclear Information System (INIS)

Balharry, Dominique; Oreffo, Victor; Richards, Roy

2005-01-01

This study was undertaken primarily to identify genetic markers of oedema and inflammation. Mild pulmonary injury was induced following the instillation of the oedema-producing agent, bleomycin (0.5 units). Oedema was then confirmed by conventional toxicology (lavage protein levels, free cell counts and lung/body weight ratios) and histology 3 days post-bleomycin instillation.The expression profile of 1176 mRNA species was determined for bleomycin-exposed lung (Clontech Atlas macroarray, n = 9). To obtain pertinent results from these data, it was necessary to develop a simple, effective method for bioinformatic analysis of altered gene expression. Data were log 10 transformed followed by global normalisation. Differential gene expression was accepted if: (a) genes were statistically significant (P ≤ 0.05) from a two-tailed t test; (b) genes were consistently outside a two standard deviation (SD) range from control levels. A combination of these techniques identified 31 mRNA transcripts (approximately 3%) which were significantly altered in bleomycin treated tissue. Of these genes, 26 were down-regulated whilst only five were up-regulated. Two distinct clusters were identified, with 17 genes classified as encoding hormone receptors, and nine as encoding ion channels. Both these clusters were consistently down-regulated.The magnitude of the changes in gene expression were quantified and confirmed by Q-PCR (n = 6), validating the macroarray data and the bioinformatic analysis employed.In conclusion, this study has developed a suitable macroarray analysis procedure and provides the basis for a better understanding of the gene expression changes occurring during the early phase of drug-induced pulmonary oedema

HIV Status Does Not Influence Outcome in Patients With Classical Hodgkin Lymphoma Treated With Chemotherapy Using Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine in the Highly Active Antiretroviral Therapy Era

Science.gov (United States)

Montoto, Silvia; Shaw, Kate; Okosun, Jessica; Gandhi, Shreyans; Fields, Paul; Wilson, Andrew; Shanyinde, Milensu; Cwynarski, Kate; Marcus, Robert; de Vos, Johannes; Young, Anna Marie; Tenant-Flowers, Melinda; Orkin, Chloe; Johnson, Margaret; Chilton, Daniella; Gribben, John G.; Bower, Mark

2012-01-01

Purpose The prognosis of HIV-infected patients with non-Hodgkin lymphoma in the highly active antiretroviral therapy (HAART) era approaches that of the general population when they are treated with the same protocols. We analyzed the outcome of patients with Hodgkin lymphoma (HL) treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the HAART era according to HIV serostatus to establish whether this also holds true for HL. Patients and Methods From 1997 to 2010, 224 patients newly diagnosed with HL, of whom 93 were HIV positive, were consecutively treated with ABVD chemotherapy. HIV-positive patients had more high-risk disease according to the International Prognostic Score (IPS) than HIV-negative patients (IPS ≥ 3: 68% v 26%, respectively; P < .001). Forty-seven HIV-positive patients had a CD4 count less than 200/μL, and 92 patients received HAART during chemotherapy. Results The complete response rate was 74% for HIV-positive patients and 79% for HIV-negative patients (P = not significant). After a median follow-up of 60 months (range, 8 to 174 months), 23 patients (16 HIV-negative and seven HIV-positive patients) have experienced relapse at a median time of 6 months (range, 1 to 106 months). Five-year event-free survival (EFS) was 59% (95% CI, 47% to 70%) for HIV-positive patients and 66% (95% CI, 57% to 74%) for HIV-negative patients (P = not significant). Five-year overall survival (OS) was 81% (95% CI, 69% to 89%) and 88% (95% CI, 80% to 93%) for HIV-positive and HIV-negative patients, respectively (P = not significant). HIV status did not predict OS or EFS on multivariate analysis including IPS and HIV status. Conclusion This mature study demonstrates that HIV-positive patients with HL have more extensive disease with more adverse prognostic factors than HIV-negative patients, but when treated with ABVD, HIV infection does not adversely affect OS or EFS. PMID:23045581

Diffusion Lung Capacity Changes in Hodgkin Lymphoma Patients Before and After ABVD Chemotherapy

International Nuclear Information System (INIS)

Abdullah, M.; Alam, S.; Majid, A.; Zafar, W.

2016-01-01

Background: Chemotherapy consisting of Adriamycin, Bleomycin, Vinblastine, and Doxorubicin (ABVD), which is the mainstay of treatment in Hodgkins Lymphoma (HL), is associated with both acute and long-term pulmonary toxicity primarily due to Bleomycin. Bleomycin induced pulmonary toxicity (BPT) is clinically detected using diffusing lung capacity for carbon monoxide (DLCO). The objective of this study was to evaluate changes in DLCO in HL patients before and after ABVD chemotherapy. Methods: Medical records of all adult HL patients treated with ABVD chemotherapy at a single centre in Lahore, Pakistan during the entire calendar year 2012 were analysed. Patients with pre-existing pulmonary dysfunction, history of thoracic surgery and smokers were excluded. Results: A total of 179 HL patients were identified during the study period who received ABVD chemotherapy. Out of these, 93 (51.95 percent) patients had undergone both a pre- and post-chemotherapy DLCO measurements. The remaining patients had only one DLCO reading available and were not included in the analysis. The mean percentage difference between pre- and post-chemotherapy values for DLCO (5.49 percent; 95 percent confidence interval [CI] 1.56-9.43 percent) and for Haemoglobin-adjusted DLCO (8.24 percent; 95 percent CI 3.90-12.57 percent) were statistically significant at p<0.01. Diffusing lung capacity for carbon (DLCO) values declined from pre-treatment to post-treatment by 1-10 percent in 23 (24.7 percent) patients, by 10-20 percent in 19 (20.4 percent) patients, by 20-30 percent in 10 (10.8 percent) patients and >30 percent in 10 (10.8 percent) patients. After adjusting for age, a 1mg/m/sup 2/ increase in dose of Bleomycin was significantly associated with 0.14 percent (95 percent CI: 0.03-0.25 percent) decline in DLCO and 0.13 percent (95 percent CI: 0.10-0.26 percent) decline in haemoglobin-adjusted DLCO from pre-treatment value. Conclusions: Mild to moderate dysfunction in diffusion lung capacity is

Ultramicronized palmitoylethanolamide (PEA-um(®)) in the treatment of idiopathic pulmonary fibrosis.

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Di Paola, Rosanna; Impellizzeri, Daniela; Fusco, Roberta; Cordaro, Marika; Siracusa, Rosalba; Crupi, Rosalia; Esposito, Emanuela; Cuzzocrea, Salvatore

2016-09-01

Pulmonary fibrosis is a chronic condition characterized by progressive scarring of lung parenchyma. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (PEA-um(®)), an endogenous fatty acid amide, in mice subjected to idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis was induced in male mice by a single intratracheal administration of saline with bleomycin sulphate (1mg/kg body weight) in a volume of 100μL. PEA-um(®) was injected intraperitoneally at 1, 3 or 10mg/kg 1h after bleomycin instillation and daily thereafter. Animals were sacrificed after 7 and 21days by pentobarbitone overdose. One cohort of mice was sacrificed after seven days of bleomycin administration, followed by bronchoalveloar lavage and determination of myeloperoxidase activity, lung edema and histopathology features. In the 21-day cohort, mortality was assessed daily, and surviving mice were sacrificed followed by the above analyses together with immunohistochemical localization of CD8, tumor necrosis factor-α, CD4, interleukin-1β, transforming growth factor-β, inducible nitric oxide synthase and basic fibroblast growth factor. Compared to bleomycin-treated mice, animals that received also PEA-um(®) (3 or 10mg/kg) had significantly decreased weight loss, mortality, inflammation, lung damage at the histological level, and lung fibrosis at 7 and 21days. PEA-um(®) (1mg/kg) did not significantly inhibit the inflammation response and lung fibrosis. This study demonstrates that PEA-um(®) (3 and 10mg/kg) reduces the extent of lung inflammation in a mouse model of idiopathic pulmonary fibrosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis

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Müller, Tobias; Fay, Susanne; Vieira, Rodolfo Paula; Karmouty-Quintana, Harry; Cicko, Sanja; Ayata, Cemil Korcan; Zissel, Gernot; Goldmann, Torsten; Lungarella, Giuseppe; Ferrari, Davide; Di Virgilio, Francesco; Robaye, Bernard; Boeynaems, Jean-Marie; Lazarowski, Eduardo R.; Blackburn, Michael R.; Idzko, Marco

2017-01-01

Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL) cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5′-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF. PMID:28878780

P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis

Directory of Open Access Journals (Sweden)

Tobias Müller

2017-08-01

Full Text Available Idiopathic pulmonary fibrosis (IPF is a disease with a poor prognosis and very few available treatment options. The involvement of the purinergic receptor subtypes P2Y2 and P2X7 in fibrotic lung disease has been demonstrated recently. In this study, we investigated the role of P2Y6 receptors in the pathogenesis of IPF in humans and in the animal model of bleomycin-induced lung injury. P2Y6R expression was upregulated in lung structural cells but not in bronchoalveolar lavage (BAL cells derived from IPF patients as well as in animals following bleomycin administration. Furthermore, BAL fluid levels of the P2Y6R agonist uridine-5′-diphosphate were elevated in animals with bleomycin-induced pulmonary fibrosis. Inflammation and fibrosis following bleomycin administration were reduced in P2Y6R-deficient compared to wild-type animals confirming the pathophysiological relevance of P2Y6R subtypes for fibrotic lung diseases. Experiments with bone marrow chimeras revealed the importance of P2Y6R expression on lung structural cells for pulmonary inflammation and fibrosis. Similar effects were obtained when animals were treated with the P2Y6R antagonist MRS2578. In vitro studies demonstrated that proliferation and secretion of the pro-inflammatory/pro-fibrotic cytokine IL-6 by lung fibroblasts are P2Y6R-mediated processes. In summary, our results clearly demonstrate the involvement of P2Y6R subtypes in the pathogenesis of pulmonary fibrosis. Thus, blocking pulmonary P2Y6 receptors might be a new target for the treatment of IPF.

The Mitochondrial Cardiolipin Remodeling Enzyme Lysocardiolipin Acyltransferase Is a Novel Target in Pulmonary Fibrosis

Science.gov (United States)

Huang, Long Shuang; Mathew, Biji; Zhao, Yutong; Noth, Imre; Reddy, Sekhar P.; Harijith, Anantha; Usatyuk, Peter V.; Berdyshev, Evgeny V.; Kaminski, Naftali; Zhou, Tong; Zhang, Wei; Zhang, Yanmin; Rehman, Jalees; Kotha, Sainath R.; Gurney, Travis O.; Parinandi, Narasimham L.; Lussier, Yves A.; Garcia, Joe G. N.

2014-01-01

Rationale: Lysocardiolipin acyltransferase (LYCAT), a cardiolipin-remodeling enzyme regulating the 18:2 linoleic acid pattern of mammalian mitochondrial cardiolipin, is necessary for maintaining normal mitochondrial function and vascular development. We hypothesized that modulation of LYCAT expression in lung epithelium regulates development of pulmonary fibrosis. Objectives: To define a role for LYCAT in human and murine models of pulmonary fibrosis. Methods: We analyzed the correlation of LYCAT expression in peripheral blood mononuclear cells (PBMCs) with the outcomes of pulmonary functions and overall survival, and used the murine models to establish the role of LYCAT in fibrogenesis. We studied the LYCAT action on cardiolipin remodeling, mitochondrial reactive oxygen species generation, and apoptosis of alveolar epithelial cells under bleomycin challenge. Measurements and Main Results: LYCAT expression was significantly altered in PBMCs and lung tissues from patients with idiopathic pulmonary fibrosis (IPF), which was confirmed in two preclinical murine models of IPF, bleomycin- and radiation-induced pulmonary fibrosis. LYCAT mRNA expression in PBMCs directly and significantly correlated with carbon monoxide diffusion capacity, pulmonary function outcomes, and overall survival. In both bleomycin- and radiation-induced pulmonary fibrosis murine models, hLYCAT overexpression reduced several indices of lung fibrosis, whereas down-regulation of native LYCAT expression by siRNA accentuated fibrogenesis. In vitro studies demonstrated that LYCAT modulated bleomycin-induced cardiolipin remodeling, mitochondrial membrane potential, reactive oxygen species generation, and apoptosis of alveolar epithelial cells, potential mechanisms of LYCAT-mediated lung protection. Conclusions: This study is the first to identify modulation of LYCAT expression in fibrotic lungs and offers a novel therapeutic approach for ameliorating lung inflammation and pulmonary fibrosis. PMID

The enhanced inhibitory effect of different antitumor agents in self-microemulsifying drug delivery systems on human cervical cancer HeLa cells.

Science.gov (United States)

Ujhelyi, Zoltán; Kalantari, Azin; Vecsernyés, Miklós; Róka, Eszter; Fenyvesi, Ferenc; Póka, Róbert; Kozma, Bence; Bácskay, Ildikó

2015-07-21

The aim of this study was to develop topical self-microemulsifying drug delivery systems (SMEDDS) containing antitumor agents (bleomycin, cisplatin and ifosfamide) and to investigate their inhibitory potential in SMEDDS on human cervical cancer HeLa cells. The physicochemical properties of cytostatic drug loaded SMEDDS were characterized. The cytotoxicity of main components of SMEDDS was also investigated. Their IC50 values were determined. HeLa cells were treated by different concentrations of cisplatin, bleomycin and ifosfamide alone and in various SMEDDS. The inhibitory effect on cell growth was analyzed by MTT cell viability assay. Inflammation is a driving force that accelerates cancer development. The inhibitory effect of these antitumor agents has also been tested on HeLa cells in the presence of inflammatory mediators (IL-1-β, TNF-α) as an in vitro model of inflamed human cervix. Significant differences in the cytotoxicity of cytostatic drugs alone and in SMEDDS have been found in a concentration-dependent manner. The self-micro emulsifying system may potentiate the effectiveness of bleomycin, cisplatin and ifosfamide topically. The effect of SMEDDS containing antitumor agents was decreased significantly in the presence of inflammatory mediators. According to our experiments, the optimal SMEDDS formulation is 1:1:2:6:2 ratios of Isopropyl myristate, Capryol 90, Kolliphor RH 40, Cremophor RH40, Transcutol HP and Labrasol. It can be concluded that SMEDDS may increase the inhibitory effect of bleomycin, ifosfamide and cisplatin on human cervical cancer HeLa cells. Inflammation on HeLa cells hinders the effectiveness of SMEDDS containing antitumor agents. Our results might ensure useful data for development of optimal antitumor formulations.

Clinical and laboratory assessment of a combination of drugs with radiation. Coordinated programme on improvement in radiotherapy of cancer using modifiers of radiosensitivity of cells

International Nuclear Information System (INIS)

Bleehen, N.

1982-01-01

Applications were clinically studied of misonidazole (MISO) as a hypoxic cell radiosensitizer with pharmacokinetic studies. Work with desmethylmisonidazole was focused on its penetration into the CNS because its low lipophilicity would predict poorer access than MISO. Laboratory work was focused on the interaction of hyperthermia with drugs. Cytotoxicity of MISO induced by hyperthermia was studied. Heat response following hypoxic pretreatment with MISO of EMT6 spheroids showed marked enhancement of subsequent heat killing dependent on the duration of the hypoxic pretreatment. The effect was studied in vitro of preheat temperature at modest temperatures (39 to 43 0 C) on thermal tolerance and subsequent hyperthermic (43 to 44 0 C) interaction with bleomycin, adriamycin and BCNU. Interaction between several cytotoxic drugs and two potentially critical normal tissues, skin and bone marrow was studied in the mouse. No increase in the heat reaction in the skin of the mouse foot was observed following single injections of adriamycin, bleomycin or 5 daily doses of bleomycin together with a single heat treatment. Single doses of BCNU and CTX increased the heat reaction. The radioprotector WR2721 failed to protect against either the heat or heat drug reactions from CTX and BCNU

Effects of antineoplastic agents and ionizing irradiation on a human testicular cancer xenograft

International Nuclear Information System (INIS)

Osieka, R.; Pfeiffer, R.; Glatte, P.; Schmidt, C.G.; Bamberg, M.; Scherer, E.

1985-01-01

Chemotherapy has afforded a high percentage of definitive cures in advanced testicular cancer. Nevertheless some patients with large tumor burden still succumb to chemorefractory disease. Therefore preclinical and clinical evaluation of new drugs and agents not primarily used against this type of disease are still mandatory. For preclinical drug screening purposes heterotransplantation of specific human tumors yields a model with high validity for tumor markers and drug response. Heterotransplantation of a human embryonal testicular cancer was used for simultaneous testing of established agents such as cisplatin, melphalan, bleomycin, vinblastine, etoposide and adriamycin and some newer derivatives such as PHM or mafosfamide. Furthermore agents such as procarbazine, dacarbazine and methyl-CCNU that cross the blood-brain-barrier displayed some interesting activity. The results hint at a unique chemosensitivity pattern of the xenograft line, with some accordance between clinical response to vinblastine and bleomycin and good response of the xenografts to bleomycin but not to vinblastine. Radiotherapy was also effective against this tumor line, but there was not much difference in response when the schedule of fractionation was changed. It is concluded that a combined modality approach might salvage patients with residual, chemorefractory disease. (orig.) [de

A Novel Genomic Signature with Translational Significance for Human Idiopathic Pulmonary Fibrosis

Science.gov (United States)

Tedrow, John; de Bernard, Simon; Birker-Robaczewska, Magdalena; Gibson, Kevin F.; Guardela, Brenda Juan; Hess, Patrick; Klenk, Axel; Lindell, Kathleen O.; Poirey, Sylvie; Renault, Bérengère; Rey, Markus; Weber, Edgar; Nayler, Oliver; Kaminski, Naftali

2015-01-01

The bleomycin-induced rodent lung fibrosis model is commonly used to study mechanisms of lung fibrosis and to test potential therapeutic interventions, despite the well recognized dissimilarities to human idiopathic pulmonary fibrosis (IPF). Therefore, in this study, we sought to identify genomic commonalities between the gene expression profiles from 100 IPF lungs and 108 control lungs that were obtained from the Lung Tissue Research Consortium, and rat lungs harvested at Days 3, 7, 14, 21, 28, 42, and 56 after bleomycin instillation. Surprisingly, the highest gene expression similarity between bleomycin-treated rat and IPF lungs was observed at Day 7. At this point of maximal rat–human commonality, we identified a novel set of 12 disease-relevant translational gene markers (C6, CTHRC1, CTSE, FHL2, GAL, GREM1, LCN2, MMP7, NELL1, PCSK1, PLA2G2A, and SLC2A5) that was able to separate almost all patients with IPF from control subjects in our cohort and in two additional IPF/control cohorts (GSE10667 and GSE24206). Furthermore, in combination with diffusing capacity of carbon monoxide measurements, four members of the translational gene marker set contributed to stratify patients with IPF according to disease severity. Significantly, pirfenidone attenuated the expression change of one (CTHRC1) translational gene marker in the bleomycin-induced lung fibrosis model, in transforming growth factor-β1–treated primary human lung fibroblasts and transforming growth factor-β1–treated human epithelial A549 cells. Our results suggest that a strategy focused on rodent model–human disease commonalities may identify genes that could be used to predict the pharmacological impact of therapeutic interventions, and thus facilitate the development of novel treatments for this devastating lung disease. PMID:25029475

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice

DEFF Research Database (Denmark)

Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua

2016-01-01

, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent...... within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180....... Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP...

Modeling Space Radiation with Bleomycin

Data.gov (United States)

National Aeronautics and Space Administration — Space radiation is a mixed field of solar particle events (proton) and particles of Galactic Cosmic Rays (GCR) with different energy levels. These radiation events...

Results of a Prospective Study of High-Dose or Conventional Anthracycline-Cyclophosphamide Regimen Plus Radiotherapy for Localized Adult Non-Hodgkin’s Primary Bone Lymphoma

Directory of Open Access Journals (Sweden)

A. Schmidt-Tanguy

2014-01-01

Full Text Available Background. Primary bone lymphoma (PBL is a rare entity that has only been reviewed in one prospective and small retrospective studies, from which it is difficult to establish treatment guidelines. We prospectively evaluated high-dose or conventional anthracycline-cyclophosphamide dose and radiotherapy for PBL. Patients and Methods. The GOELAMS prospective multicenter study (1986–1998 enrolled adults with localized high-grade PBL according to age and performance status (PS. Patients <60 years received a high-dose CHOP regimen (VCAP and those ≥60 years a conventional anthracycline-cyclophosphamide regimen (VCEP-bleomycin; all received intrathecal chemotherapy and local radiotherapy. Results. Among the 26 patients included (VCAP: 19; VCEP-bleomycin: 7, 39% had poor PS ≥2. With a median follow-up of 8 years, overall survival, event-free survival, and relapse-free survival were 64%, 62%, and 65%, respectively, with no significant difference between treatment groups. Poor PS was significantly associated with shorter OS and EFS. Conclusions. Our results confirm the efficacy of our age-based therapeutic strategy. High-doses anthracycline-cyclophosphamide did not improve the outcome. VCEP-bleomycin is effective and well tolerated for old patients. The intensification must be considered for patients with PS ≥2, a poor prognostic factor.

Targeting miR-155 to Treat Experimental Scleroderma.

Science.gov (United States)

Yan, Qingran; Chen, Jie; Li, Wei; Bao, Chunde; Fu, Qiong

2016-02-01

Scleroderma is a refractory autoimmune skin fibrotic disorder. Alterations of microRNAs in lesional skin could be a new approach to treating the disease. Here, we found that expression of miR-155 was up regulated in lesional skin tissue from patients with either systemic or localized scleroderma, and correlated with fibrosis area. Then we demonstrated the potential of miR-155 as a therapeutic target in pre-clinical scleroderma models. MiR-155(-/-) mice were resistant to bleomycin induced skin fibrosis. Moreover, topical antagomiR-155 could effectively treat mice primed with subcutaneous bleomycin. In primary skin fibroblast, miR-155 silencing could inhibit collagen synthesis function, as well as signaling intensity of two pro-fibrotic pathways, Wnt/β-catenin and Akt, simultaneously. We further showed that miR-155 could regulate the two pathways via directly targeting casein kinase 1α (CK1α) and Src homology 2-containing inositol phosphatase-1 (SHIP-1), as previous reports. Mice with miR-155 knockout or topical antagomir-155 treatment showed inhibited Wnt/β-catenin and Akt signaling in skin upon bleomycin challenge. Together, our data suggest the potential of miR-155 silencing as a promising treatment for dermal fibrosis, especially in topical applications.

Role of chest ultrasound in detecting successful pleurodesis

Directory of Open Access Journals (Sweden)

Ahmed Abd El Megied El Hadidy

2017-04-01

Conclusions: Thoracic ultrasonography for the evaluation of pleurodesis is feasible and simple. Iodopovidone was more effective than bleomycin and doxycyclin in inducing pleurodesis in patients with malignant pleural effusion.

Anticlastogenic potential and antioxidant effects of an aqueous extract of pulp from the pequi tree (Caryocar brasiliense Camb

Directory of Open Access Journals (Sweden)

Juliana Khouri

2007-03-01

Full Text Available The effectiveness of an aqueous extract of Caryocar brasiliense (Caryocaraceae Camb pulp, popularly known in Brazil as pequi, against clastogenicity induced by cyclophosphamide and bleomycin was evaluated using an in vivo mouse bone marrow cell micronuclei test, an in vitro Chinese hamster ovary cell (CHO-K1 chromosome aberration test and an in vitro antioxidant assay based on the oxidative damage to 2-deoxy-D-ribose (2-DR induced by hydroxyl radicals (•OH generated by the reaction between ascorbic acid and (Fe III-EDTA. In mouse bone marrow cells the extract showed a protective effect against micronuclei induced by cyclophosphamide and bleomycin but did not interfere with polychromatic bone marrow erythrocyte proliferation, except when the mice had been treated with the highest dose of cyclophosphamide. When CHO-K1 cells were pretreated by adding 0.01, 0.05 or 0.1 mL of extract per mL of cell culture medium 24 or 48 h before bleomycin or cyclophosphamide there was a protective effect against chromosome breaks and a significant decrease in the mitotic index (a measure of cytotoxicity of the CHO-K1 cells. The extract also had a protective effect against oxidative hydroxyl radical damage to 2-DR. This study suggests that C. brasiliense pulp aqueous extract has anticlastogenic potential, possibly due to its antioxidative properties.

Oxidative stress in chemical toxicity

Energy Technology Data Exchange (ETDEWEB)

Kappus, H.

1986-05-01

The toxic effect of compounds which undergo redox cycling enzymatic one-electron reduction are reviewed. First of all, the enzymatic reduction of these compounds leads to reactive intermediates, mainly radicals which react with oxygen, whereby superoxide anion radicals are formed. Further oxygen metabolites are hydrogen peroxide, singlet oxygen and hydroxyl radicals. The role of these oxygen metabolites in toxicity is discussed. The occurrence of lipid peroxidation during redox cycling of quinonoide compounds, e.g., adriamycin, and the possible relationship to their toxicity is critically evaluated. It is shown that iron ions play a crucial role in lipid peroxidation induced by redox cycling compounds. DNA damage by metal chelates, e.g., bleomycin, is discussed on the basis of findings that enzymatic redox cycling of a bleomycin-iron complex has been observed. The involvement of hydroxyl radicals in bleomycin-induced DNA damage occurring during redox cycling in cell nuclei is claimed. Redox cycling of other substances, e.g., aromatic amines, is discussed in relation to carcinogenesis. Other chemical groups, e.g., nitroaromatic compounds, hydroxylamines and azo compounds are included. Other targets for oxygen radical attack, e.g., proteins, are also dealt with. It is concluded that oxygen radical formation by redox cycling may be a critical event in toxic effects of several compounds if the protective mechanisms of cells are overwhelmed.

Antimutagenic properties of Mangifera indica L. stem bark extract and evaluation of its effects on hepatic CYP1A1.

Science.gov (United States)

Morffi, Janet; Rodeiro, Idania; Hernández, Sandra Luz; González, Leonora; Herrera, Jose; Espinosa-Aguirre, J Javier

2012-09-01

Mangifera indica stem bark extract (MSBE) is a Cuban natural product which has shown strong antioxidant properties. In this work, the antimutagenic effect of MSBE was tested against 10 well-known mutagens/carcinogens in the Ames test in the absence or presence of metabolic fraction (S9). The chemical mutagens tested included: cyclophosphamide, mitomycin C, bleomycin, cisplatin, dimethylnitrosamine (DMNA), benzo[a]pyrene (BP), 2-acetylaminofluorene (2-AAF), sodium azide, 1-nitropyrene (1-NP) and picrolonic acid. Protective effects of the extract were also evaluated by comparing the efficiency of S9 fraction obtained from rats treated during 28 days with oral doses of MSBE (50-500 mg/kg) with that obtained from rats treated with vehicle (control) to activate bleomycin and cyclophosphamide in the Ames test. MSBE concentrations between 50 and 500 μg/plate significantly reduced the mutagenicity mediated by all the chemicals tested with the exception of sodium azide. Higher mutagenicity was found when bleomycin and cyclophosphamide (CP) were activated by control S9 than by MSBE S9. In addition, inhibition of CYP1A1 microsomal activity was observed in the presence of MSBE (10-20 μg/ml). We can conclude that besides its potent antioxidant activity previously reported, MSBE may also exert a chemoprotective effect due to its capacity to inhibit CYP activity.

Protein S is protective in pulmonary fibrosis.

Science.gov (United States)

Urawa, M; Kobayashi, T; D'Alessandro-Gabazza, C N; Fujimoto, H; Toda, M; Roeen, Z; Hinneh, J A; Yasuma, T; Takei, Y; Taguchi, O; Gabazza, E C

2016-08-01

Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis. Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar

Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia

Directory of Open Access Journals (Sweden)

Laurie G. Sherlock

2018-03-01

Full Text Available Background: A naturally occurring single nucleotide polymorphism (SNP, (R213G, in extracellular superoxide dismutase (SOD3, decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown. Methods: Wild type and homozygous R213G mice were injected with intraperitoneal bleomycin or phosphate buffered saline (PBS three times weekly for three weeks and tissue harvested at 22 days of life. Vascular and alveolar development were evaluated by morphometric analysis and immunostaining of lung sections. Pulmonary hypertension (PH was assessed by right ventricular hypertrophy (RVH. Lung protein expression for superoxide dismutase (SOD isoforms, catalase, vascular endothelial growth factor receptor 2 (VEGFR2, endothelial nitric oxide synthase (eNOS and guanosine triphosphate cyclohydrolase-1 (GTPCH-1 was evaluated by western blot. SOD activity and SOD3 expression were measured in serum. Results: In R213G mice, SOD3 lung protein expression decreased, serum SOD3 protein expression and SOD serum activity increased compared to wild type (WT mice. Under control conditions, R213G mice developed pulmonary vascular remodeling (decreased vessel density and increased medial wall thickness and PH; alveolar development was similar between strains. After bleomycin injury, in contrast to WT, R213G mice were protected from impaired alveolar development and their vascular abnormalities and PH did not worsen. Bleomycin decreased VEGFR2 and GTPCH-1 only in WT mice. Conclusion: R213G neonatal mice demonstrate impaired vascular development and PH at baseline without alveolar simplification, yet are protected from bleomycin induced lung injury and worsening of pulmonary vascular remodeling and PH. These results show that vessel bound SOD3 is essential in normal pulmonary vascular development, and

Anti-inflammatory and antifibrotic effects of methyl palmitate

International Nuclear Information System (INIS)

El-Demerdash, Ebtehal

2011-01-01

Methyl palmitate (MP) has been shown earlier to inhibit Kupffer cells and rat peritoneal macrophages. To evaluate the potential of MP to inhibit the activation of other macrophages, RAW cells (macrophages of alveolar origin) were treated with varying concentrations of MP (0.25, 0.5, 1 mM). Assessment of cytotoxicity using MTT assay revealed that 0.25 and 0.5 mM are not toxic to RAW cells. MP was able to inhibit the phagocytic function of RAW cells. Treatment of cells with MP 24 hours prior to LPS stimulation significantly decreased nitric oxide release and altered the pattern of cytokines release; there was a significant decrease in TNF-α and a significant increase in IL-10 compared to the controls. However, there is a non-significant change in IL-6 level. Furthermore, phosphorylation of inhibitory kappa B (IκBα) protein was significantly decreased in RAW cells treated with 0.5 mM MP after LPS stimulation. Based upon the in-vitro results, it was examined whether MP treatment will be effective in preventing bleomycin-induced lung inflammation and fibrosis in-vivo. Bleomycin given by itself caused destruction of the lung architecture characterized by pulmonary fibrosis with collapse of air alveoli and emphysematous. Bleomycin induced a significant increase in hydroxyproline level and activated NF-κB, p65 expression in the lung. MP co-treatment significantly ameliorated bleomycin effects. These results suggest that MP has a potential of inhibiting macrophages in general. The present study demonstrated for the first time that MP has anti-inflammatory and antifibrotic effect that could be through NF-kB inhibition. Thus MP like molecule could be a promising anti-inflammatory and antifibrotic drug. - Research highlights: →Methyl palmitate is a universal macrophage inhibitor. →It could be a promising nucleus of anti-inflammatory and antifibrotic drugs. →The underlying mechanism of these effects could be through NF-kB inhibition.

Mutagen Sensitivity, Apoptosis, and Polymorphism in DNA Repair as Measures of Prostate Cancer Risk

National Research Council Canada - National Science Library

Goldman, Radoslav

2006-01-01

.... We also created a computerized database of the samples in Microsoft Access. We developed assays for mutagen sensitivity, comet assay, and apoptosis in white blood cells exposed to bleomycin and ionizing radiation to evaluate...

Radiochemotherapy of head and neck cancers

International Nuclear Information System (INIS)

Mishina, Hitoshi; Okuyama, Shinichi; Yuasa, Ryo; Saijo, Shigeru; Kaneko, Yutaka

1985-01-01

Twenty-four cases of squamous cell carcinomas of the larynx and maxillary sinus were irradiated with or without cisplatin during a period from April 1973 through March 1984. Both bleomycin in oil and tegafur were adminstrered irrespective of cisplatin. Therapeutic effectiveness was critically evaluated by means of serial biopsy and/or surgery. Radiotherapy alone could not bring about negative conversion of the biopsies, but ultimate negative conversion was observed in 18 out of the 24 cases when chemotherapeutics were appropriately combined. The five positives underwent surgery. In the cases of maxillary cancer, mixed infections appeared to interfere with the curative effectiveness of the radiochemotherapy. A resulting dosage reduction of 15Gy was observed in radiotherapy for negative conversion and one of 10mg for bleomycin as a result of incorporation of cisplatin. (author)

Cellular mechanisms in drug - radiation interaction

International Nuclear Information System (INIS)

Trott, K.R.

1979-01-01

Some cytotoxic drugs, especially those belonging to the group of antibiotics and antimetabolites, sensitize the cells having survived drug treatment to the subsequent irradiation by either increasing the slope of the radiation dose response curves or by decreasing extrapolation number. Bleomycin was found to interact with radiation in L-cells and FM3A cells, but not in HeLa-cells. The data with EMT-6 cells suggest that the interaction depends on drug dose: no interaction occurred after the exposure to bleomycin which killed only 20 - 40% of the cells; yet the exposure to bleomycin which killed 90% of the cells in addition sensitized the surviving cells by the DMF of 1.3. The sensitization found 24 hr after the exposure of HeLa cells to methotrexate was due to cell synchronization. Other cytostatic drugs were found to synchronize proliferating cells even better. Therefore, the fluctuation of radiosensitivity has been commonly observed after the termination of exposure to these drugs. Preirradiation may lead to the change in drug dose response curves. The recruitment of resting cells into cycle occurs hours or days later, in some irradiated normal and malignant tissues. Since many cytostatic drugs are far more active in proliferating cells than in resting cells, the recruitment after irradiation may lead to the sudden increase in drug sensitivity, days after the irradiation. No single, simple theory seems to exist to classify and predict the cellular response to combined modality treatment. (Yamashita, S.)

Browse Title Index

African Journals Online (AJOL)

Items 51 - 100 of 273 ... ... testicular ectopia: a case report and review of the literature, Abstract PDF ... breast in an infant successfully managed with intralesional bleomycin: a .... Vol 11, No 2 (2015), Giant juvenile xanthogranuloma of the tongue ...

Taurine attenuates radiation-induced lung fibrosis in C57/Bl6 fibrosis prone mice.

LENUS (Irish Health Repository)

Robb, W B

2010-03-01

The amino acid taurine has an established role in attenuating lung fibrosis secondary to bleomycin-induced injury. This study evaluates taurine\\'s effect on TGF-beta1 expression and the development of lung fibrosis after single-dose thoracic radiotherapy.

Protease-activated receptor (PAR)-2 is required for PAR-1 signalling in pulmonary fibrosis

NARCIS (Netherlands)

Lin, Cong; von der Thüsen, Jan; Daalhuisen, Joost; ten Brink, Marieke; Crestani, Bruno; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

2015-01-01

Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease of unknown aetiology. Compelling evidence suggests that both protease-activated receptor (PAR)-1 and PAR-2 participate in the development of pulmonary fibrosis. Previous studies have shown that bleomycin-induced

Development of a new medium containing date syrup for production ...

African Journals Online (AJOL)

Development of a new medium containing date syrup for production of bleomycin by Streptomyces mobaraensis ATCC 15003 using response surface methodology. Hesham H Radwan, Fars K Alanazi, Ehab I Taha, Hamdy A Dardir, Ihab M Moussa, Ibrahim A Alsarra ...

A randomised phase 2 trial of intensive induction chemotherapy (CBOP/BEP) and standard BEP in poor-prognosis germ cell tumours (MRC TE23, CRUK 05/014, ISRCTN 53643604).

Science.gov (United States)

Huddart, Robert A; Gabe, Rhian; Cafferty, Fay H; Pollock, Philip; White, Jeff D; Shamash, Jonathan; Cullen, Michael H; Stenning, Sally P

2015-03-01

Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required. To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial. We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres. BEP (bleomycin 30,000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2×CBOP, 2×BO, and 3×BEP (bleomycin 15,000 IU). Primary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≥80%. Equal numbers were randomised to BEP to benchmark contemporary response rates. A total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≥3). FRRs were 74% (90% confidence interval [CI], 61-85) with CBOP/BEP, 61% with BEP (90% CI, 48-73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33-1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS. The primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data

α1A-Subtype adrenergic agonist therapy for the failing right ventricle.

Science.gov (United States)

Cowley, Patrick M; Wang, Guanying; Joshi, Sunil; Swigart, Philip M; Lovett, David H; Simpson, Paul C; Baker, Anthony J

2017-12-01

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α 1 -adrenergic receptors (α 1 -ARs), in particular the α 1A -subtype, mediate cardioprotective effects in multiple heart failure models. Recent studies have shown that chronic treatment with the α 1A -subtype agonist A61603 improves function and survival in a model of left ventricular failure. The goal of the present study was to determine if chronic A61603 treatment is beneficial in a RV failure model. We used tracheal instillation of the fibrogenic antibiotic bleomycin in mice to induce pulmonary fibrosis, pulmonary hypertension, and RV failure within 2 wk. Some mice were chronically treated with a low dose of A61603 (10 ng·kg -1 ·day -1 ). In the bleomycin model of RV failure, chronic A61603 treatment was associated with improved RV fractional shortening and greater in vitro force development by RV muscle preparations. Cell injury markers were reduced with A61603 treatment (serum cardiac troponin I, RV fibrosis, and expression of matrix metalloproteinase-2). RV oxidative stress was reduced (using the probes dihydroethidium and 4-hydroxynonenal). Consistent with lowered RV oxidative stress, A61603 was associated with an increased level of the cellular antioxidant superoxide dismutase 1 and a lower level of the prooxidant NAD(P)H oxidase isoform NOX4. In summary, in the bleomycin model of RV failure, chronic A61603 treatment reduced RV oxidative stress, RV myocyte necrosis, and RV fibrosis and increased both RV function and in vitro force development. These findings suggest that in the context of pulmonary fibrosis, the α 1A -subtype is a potential therapeutic target to treat the failing RV. NEW & NOTEWORTHY Right ventricular (RV) failure is a serious disease with a poor prognosis and no effective treatments. In the mouse bleomycin model of RV failure, we tested the efficacy of a treatment using the α 1A -adrenergic receptor subtype

Mitochondrial catalase overexpressed transgenic mice are protected against lung fibrosis in part via preventing alveolar epithelial cell mitochondrial DNA damage.

Science.gov (United States)

Kim, Seok-Jo; Cheresh, Paul; Jablonski, Renea P; Morales-Nebreda, Luisa; Cheng, Yuan; Hogan, Erin; Yeldandi, Anjana; Chi, Monica; Piseaux, Raul; Ridge, Karen; Michael Hart, C; Chandel, Navdeep; Scott Budinger, G R; Kamp, David W

2016-12-01

Alveolar epithelial cell (AEC) injury and mitochondrial dysfunction are important in the development of lung fibrosis. Our group has shown that in the asbestos exposed lung, the generation of mitochondrial reactive oxygen species (ROS) in AEC mediate mitochondrial DNA (mtDNA) damage and apoptosis which are necessary for lung fibrosis. These data suggest that mitochondrial-targeted antioxidants should ameliorate asbestos-induced lung. To determine whether transgenic mice that express mitochondrial-targeted catalase (MCAT) have reduced lung fibrosis following exposure to asbestos or bleomycin and, if so, whether this occurs in association with reduced AEC mtDNA damage and apoptosis. Crocidolite asbestos (100µg/50µL), TiO 2 (negative control), bleomycin (0.025 units/50µL), or PBS was instilled intratracheally in 8-10 week-old wild-type (WT - C57Bl/6J) or MCAT mice. The lungs were harvested at 21d. Lung fibrosis was quantified by collagen levels (Sircol) and lung fibrosis scores. AEC apoptosis was assessed by cleaved caspase-3 (CC-3)/Surfactant protein C (SFTPC) immunohistochemistry (IHC) and semi-quantitative analysis. AEC (primary AT2 cells from WT and MCAT mice and MLE-12 cells) mtDNA damage was assessed by a quantitative PCR-based assay, apoptosis was assessed by DNA fragmentation, and ROS production was assessed by a Mito-Sox assay. Compared to WT, crocidolite-exposed MCAT mice exhibit reduced pulmonary fibrosis as measured by lung collagen levels and lung fibrosis score. The protective effects in MCAT mice were accompanied by reduced AEC mtDNA damage and apoptosis. Similar findings were noted following bleomycin exposure. Euk-134, a mitochondrial SOD/catalase mimetic, attenuated MLE-12 cell DNA damage and apoptosis. Finally, compared to WT, asbestos-induced MCAT AT2 cell ROS production was reduced. Our finding that MCAT mice have reduced pulmonary fibrosis, AEC mtDNA damage and apoptosis following exposure to asbestos or bleomycin suggests an important role

Case report

African Journals Online (AJOL)

abp

2017-09-07

Sep 7, 2017 ... protocol) and radiotherapy with a favorable follow up. Pan African Medical ... liver and kidney functions tests were normal. The tuberculin skin ... Chemotherapy was indicated, the patient received ABVD protocol. (Adriamycin, Bleomycin, Vinblastine, Dacarbazine) followed by radiotherapy. The clinical and ...

Base-oxidant promoted metal-free N-demethylation of arylamines

Indian Academy of Sciences (India)

alkylation damage repair, cancer metastatic chemopre- vention and also for drug metabolism.3 In classical methods, enzymatic processes are mostly responsible for this conversion in which metal complexes4 and various oxidases or peroxidases, like horseradish per- oxidase, lipogenase, cytochrome P-450, bleomycin,.

Chemotherapy-induced hypercoagulability and biomarkers for prediction of thromboembolic events in patients with metastatic testicular cancer

NARCIS (Netherlands)

Lubberts, S.; Boer, H.; Altena, R.; Meijer, C.; Lefrandt, J.D.; Nuver, J.; Mulder, A.B.; Lisman, T.; Kamphuisen, P.W.; Gietema, J.A.

The majority of patients with disseminated testicular cancer can be cured with combination chemotherapy consisting of bleomycin, etoposide and cisplatin (BEP). Because of this success, focus shifts to adverse effects of this treatment. The incidences of venous and arterial thromboembolism (VTE and

Germ cell tumors of testis; an update in chemotherapy treatment

International Nuclear Information System (INIS)

Parvez, T.

2002-01-01

Prior to the use of cisplatin, durable complete remission of metastatic testicular cancer were rare. In 1977, a chemotherapy treatment program including cisplatin, vinblastine, and bleomycin (PVB) let to high response rates and acceptable toxicity in patients with disseminated testicular cancer. After that, bleomycin, etoposide, and cisplatin (BEP) chemotherapy regimen was established as a standard therapy for good- and poor-risk disease and further, ifosfamide-based regimens or high-dose chemotherapy with stem cell rescue as the salvage therapy. The results of these prospective, randomized clinical trials that have markedly improved the outlook of patients with this type of cancer have been reviewed in this article. While the present state-of-the-art treatment for metastatic testicular cancer is promising approximately one-third of patients with poor risk disease will not achieve a remission. Trials of new agents and approaches are needed to increase the patient survival. (author)

Long-term effects of chemotherapy in patients with testicular cancer

NARCIS (Netherlands)

Osanto, S.; Bukman, A.; van Hoek, F.; Sterk, P. J.; de Laat, J. A.; Hermans, J.

1992-01-01

Combination chemotherapy regimens that include cisplatin (CDDP) and bleomycin (BLE) result in the cure of the majority of patients with malignant germ cell tumors of the testis. We investigated the long-term damage of such chemotherapy to renal, pulmonary, and hearing function. Forty-three patients

Isolated limb perfusion electrochemotherapy for the treatment of an ...

African Journals Online (AJOL)

After completing staging procedures, the lesion was approached with surgery and intraoperative electrochemotherapy (ECT) administration of bleomycin in isolated limb perfusion. A second session of surgery and ECT was performed one month later, followed by three additional monthly sessions of ECT. During periodic ...

Ultrasound guided electrochemotherapy for the treatment of a clear ...

African Journals Online (AJOL)

Ultrasound guided biopsy yielded a diagnosis of clear cell thymoma upon histopathology. After complete staging procedures, the owner elected to treat the cat with electrochemotherapy (ECT) using systemic bleomycin. Two sessions of ultrasound guided ECT were performed at two week intervals with trains of biphasic ...

African Journal of Biotechnology - Vol 9, No 33 (2010)

African Journals Online (AJOL)

Development of a new medium containing date syrup for production of bleomycin by Streptomyces mobaraensis ATCC 15003 using response surface methodology · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. Hesham H Radwan, Fars K Alanazi, Ehab I Taha, ...

Cystic lymphangioma of the breast in an infant successfully ...

African Journals Online (AJOL)

breast lymphangioma in a 3-month-old male child, which was managed successfully by intralesional ... Annals of Pediatric Surgery 2017, 13:163–165. Keywords: breast, bleomycin, intralesional sclerosing agent, macrocystic .... histology, they are characterized by a single layer of endothelium containing, usually, a clear ...

Gallium-67-citrate uptake in a case of acne vulgaris

International Nuclear Information System (INIS)

Kipper, M.S.; Taylor, A.; Ashburn, W.L.

1981-01-01

A case of increased Ga-67 uptake in a patient with active acne vulgaris is reported. The scan was requested in a search for metastatic testicular carcinoma or bleomycin pulmonary toxicity. Careful clinical evaluation including physical examination was necessary in order to avoid an erroneous scan interpretation

Triphala, a formulation of traditional Ayurvedic medicine, shows protective effect against X-radiation in HeLa cells.

Science.gov (United States)

Takauji, Yuki; Miki, Kensuke; Mita, Juma; Hossain, Mohammad Nazir; Yamauchi, Masatake; Kioi, Mitomu; Ayusawa, Dai; Fujii, Michihiko

2016-12-01

Ayurveda is a holistic medical system of traditional medicine, and Triphala is one of the most popular formulations in Ayurveda. Triphala is composed of three kinds of herb, Terminalia chebula, Terminalia bellirica, and Emblica officinalis. Since Triphala is shown to exhibit a protective activity against ionizing radiation in mice, we investigated its activity in HeLa cells. We found that Triphala showed the protective effects against X-radiation and bleomycin, both of which generate DNA strand breaks, in HeLa cells. Further, Triphala efficiently eliminated reactive oxygen species (ROS) in HeLa cells. Thus, the antioxidant activity of Triphala would likely play a role in its protective actions against X-radiation and bleomycin because both agents damage DNA through the generation of ROS. These observations suggested that the radioprotective activity of Triphala can be, at least partly, studied with the cells cultured in vitro. The simple bioassay system with human cultured cells would facilitate the understanding of the molecular basis for the beneficial effects of Triphala.

Effect of some radioprotective and radiosensitizing substances on the semiconservative and unscheduled DNA biosynthesis of rat thymocytes

International Nuclear Information System (INIS)

Winkle, J.

1981-01-01

The effect on the semiconservative and unscheduled insertion of 3 H-methyl-thymidine (TdR- 3 H) into the DNA was tested on rat thymocytes in vitro. The semiconservative incorporation of TdR- 3 H was inhibited by AET, cysteine glutathione, N-ethylmaleimide, cytosine arabinoside, ethidiumbromide, bleomycin and diethyldithiocarbamate. Metronidazole and caffeine had no effect. Aminothiols and bleomycin stimulated, cytosine arabinoside, N-ethylmaleimide, ethidiumbromide and diethyldithiocarbamate decreased the unscheduled TdR- 3 H incorporation. There was no substantial effect of an exposure to UV-rays. The results lead to the following conclusions: The aminothiol-effect on the excision repair suggest that inhibition of the semiconservative DNA-synthesis will amplify regenerative capacity of the cells. The effect of most substances investigated accord with the present views on their mechanisms of action. The present investigations do not allow an explanation of the influence of diethyldithiocarbamate unspecific effects (such as complexing activity) and more specialized reactions (such as inhibition of superoxide dismutase) must be kept in mind. (orig./MG)

A randomized phase III study comparing standard dose BEP with sequential high-dose cisplatin, etoposide, and ifosfamide (VIP) plus stem-cell support in males with poor-prognosis germ-cell cancer. An intergroup study of EORTC, GTCSG, and Grupo Germinal (EORTC 30974)

DEFF Research Database (Denmark)

Daugaard, G; Skoneczna, I; Aass, N

2011-01-01

To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor-progno...

Knockout of endothelial cell-derived endothelin-1 attenuates skin fibrosis but accelerates cutaneous wound healing.

Directory of Open Access Journals (Sweden)

Katsunari Makino

Full Text Available Endothelin (ET-1 is known for the most potent vasoconstrictive peptide that is released mainly from endothelial cells. Several studies have reported ET-1 signaling is involved in the process of wound healing or fibrosis as well as vasodilation. However, little is known about the role of ET-1 in these processes. To clarify its mechanism, we compared skin fibrogenesis and wound repair between vascular endothelial cell-specific ET-1 knockout mice and their wild-type littermates. Bleomycin-injected fibrotic skin of the knockout mice showed significantly decreased skin thickness and collagen content compared to that of wild-type mice, indicating that bleomycin-induced skin fibrosis is attenuated in the knockout mice. The mRNA levels of transforming growth factor (TGF-β were decreased in the bleomycin-treated skin of ET-1 knockout mice. On the other hand, skin wound healing was accelerated in ET-1 knockout mice, which was indicated by earlier granulation tissue reduction and re-epithelialization in these mice. The mRNA levels of TGF-β, tumor necrosis factor (TNF-α and connective tissue growth factor (CTGF were reduced in the wound of ET-1 knockout mice. In endothelial ET-1 knockout mouse, the expression of TNF-α, CTGF and TGF-β was down-regulated. Bosentan, an antagonist of dual ET receptors, is known to attenuate skin fibrosis and accelerate wound healing in systemic sclerosis, and such contradictory effect may be mediated by above molecules. The endothelial cell-derived ET-1 is the potent therapeutic target in fibrosis or wound healing, and investigations of the overall regulatory mechanisms of these pathological conditions by ET-1 may lead to a new therapeutic approach.

Experimental studies of metastases of esophageal carcinoma to lymph nodes

International Nuclear Information System (INIS)

Inoue, Kazumasa

1977-01-01

Marked progress has been made in surgery for esophageal carcinoma, however, when compared to results of surgery for other carcinomas of the digestive tract, much research remains to be done. The author transplanted VX2 carcinoma, a transplantable tumor of the rabbit, to the esophagus in attempt to determine the mode of metastases of esophageal carcinoma to lymph nodes and also to observe the effect of chemotherapy (Bleomycin) and radiotherapy (Betatron). Carcinoma of the cervical esophagus metastasized to the cervical lymph nodes and then to the paratracheal lymph nodes. Carcinoma of the upper thoracic esophagus metastasized to the paratracheal lymph nodes and then to the cervical lymph nodes. Carcinoma of the mid-thoracic esophagus metastasized to the intrathoracic lymph nodes and then to the intraperitoneal lymph nodes. Carcinoma of the abdominal esophagus metastasized to the intraperitoneal lymph nodes and then to the intrathoracic lymph nodes. Skipping metastasis was rarely observed. Carcinoma of the thoracic esophagus with metastases of lymph nodes in the cervical or abdominal portion was considerably advanced, therefore it is considered that cleaning of the intrathoracic lymph nodes and simultaneous chemotherapy are required when such cases are encountered clinically. Irradiation resulted in regression in the size of the tumor and metastases to lymph nodes and there was a decrease in metastases to the distant lymph nodes. Effects of irradiation were similar on tumors and lymph nodes with positive metastases located within the field of irradiation. Bleomycin medication resulted in regression in the size of tumor and metastases to lymph nodes. Effects of Bleomycin medication were similar on tumors and lymph nodes with positive metastases. (auth.)

Cell cycle analyses with a pulse cytophotometer: the effect of chemical and physical noxae on the kinetics of the proliferation of tumor cells

International Nuclear Information System (INIS)

Goehde, W.

The following studies were conducted on Ehrlich ascites tumor cells using the pulse cytophotometer: rate of DNA synthesis during the S phase; the effect of cytostatic drugs, endoxan, bleomycin, and other antibiotics on cell kinetics; and effects of x radiation and 1 to 6 MeV neutrons on cell kinetics

Effects of matrine on JAK-STAT signaling transduction pathways in ...

African Journals Online (AJOL)

The current study aims to investigate the effects of matrine on the JAK-STAT signaling transduction pathways in bleomycin (BLM)-induced pulmonary fibrosis (PF) and to explore its action mechanism. A total of 72 male C57BL/6 mice were randomized into the control, model, and treatment groups. PF models were ...

MFAP4: a candidate biomarker for hepatic and pulmonary fibrosis?

Science.gov (United States)

Mölleken, Christian; Poschmann, Gereon; Bonella, Francesco; Costabel, Ulrich; Sitek, Barbara; Stühler, Kai; Meyer, Helmut E; Schmiegel, Wolff H; Marcussen, Niels; Helmer, Michael; Nielsen, Ole; Hansen, Søren; Schlosser, Anders; Holmskov, Uffe; Sorensen, Grith Lykke

2016-03-29

Several comparable mechanisms have been identified for hepatic and pulmonary fibrosis. The human microfibrillar associated glycoprotein 4 (MFAP4), produced by activated myofibroblasts, is a ubiquitous protein playing a potential role in extracellular matrix (ECM) turnover and was recently identified as biomarker for hepatic fibrosis in hepatitis C patients. The current study aimed to evaluate serum levels of MFAP4 in patients with pulmonary fibrosis in order to test its potential as biomarker in clinical practice. A further aim was to determine whether MFAP4 deficiency in mice affects the formation of pulmonary fibrosis in the bleomycin model of lung fibrosis. 91 patients with idiopathic pulmonary fibrosis (IPF), 23 with hypersensitivity pneumonitis (HP) and 31 healthy subjects were studied. In the mouse model, C57BL/6 Mfap4+/+ and Mfap4-/- mice between 6-8 weeks of age were studied. Serum levels of MFAP4 were measured by ELISA in patients and in mice. Surfactant protein D (SP-D) and LDH were measured as comparison biomarkers in patients with pulmonary fibrosis. Morphometric assessment and the Sircol kit were used to determine the amount of collagen in the lung tissue in the mouse model. Serum levels of MFAP4 were not elevated in lung fibrosis - neither in the patients with IPF or HP nor in the animal model. Furthermore no significant correlations with pulmonary function tests of IPF patients could be found for MFAP4. MFAP4 levels were increased in BAL of bleomycin treated mice with pulmonary fibrosis. MFAP4 is not elevated in sera of patients with pulmonary fibrosis or bleomycin treated mice with pulmonary fibrosis. This may be due to different pathogenic mechanisms of liver and lung fibrogenesis. MFAP4 seems to be useful as serum biomarker for hepatic but not for lung fibrosis.

Different G2/M accumulation in M059J and M059K cells after exposure to DNA double-strand break-inducing agents

International Nuclear Information System (INIS)

Holgersson, Asa; Heiden, Thomas; Castro, Juan; Edgren, Margareta R.; Lewensohn, Rolf; Meijer, Annelie E.

2005-01-01

Purpose: To investigate and compare the cell cycle progression in relation to cell death in the human glioma cell lines, M059J and M059K, after exposure to DNA double-strand break-inducing agents. Methods and materials: The M059J and M059K cells, deficient and proficient in the catalytic subunit of the DNA-dependent protein kinase, respectively, were exposed to 1 and 4 Gy of photons or accelerated nitrogen ions. In addition, M059J and M059K cells were treated with 10 and 40 μg/mL of bleomycin for 30 min, respectively. Cell cycle progression, monitored by DNA flow cytometry, was measured up to 72 h after treatment. Results: M059J, but not M059K, cells displayed G 2 /M accumulation after low linear energy transfer irradiation. High linear energy transfer radiation exposure however, resulted in a substantial increase of M059K cells in the G 2 /M phase detected at 48 h. At 72 h, the number of cells in the G 2 /M phase was equivalent to its control. M059J cells accumulated mainly in S phase after high linear energy transfer irradiation. In contrast to M059K, M059J cells were still blocked at 72 h. Bleomycin induced G 2 /M accumulation for both M059J and M059K cells detected 24 h after treatment. At 48 h, the percentage of bleomycin-treated M059J cells in G 2 /M phase remained high, and the number of M059K cells had decreased to control levels. Neither cell line showed cell cycle arrest (≤10 h) after exposure to these agents. Conclusion: Distinct cell cycle block and release is dependent on the complexity of the induced DNA damage and the presence of the DNA-dependent protein kinase catalytic subunit

Validation of the 2nd Generation Proteasome Inhibitor Oprozomib for Local Therapy of Pulmonary Fibrosis.

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Nora Semren

Full Text Available Proteasome inhibition has been shown to prevent development of fibrosis in several organs including the lung. However, effects of proteasome inhibitors on lung fibrosis are controversial and cytotoxic side effects of the overall inhibition of proteasomal protein degradation cannot be excluded. Therefore, we hypothesized that local lung-specific application of a novel, selective proteasome inhibitor, oprozomib (OZ, provides antifibrotic effects without systemic toxicity in a mouse model of lung fibrosis. Oprozomib was first tested on the human alveolar epithelial cancer cell line A549 and in primary mouse alveolar epithelial type II cells regarding its cytotoxic effects on alveolar epithelial cells and compared to the FDA approved proteasome inhibitor bortezomib (BZ. OZ was less toxic than BZ and provided high selectivity for the chymotrypsin-like active site of the proteasome. In primary mouse lung fibroblasts, OZ showed significant anti-fibrotic effects, i.e. reduction of collagen I and α smooth muscle actin expression, in the absence of cytotoxicity. When applied locally into the lungs of healthy mice via instillation, OZ was well tolerated and effectively reduced proteasome activity in the lungs. In bleomycin challenged mice, however, locally applied OZ resulted in accelerated weight loss and increased mortality of treated mice. Further, OZ failed to reduce fibrosis in these mice. While upon systemic application OZ was well tolerated in healthy mice, it rather augmented instead of attenuated fibrotic remodelling of the lung in bleomycin challenged mice. To conclude, low toxicity and antifibrotic effects of OZ in pulmonary fibroblasts could not be confirmed for pulmonary fibrosis of bleomycin-treated mice. In light of these data, the use of proteasome inhibitors as therapeutic agents for the treatment of fibrotic lung diseases should thus be considered with caution.

Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

International Nuclear Information System (INIS)

Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G.; Castiglione, F.; Vanzi, E.; Bottoncetti, A.; Pupi, A.

2011-01-01

Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

The use of chemotherapeutics for the treatment of keloid scars

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Christopher David Jones

2015-05-01

Full Text Available Keloid scars are pathological scars, which develop as a result of exaggerated dermal tissue proliferation following cutaneous injury and often cause physical, psychological and cosmetic problems. Various theories regarding keloidogenesis exist, however the precise pathophysiological events remain unclear. Many different treatment modalities have been implicated in their management, but currently there is no entirely satisfactory method for treating all keloid lesions. We review a number of different chemotherapeutic agents which have been proposed for the treatment of keloid and hypertrophic scars while giving insight into some of the novel chemotherapeutic drugs which are currently being investigated. Non-randomized trials evaluating the influence of different chemotherapeutic agents, such as 5-fluorouracil (5-FU; mitomycin C; bleomycin and steroid injection, either alone or in combination with other chemotherapeutic agents or alternative treatment modalities, for the treatment of keloids were identified using a predefined PubMed search strategy. Twenty seven papers were identified. Scar improvement ≥50% was found in the majority of cases treated with 5-FU, with similar results found for mitomycin C, bleomycin and steroid injection. Combined intralesional 5-FU and steroid injection produced statistically significant improvements when compared to monotherapy. Monotherapy recurrence rates ranged from 0-47% for 5-FU, 0-15% for bleomycin and 0-50% for steroid injection. However, combined therapy in the form of surgical excision and adjuvant 5-FU or steroid injections demonstrated lower recurrence rates; 19% and 6% respectively. Currently, most of the literature supports the use of combination therapy (usually surgery and adjuvant chemotherapy as the mainstay treatment of keloids, however further investigation is necessary to determine success rates over longer time frames. Furthermore, there is the potential for novel therapies, but further

Adenovirus dodecahedron, as a drug delivery vector.

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Monika Zochowska

Full Text Available BACKGROUND: Bleomycin (BLM is an anticancer antibiotic used in many cancer regimens. Its utility is limited by systemic toxicity and dose-dependent pneumonitis able to progress to lung fibrosis. The latter can affect up to nearly 50% of the total patient population, out of which 3% will die. We propose to improve BLM delivery by tethering it to an efficient delivery vector. Adenovirus (Ad dodecahedron base (DB is a particulate vector composed of 12 copies of a pentameric viral protein responsible for virus penetration. The vector efficiently penetrates the plasma membrane, is liberated in the cytoplasm and has a propensity to concentrate around the nucleus; up to 300000 particles can be observed in one cell in vitro. PRINCIPAL FINDINGS: Dodecahedron (Dd structure is preserved at up to about 50 degrees C at pH 7-8 and during dialysis, freezing and drying in the speed-vac in the presence of 150 mM ammonium sulfate, as well as during lyophilization in the presence of cryoprotectants. The vector is also stable in human serum for 2 h at 37 degrees C. We prepared a Dd-BLM conjugate which upon penetration induced death of transformed cells. Similarly to free bleomycin, Dd-BLM caused dsDNA breaks. Significantly, effective cytotoxic concentration of BLM delivered with Dd was 100 times lower than that of free bleomycin. CONCLUSIONS/SIGNIFICANCE: Stability studies show that Dds can be conveniently stored and transported, and can potentially be used for therapeutic purposes under various climates. Successful BLM delivery by Ad Dds demonstrates that the use of virus like particle (VLP results in significantly improved drug bioavailability. These experiments open new vistas for delivery of non-permeant labile drugs.

The Effect of 217 Hz Magnetic Field of Cell Phone with Different Intensities on Apoptosis of Normal and Cancerous Cells Treated with Chemotherapy Drug

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Mahsa Mansourian

2012-03-01

Full Text Available Background: According to the increasing development of home and business electronic equipment in today's world, the biological effects of ELF magnetic fields have been studied at two molecular-cellular and animal- human levels. Considering the therapeutic viewpoint of this study regarding the effects of low-frequency fields of mobile phone, the effect of acute exposure to this field on chemotherapy will be studied.Materials and Methods: In this experimental study, based on measurement of the intensity of the magnetic fields from mobile phones in another research, flux densities of magnetic field of 159.44, 93.25 and 120µ tesla with frequency of 217Hz was generated in magnetic field generator system, and the apoptosis level in K562 cancer cells and healthy cells of lymphocytes was assessed after exposure to field using flow cytometry method. This evaluation method was also performed for the cells treated with bleomycin after exposure to this field.Results: 217 Hz magnetic field exposure significantly increases the rate of apoptosis percentage (p > 0.05 in K562 cancer cells and in two intensities of 120 and 159.44µ tesla compared to the control group, but such effect is not observed in lymphocyte cells. Bleomycin-induced apoptosis percentage following exposure to the mentioned magnetic field shows no significant difference compared to the group of treatment with drug and without field exposure. This lack of significant difference is observed between the groups of drug after field exposure and field alone as well as between groups exposed to field and groups treated with bleomycin.Conclusion: Study results showed that 217 Hz magnetic field of mobile phone can induce apoptosis on cancer cells, but it has no effect on healthy cells. Thus, in order to use mobile phone as an effective factor in their treatment, some studies should be conducted at animal-human level.

Rosiglitazone attenuates pulmonary fibrosis and radiation-induced intestinal damage

Energy Technology Data Exchange (ETDEWEB)

Mangoni, M.; Gerini, C.; Sottili, M.; Cassani, S.; Stefania, G.; Biti, G. [Radiotherapy Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy); Castiglione, F. [Department of Human Pathology and Oncology, University of Florence, Firenze (Italy); Vanzi, E.; Bottoncetti, A.; Pupi, A. [Nuclear Medicine Unit, Clinical Physiopathology Department, University of Florence, Firenze (Italy)

2011-10-15

Full text of publication follows: Purpose.-The aim of the study was to evaluate radioprotective effect of rosiglitazone (RGZ) on a murine model of late pulmonary damage and of acute intestinal damage. Methods.- Lung fibrosis: C57 mice were treated with the radiomimetic agent bleomycin, with or without rosiglitazone (5 mg/kg/day). To obtain an independent qualitative and quantitative measure for lung fibrosis we used high resolution CT, performed twice a week during the entire observation period. Hounsfield Units (HU) of section slides from the upper and lower lung region were determined. On day 31 lungs were collected for histological analysis. Acute intestinal damage: mice underwent 12 Gy total body irradiation with or without rosiglitazone. Mice were sacrificed 24 or 72 h after total body irradiation and ileum and colon were collected. Results.- Lung fibrosis: after bleomycin treatment, mice showed typical CT features of lung fibrosis, including irregular septal thickening and patchy peripheral reticular abnormalities. Accordingly, HU lung density was dramatically increased. Rosiglitazone markedly attenuated the radiological signs of fibrosis and strongly inhibited HU lung density increase (60% inhibition at the end of the observation period). Histological analysis revealed that in bleomycin-treated mice, fibrosis involved 50-55% of pulmonary parenchyma and caused an alteration of the alveolar structures in 10% of parenchyma, while in rosiglitazone-treated mice, fibrosis involved only 20-25% of pulmonary parenchyma, without alterations of the alveolar structures. Acute intestinal damage: 24 h after 12 Gy of total body irradiation intestinal mucosa showed villi shortening, mucosal thickness and crypt necrotic changes. Rosiglitazone showed a histological improvement of tissue structure, with villi and crypts normalization and oedema reduction. Conclusion.- These results demonstrate that rosiglitazone displays a protective effect on pulmonary fibrosis and radiation

People’s Republic of China Scientific Abstracts, Number 170

Science.gov (United States)

1977-06-30

ORO: Wong-sze Hosoital, Nan-p’i County, Ho-pei TITLE: "Use of Bleomycin Eyedrops in the Prevention of Postoperative Recurrence of Pannus " SOTTRCE...to prevent postoperative recurrence of pannus . It was used in 24 e^es (2 had 3 recurrences). All cases were operated by the D’ombrain orocedure

Browse Title Index

African Journals Online (AJOL)

Vol 107, No 11 (2017), Kaposi's sarcoma: Good outcome with doxorubicin, bleomycin and vincristine sulphate (ABV) chemotherapy and highly active antiretroviral therapy, Abstract PDF. P.B. Hesseling, E Katayi, P Wharin, R Bardin, F Kouya, D Palmer, M Glenn, M Kruger. Vol 47, No ... P. Jacobs, J.D.M. Richards. Vol 91, No ...

comparative study on the proximate content of the flesh of red and ...

African Journals Online (AJOL)

Bashar

bleomycin-induced genotoxicity in Chinese hamster ovary cells. Cancer Letters. 152;. 115-122. Christian, A. and Ukhun, E. (2006): Nutritional potential of the nut of tropical almond. (Terminalia catappa. L.). Pakistan Journal of. Nutrition. 5(4); 334-336. Corner, E.J.H. (1997): Way side trees of Malaya. 4th edition: The Malayan ...

Electrochemotherapy of tumours

International Nuclear Information System (INIS)

Sersa, G.; Cemazar, M.; Rudolf, Z.; Miklavcic, D.

2006-01-01

Electrochemotherapy consists of chemotherapy followed by local application of electric pulses to the tumour to increase drug delivery into cells. Drug uptake can be increased by electroporation for only those drugs whose transport through the plasma membrane is impeded. Among many drugs that have been tested so far, only bleomycin and cisplatin found their way from preclinical testing to clinical trials. In vitro studies demonstrated several fold increase of their cytotoxicity after electroporation of cells. In vivo, electroporation of tumours after local or systemic administration of either of the drugs, i.e. electrochemotherapy, proved to be an effective antitumour treatment. In preclinical studies on several tumour models, electrochemotherapy either with bleomycin or cisplatin was elaborated and parameters for effective local tumour control were determined. In veterinary medicine, electrochemotherapy also proved to be effective in the treatment of primary tumours in cats, dogs and horses. In human clinical studies, electrochemotherapy was performed on the patients with progressive disease and accessible tumour nodules of different malignancies. All clinical studies demonstrated that electrochemotherapy is an effective treatment for local tumour control in cancer patients. (author)

Modifying effects of pre-existing fibrosis in rats exposed to aerosols of {sup 239}PuO{sub 2}. II

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Lundgren, D L; Mauderly, J L; Gillett, N A; Hahn, F F

1988-12-01

We have initiated a study using rats to determine the modifying effects of pre-existing pulmonary fibrosis on the retention and biological effects of inhaled {sup 239}PuO{sub 2}. Pulmonary fibrosis was induced by intratracheal instillation of 8.5 IU/kg body weight of bleomycin at 45 to 49 days before inhalation exposure to an aerosol of {sup 239}PuO{sub 2}. The clearance of {sup 239}Pu from the lungs of rats was decreased significantly (p < 0.01) in rats with pre-existing pulmonary fibrosis compared with controls. Respiratory function, lung morphometric measurements and histological evaluations were all consistent with the presence of mild pulmonary fibrosis in the rats treated with bleomycin. Pre-existing pulmonary fibrosis resulted in an increased retention of the initial lung burdens of {sup 239}Pu, apparently by entrapping the particles in fibrotic areas of the lung. The life span of the rats with pulmonary fibrosis was decreased by up to 25% compared with control rats having similar initial lung burdens of {sup 239}Pu. (author)

Analysis of DNA polymerase activity in Petunia protoplasts treated with clastogenic agents

International Nuclear Information System (INIS)

Benediktsson, I.; Spampinato, C.P.; Andreo, C.S.; Schieder, O.

1994-01-01

Clastogenic agents, i.e. agents that can induce chromosome or DNA breakage, have been shown to enhance the role of direct gene transfer to protoplasts. The effect was analysed at the enzymatic level using protoplast homogenates as well as intact protoplasts. For that purpose existing procedures were modified to enable measurement of DNA polymerase in vivo. In the system used, external DNA was able to enter the cells without the addition of membrane-permeabilizing compounds. When comparing total DNA polymerase activity of protoplasts irradiated with X-rays or UV-light with that of untreated cells we did not observe significant differences. Incubation of protoplasts with high doses of bleomycin affected total DNA polymerase activity negatively. but dideoxythymidine triphosphate-sensitive activity was not influenced. We conclude that the DNA strand-breaks induced by low doses of X-rays. UV-light or bleomycin do not increase the total or the repair-DNA polymerase activity and. therefore. that the increase in the transformation rates after DNA strand-breaking is not preceded by enhanced DNA polymerase activity. (author)

Chemical composition and antigenotoxic properties of Lippia alba essential oils

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Molkary Andrea López

2011-01-01

Full Text Available The present work evaluated the chemical composition and the DNA protective effect of the essential oils (EOs from Lippia alba against bleomycin-induced genotoxicity. EO constituents were determined by Gas Chromatography/Mass Spectrometric (GC-MS analysis. The major compounds encountered being citral (33% geranial and 25% neral, geraniol (7% and trans-β-caryophyllene (7% for L. alba specimen COL512077, and carvone (38%, limonene (33% and bicyclosesquiphellandrene (8% for the other, COL512078. The genotoxicity and antigenotoxicity of EO and the compounds citral, carvone and limonene, were assayed using the SOS Chromotest in Escherichia coli. The EOs were not genotoxic in the SOS chromotest, but one of the major compound (limonene showed genotoxicity at doses between 97 and 1549 mM. Both EOs protected bacterial cells against bleomycin-induced genotoxicity. Antigenotoxicity in the two L. alba chemotypes was related to the major compounds, citral and carvone, respectively. The results were discussed in relation to the chemopreventive potential of L. alba EOs and its major compounds.

Variation in the activities of late stage filaggrin processing enzymes, calpain-1 and bleomycin hydrolase, together with pyrrolidone carboxylic acid levels, corneocyte phenotypes and plasmin activities in non-sun-exposed and sun-exposed facial stratum corneum of different ethnicities.

Science.gov (United States)

Raj, N; Voegeli, R; Rawlings, A V; Summers, B; Munday, M R; Lane, M E

2016-12-01

Knowledge of the ethnic differences and effects of photodamage on the relative amounts of natural moisturizing factor (NMF) together with filaggrin processing enzymes in facial stratum corneum is limited. Our aim was to characterize the activities of calpain-1 (C-1), bleomycin hydrolase (BH) and the levels of pyrrolidone carboxylic acid (PCA) as a marker for total NMF levels and to relate them to plasmin activities and corneocyte maturation. Enzyme activities, PCA levels and corneocyte maturation were determined from facial tape strippings of photoexposed cheek and photoprotected post-auricular areas (PA) of healthy Caucasian (C), Black African (BA) and albino African (AA) female subjects living in South Africa. PCA concentration levels were of the order AA > BA > C subjects, and the highest activities of BH were present in the AA subjects. BH activities were greater on the photoexposed sites for the BA and C subjects, but they were only numerically elevated in the AA subjects. Photoprotected sites had an increase in C-1 activity in pigmented groups (C and BA), whereas in the AA subjects, the opposite was measured. Plasmin activities were greater on the cheek compared with the PA site for the AA and C subjects, but the activity was low in the BA subjects. In both test sites, the AA, but not the BA and C subjects, had smaller, parakeratotic and less mature corneocytes. Variation in PCA levels has been found for different ethnic groups in this study (AA > BA > C subjects). The values in the AA subjects are surprising as one might expect that the lack of pigmentation, and thereby increased photodamage, might lead to lower levels. Increased BH, but not C-1 activity, was observed in the AA subjects indicating that BH is associated with PCA production to a greater extent. Surprisingly, corneocyte maturation is still impaired with elevated PCA levels in AA subjects. The higher levels of plasmin and BH activities on the cheeks, especially for AA and C subjects, suggest

CASE REPORT Bleomycin toxicity post injection into cranio ...

African Journals Online (AJOL)

diabetes insipidus and total blindness. Following radiation ... The MR appearance of the cystic component is varied, but commonly the content is ... severe delayed side-effects are highly varied, but much more rare, and occurred in only 2 out of ...

Fluoroscopically Guided Interventional Procedures: A Review of Radiation Effects on Patients’ Skin and Hair

Science.gov (United States)

2010-02-01

severe radiation injuries can extend into the subcutaneous fat and muscle ( 21 ). Patients may face years of associated pain , multiple surgical...skin injury has been reviewed in detail ( 9 ). Tissues at risk include the skin, hair, subcutaneous fat, and muscle . The expression of this injury...bleomycin, epirubicin, and gemcitabine), antibiot- ics (cefotetan), statins (simvastatin), and herbal preparations (hypericin, otherwise known as St

Rapid repair of DNA double strand breaks in Arabidopsis thaliana is dependent on proteins involved in chromosome structure maintenance

Czech Academy of Sciences Publication Activity Database

Kozák, Jaroslav; West, C.E.; White, C.; da Costa-Nunes, J.A.; Angelis, Karel

2009-01-01

Roč. 8, č. 3 (2009), s. 413-419 ISSN 1568-7864 R&D Projects: GA MŠk(CZ) LC06004; GA MŠk 1M0505 Institutional research plan: CEZ:AV0Z50380511 Keywords : AtKU80 * AtLIG4-4 * AtRAD21.1 * Bleomycin * Comet assay * MIM Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.199, year: 2009

P53 Suppression of Homologous Recombination and Tumorigenesis

Science.gov (United States)

2013-07-01

epithelium: something more than a constituent of the blood-retinal barrier--implications for the pathogenesis of diabetic retinopathy . J Biomed...ethyl methanesulfonate, 3-aminobenzamide, bleomycin, and etoposide with a contrasting decrease in the frequency of detectable reversion events...as strand breaks, DNA adducts, and DNA cross-links, among others. These lesions are detected by surveillance machinery that operates by triggering a

Flagellate dermatitis following consumption of shiitake mushroom

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Hui Voon Loo

2011-10-01

Full Text Available Japanese dermatologists were the first to describe the very characteristic flagellate dermatitis following consumption of under-cooked or raw shiitake mushroom (Lentinus edodes. These similar eruptions were also reported in patients treated with bleomycin, in dermatomyositis and adult onset Still’s disease. We report a case where a 40 year old chinese female developed flagellate dermatitis following ingestion of a bun containing shiitake mushroom.

Enhancement of therapeutic drug and DNA delivery into cells by electroporation

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Rabussay, Dietmar [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Dev, Nagendu B [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Fewell, Jason [Valentis, Inc., 8301 New Trails Drive, The Woodlands, TX (United States); Smith, Louis C [Valentis, Inc., 8301 New Trails Drive, The Woodlands, TX (United States); Widera, Georg [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States); Zhang Lei [Genetronics, Inc., Department of Research and Development, 11199 Sorrento Valley Road, San Diego, CA (United States)

2003-02-21

The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as 'electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing 'pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm{sup -1} generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes

Enhancement of therapeutic drug and DNA delivery into cells by electroporation

International Nuclear Information System (INIS)

Rabussay, Dietmar; Dev, Nagendu B; Fewell, Jason; Smith, Louis C; Widera, Georg; Zhang Lei

2003-01-01

The effectiveness of potentially powerful therapeutics, including DNA, is often limited by their inability to permeate the cell membrane efficiently. Electroporation (EP) also referred to as 'electropermeabilization' of the outer cell membrane renders this barrier temporarily permeable by inducing 'pores' across the lipid bilayer. For in vivo EP, the drug or DNA is delivered into the interstitial space of the target tissue by conventional means, followed by local EP. EP pulses of micro- to millisecond duration and field strengths of 100-1500 V cm -1 generally enhance the delivery of certain chemotherapeutic drugs by three to four orders of magnitude and intracellular delivery of DNA several hundred-fold. We have used EP in clinical studies for human cancer therapy and in animals for gene therapy and DNA vaccination. Late stage squamous cell carcinomas of the head and neck were treated with intratumoural injection of bleomycin and subsequent EP. Of the 69 tumours treated, 25% disappeared completely and another 32% were reduced in volume by more than half. Residence time of bleomycin in electroporated tumours was significantly greater than in non-electroporated lesions. Histological findings and gene expression patterns after bleomycin-EP treatment indicated rapid apoptosis of the majority of tumour cells. In animals, we demonstrated the usefulness of EP for enhanced DNA delivery by achieving normalization of blood clotting times in haemophilic dogs, and by substantially increasing transgene expression in smooth muscle cells of arterial walls using a novel porous balloon EP catheter. Finally, we have found in animal experiments that the immune response to DNA vaccines can be dramatically enhanced and accelerated by EP and co-injection of micron-sized particles. We conclude that EP represents an effective, economical and safe approach to enhance the intracellular delivery, and thus potency, of important drugs and genes for therapeutic purposes. The safety and pharmaco

Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation

International Nuclear Information System (INIS)

Girelli, Roberto; Prejanò, Simona; Cataldo, Ivana; Corbo, Vincenzo; Martini, Lucia; Scarpa, Aldo; Claudio, Bassi

2015-01-01

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl) -2H-tetrazolium (MTS) assay. In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma

Quantification of lung fibrosis and emphysema in mice using automated micro-computed tomography.

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Ellen De Langhe

Full Text Available BACKGROUND: In vivo high-resolution micro-computed tomography allows for longitudinal image-based measurements in animal models of lung disease. The combination of repetitive high resolution imaging with fully automated quantitative image analysis in mouse models of lung fibrosis lung benefits preclinical research. This study aimed to develop and validate such an automated micro-computed tomography analysis algorithm for quantification of aerated lung volume in mice; an indicator of pulmonary fibrosis and emphysema severity. METHODOLOGY: Mice received an intratracheal instillation of bleomycin (n = 8, elastase (0.25 U elastase n = 9, 0.5 U elastase n = 8 or saline control (n = 6 for fibrosis, n = 5 for emphysema. A subset of mice was scanned without intervention, to evaluate potential radiation-induced toxicity (n = 4. Some bleomycin-instilled mice were treated with imatinib for proof of concept (n = 8. Mice were scanned weekly, until four weeks after induction, when they underwent pulmonary function testing, lung histology and collagen quantification. Aerated lung volumes were calculated with our automated algorithm. PRINCIPAL FINDINGS: Our automated image-based aerated lung volume quantification method is reproducible with low intra-subject variability. Bleomycin-treated mice had significantly lower scan-derived aerated lung volumes, compared to controls. Aerated lung volume correlated with the histopathological fibrosis score and total lung collagen content. Inversely, a dose-dependent increase in lung volume was observed in elastase-treated mice. Serial scanning of individual mice is feasible and visualized dynamic disease progression. No radiation-induced toxicity was observed. Three-dimensional images provided critical topographical information. CONCLUSIONS: We report on a high resolution in vivo micro-computed tomography image analysis algorithm that runs fully automated and allows quantification of aerated lung volume in mice. This

Evaluation of the in vitro antioxidant activity of Mangifera indica L. extract (Vimang).

Science.gov (United States)

Martínez, G; Delgado, R; Pérez, G; Garrido, G; Núñez Sellés, A J; León, O S

2000-09-01

An extract of Mangifera indica L. (Vimang) was tested in vitro for its antioxidant activity using commonly accepted assays. It showed a powerful scavenger activity of hydroxyl radicals and hypochlorous acid and acted as an iron chelator. The extract also showed a significant inhibitory effect on the peroxidation of rat-brain phospholipid and inhibited DNA damage by bleomycin or copper-phenanthroline systems. Copyright 2000 John Wiley & Sons, Ltd.

An Interesting Fistula Tract Presenting with Recurrent Gluteal Abscess: Instructive Case

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Gulsum Iclal Bayhan

2015-01-01

Full Text Available A fistula extending from the gluteus to penis is an extremely rare entity. In this paper, we have highlighted novel variant of congenital penile to gluteal fistula complicated with gluteal and penoscrotal abscess in a previously healthy boy. A fistulous tract extending from the gluteus to penis has been shown by fistulogram. Bleomycin has been used in fistula tract with successful results in our patient.

Changes in protein expression in p53 deleted spontaneous thymic lymphomas

DEFF Research Database (Denmark)

Honoré, Bent; Vorum, Henrik; Pedersen, Anders Elm

2004-01-01

with the protein expression in p53+/+ and p53-/- thymocytes. Only a minority (13 proteins) of the quantitatively changed proteins were common for the two thymic lymphoma cell lines, suggesting that the p53 deficiency mainly results in genetic dysfunctions which are individual for a given tumor. Two of the detected...... structure containing motifs of the glyoxalase-bleomycin resistance protein family (MDR) as deduced from the cDNA....

The prognostic value of biological markers in paediatric Hodgkin lymphoma.

Science.gov (United States)

Farruggia, Piero; Puccio, Giuseppe; Sala, Alessandra; Todesco, Alessandra; Buffardi, Salvatore; Garaventa, Alberto; Bottigliero, Gaetano; Bianchi, Maurizio; Zecca, Marco; Locatelli, Franco; Pession, Andrea; Pillon, Marta; Favre, Claudio; D'Amico, Salvatore; Provenzi, Massimo; Trizzino, Angela; Zanazzo, Giulio Andrea; Sau, Antonella; Santoro, Nicola; Murgia, Giulio; Casini, Tommaso; Mascarin, Maurizio; Burnelli, Roberta

2016-01-01

Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children. By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens. On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography. Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

The efficacy of superselective intra-arterial infusion in patients with T4 oral cancer. Comparison with conventional chemotherapy

International Nuclear Information System (INIS)

Arakaki, Keiichi; Arasaki, Akira; Kano, Takeshi

2009-01-01

Since 1985, we have applied systematic treatment to improve radicality and postoperative oral dysfunction, as well as maxillofacial deformity. However, most T4 cases of oral cancer have remained difficult to treat, and diverse methods and results for progressive cancer have been reported by many institutions. For high-grade malignancy cases, we changed the treatment from bleomycin or cisplatin in induction chemotherapy to targeted intra-arterial infusions of carboplatin with radiation-combined therapy. In this study, we compared the effects of conventional therapy with targeted intra-arterial infusions of carboplatin for T4 cases of oral cancer. In this retrospective review, we analyzed a subset of patients who were treated with induction chemotherapy using bleomycin (BLM) and targeted intra-arterial infusions of carboplatin (CBDCA) with radiation-combined therapy patients who received treatment between June 1985 and December 2006. Of the 105 patients who had T4 disease, the proportion with grade IIb to IV in the carboplatin with radiation-combined therapy (88.9%) was higher than that in induction chemotherapy (45.0%). Targeted chemoradiation therapy followed by surgical salvage is a highly effective approach for the regional control of patients with T4, although additional strategies are required to address the problem of distant metastases. (author)

Biomonitoring of genotoxic risk in radar facility workers: comparison of the comet assay with micronucleus assay and chromatid breakage assay

International Nuclear Information System (INIS)

Garaj-Vrhovac, V.; Kopjar, N.

2003-01-01

Genotoxic risks of occupational exposure in a radar facility were evaluated by using alkaline comet assay, micronucleus assay and chromatid breakage assay on peripheral blood leukocytes in exposed subjects and corresponding controls. Results show that occupational exposure to microwave radiation correlates with an increase of genome damage in somatic cells. The levels of DNA damage in exposed subjects determined by using alkaline comet assay were increased compared to control and showed interindividual variations. Incidence of micronuclei was also significantly increased compared to baseline control values. After short exposure of cultured lymphocytes to bleomycin, cells of occupationally exposed subjects responded with high numbers of chromatid breaks. Although the level of chromosome damage generated by bleomycin varied greatly between individuals, in exposed subjects a significantly elevated number of chromatid breaks was observed. Our results support data reported in literature indicating that microwave radiation represents a potential DNA-damaging hazard. Alkaline comet assay is confirmed as a sensitive and highly reproducible technique for detection of primary DNA damage inflicted in somatic cells. Micronucleus assay was confirmed as reliable bio-markers of effect and chromatid breakage assay as sensitive bio-marker of individual cancer susceptibility. The results obtained also confirm the necessity to improve measures and to perform accurate health surveillance of individuals occupationally exposed to microwave radiation

Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis.

Science.gov (United States)

Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y; Fong, Guo-Hua; Sakmar, Thomas P; Rafii, Shahin; Ding, Bi-Sen

2016-02-01

Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin-dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

Targeted inhibition of disheveled PDZ domain via NSC668036 depresses fibrotic process

Energy Technology Data Exchange (ETDEWEB)

Wang, Cong, E-mail: wangcongweihai@126.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Dai, Jinghong, E-mail: daijinghongnew@163.com [Department of Respiratory Medicine, Nanjing Drum Tower Hospital Affiliated to Medical School of Nanjing University (China); Sun, Zhaorui, E-mail: lanseyunduan@163.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Department of Emergency, Jinling Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210093 (China); Shi, Chaowen, E-mail: willscw@live.cn [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); Cao, Honghui, E-mail: caohonghui92@gmail.com [Immunology and Reproduction Biology Laboratory, Medical School, Nanjing University, Nanjing, Hankou Road 22, Jiangsu 210093 (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu 210093 (China); State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, Jiangsu 210093 (China); and others

2015-02-01

In this study, we determined the effects of transforming growth factor-beta (TGF-β) and Wnt/β-catenin signaling on myofibroblast differentiation of NIH/3T3 fibroblasts in vitro and evaluated the therapeutic efficacy of NSC668036 in bleomycin-induced pulmonary fibrosis murine model. In vitro study, NSC668036, a small organic inhibitor of the PDZ domain in Dvl, suppressed β-catenin-driven gene transcription and abolished TGF-β1-induced migration, expression of collagen I and α-smooth muscle actin (α-SMA) in fibroblasts. In vivo study, we found that NSC668036 significantly suppressed accumulation of collagen I, α-SMA, and TGF-β1 but increased the expression of CK19, Occludin and E-cadherin that can inhibit pulmonary fibrogenesis. Because fibrotic lung exhibit aberrant activation of Wnt/β-catenin signaling, these data collectively suggest that inhibition of Wnt/β-catenin signaling at the Dvl level may be an effective approach to the treatment of fibrotic lung diseases. - Highlights: • NSC668036 inhibited the proliferation and migration of NIH/3T3 fibroblasts. • NSC668036 suppressed the Wnt/β-catenin signaling pathway. • TGF-β-induced stimulation of profibrotic responses were inhibited by NSC668036. • NSC668036 can inhibit the development of bleomycin-induced pulmonary fibrosis.

Report of an autopsyzed case of Kaposi sarcoma developed in therapeutically irradiated region

International Nuclear Information System (INIS)

Tanahashi, Yoshio; Sato, Akihiko

1975-01-01

A case of Kaposi sarcoma developed in the right gluteal region of 57 year-old woman was reported in the present paper. The patient received surgical excision of uterine cervical cancer and also gastric cancer in the different time in her past history. Post-operative radiotherapy following uterine excision consisted of 3,350 to 3,650 R of respective 180 kV of X-ray and 60 Co. The mass developed in the region irradiated during the past deep therapy, and showed resistance to Linac irradiation and bleomycin. The masses which seemed to be the same with that in the skin developed in the both lung, and bleomycin administered was not effective. In addition, a mass developed in the right inguinal lymphnode which was considered to be the metastasis from cervical cancer, and was wholly excised. The patient died from pneumonia one year after the manifestation of Kaposi sarcoma. This case was very extraordinary because of the triplicated tumors, i.e., gastric cancer, uterine cervical cancer, and Kaposi sarcoma. The nature of Kaposi sarcoma was discussed from our experience and literature. Kaposi sarcoma in our case, was suggested to be a radiation-induced tumor, and the mechanism of occurrence was considered to be that of multi-centric tumor. (Tsukamoto, Y.)

Dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis.

Directory of Open Access Journals (Sweden)

François Huaux

Full Text Available Morbi-mortality in cystic fibrosis (CF is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.

Report of an autopsyed case of Kaposi sarcoma developed in therapeutically irradiated region

Energy Technology Data Exchange (ETDEWEB)

Tanahashi, Y; Sato, A [Tohoku Univ., Sendai (Japan). School of Medicine

1975-04-01

A case of Kaposi sarcoma developed in the right gluteal region of 57 year-old woman was reported in the present paper. The patient received surgical excision of uterine cervical cancer and also gastric cancer in the different time in her past history. Post-operative radiotherapy following uterine excision consisted of 3,350 to 3,650 R of respective 180 kV of X-ray and /sup 60/Co. The mass developed in the region irradiated during the past deep therapy, and showed resistance to Linac irradiation and bleomycin. The masses which seemed to be the same with that in the skin developed in the both lung, and bleomycin administered was not effective. In addition, a mass developed in the right inguinal lymphnode which was considered to be the metastasis from cervical cancer, and was wholly excised. The patient died from pneumonia one year after the manifestation of Kaposi sarcoma. This case was very extraordinary because of the triplicated tumors, i.e., gastric cancer, uterine cervical cancer, and Kaposi sarcoma. The nature of Kaposi sarcoma was discussed from our experience and literature. Kaposi sarcoma in our case, was suggested to be a radiation-induced tumor, and the mechanism of occurrence was considered to be that of multi-centric tumor.

A novel telomerase activator suppresses lung damage in a murine model of idiopathic pulmonary fibrosis.

Science.gov (United States)

Le Saux, Claude Jourdan; Davy, Philip; Brampton, Christopher; Ahuja, Seema S; Fauce, Steven; Shivshankar, Pooja; Nguyen, Hieu; Ramaseshan, Mahesh; Tressler, Robert; Pirot, Zhu; Harley, Calvin B; Allsopp, Richard

2013-01-01

The emergence of diseases associated with telomere dysfunction, including AIDS, aplastic anemia and pulmonary fibrosis, has bolstered interest in telomerase activators. We report identification of a new small molecule activator, GRN510, with activity ex vivo and in vivo. Using a novel mouse model, we tested the potential of GRN510 to limit fibrosis induced by bleomycin in mTERT heterozygous mice. Treatment with GRN510 at 10 mg/kg/day activated telomerase 2-4 fold both in hematopoietic progenitors ex vivo and in bone marrow and lung tissue in vivo, respectively. Telomerase activation was countered by co-treatment with Imetelstat (GRN163L), a potent telomerase inhibitor. In this model of bleomycin-induced fibrosis, treatment with GRN510 suppressed the development of fibrosis and accumulation of senescent cells in the lung via a mechanism dependent upon telomerase activation. Treatment of small airway epithelial cells (SAEC) or lung fibroblasts ex vivo with GRN510 revealed telomerase activating and replicative lifespan promoting effects only in the SAEC, suggesting that the mechanism accounting for the protective effects of GRN510 against induced lung fibrosis involves specific types of lung cells. Together, these results support the use of small molecule activators of telomerase in therapies to treat idiopathic pulmonary fibrosis.

SNEV overexpression extends the life span of human endothelial cells

International Nuclear Information System (INIS)

Voglauer, Regina; Chang, Martina Wei-Fen; Dampier, Brigitta; Wieser, Matthias; Baumann, Kristin; Sterovsky, Thomas; Schreiber, Martin; Katinger, Hermann; Grillari, Johannes

2006-01-01

In a recent screening for genes downregulated in replicatively senescent human umbilical vein endothelial cells (HUVECs), we have isolated the novel protein SNEV. Since then SNEV has proven as a multifaceted protein playing a role in pre-mRNA splicing, DNA repair, and the ubiquitin/proteosome system. Here, we report that SNEV mRNA decreases in various cell types during replicative senescence, and that it is increased in various immortalized cell lines, as well as in breast tumors, where SNEV transcript levels also correlate with the survival of breast cancer patients. Since these mRNA profiles suggested a role of SNEV in the regulation of cell proliferation, the effect of its overexpression was tested. Thereby, a significant extension of the cellular life span was observed, which was not caused by altered telomerase activity or telomere dynamics but rather by enhanced stress resistance. When SNEV overexpressing cells were treated with bleomycin or bleomycin combined with BSO, inducing DNA damage as well as reactive oxygen species, a significantly lower fraction of apoptotic cells was found in comparison to vector control cells. These data suggest that high levels of SNEV might extend the cellular life span by increasing the resistance to stress or by improving the DNA repair capacity of the cells

Targeting of the pulmonary capillary vascular niche promotes lung alveolar repair and ameliorates fibrosis

Science.gov (United States)

Cao, Zhongwei; Lis, Raphael; Ginsberg, Michael; Chavez, Deebly; Shido, Koji; Rabbany, Sina Y.; Fong, Guo-Hua; Sakmar, Thomas P.; Rafii, Shahin; Ding, Bi-Sen

2016-01-01

Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladaptbed hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis. PMID:26779814

Identification of the Gene for Scleroderma in the Tsk/2 Mouse Strain: Implications for Human Scleroderma Pathogenesis and Subset Distinctions

Science.gov (United States)

2015-09-01

models of SSc to identify those models in which skin gene expression and deregulated pathways most accurately reflects that of the molecular subsets... Germany ) in blocking buffer was applied to the sections overnight at 4˚C. Slides were washed three times with PBS and incubated with Cy3...leading to activation of the Tweak / Fn14 signaling axis. The deregulation of TGFβ signaling in the bleomycin model has been previously demonstrated

Radionuclide and thermographic diagnosis of head and neck tumors

Energy Technology Data Exchange (ETDEWEB)

Bogdasarov, Yu.B.; Lenskaya, O.P.; Polyakov, B.I.; Belkina, B.M. (Akademiya Meditsinskikh Nauk SSSR, Moscow. Onkologicheskij Nauchnyj Tsentr)

1983-10-01

Radionuclide and thermographic studies using /sup 67/Ga-citrate and /sup 111/In-bleomycin were performed in 129 patients with laryngeal cancer, chemodectoma of the neck, retinoblastoma, rhabdomyosarcoma of the orbital and facial soft tissues and cancer of the tongue. Elevated amounts of the radiopharmaceuticals were found in patients with tumors. In thermographic studies higher temperature activity corresponding to the tumor was noted. Radio-nuclide thermographic studies extend diagnostic opportunities for head and neck tumors.

Radionuclide and thermographic diagnosis of head and neck tumors

International Nuclear Information System (INIS)

Bogdasarov, Yu.B.; Lenskaya, O.P.; Polyakov, B.I.; Belkina, B.M.

1983-01-01

Radionuclide and thermographic studies using 67 Ga-citrate and 111 In-bleomycin were performed in 129 patients with laryngeal cancer, chemodectoma of the neck, retinoblastoma, rhabdomyosarcoma of the orbital and facial soft tissues and cancer of the tongue. Elevated amounts of the radiopharmaceuticals were found in patients with tumors. In thermographic studies higher temperature activity corresponding to the tumor was noted. Radio-nuclide thermographic studies extend diagnostic opportunities for head and neck tumors

COPBLAM: infusion chemotherapy for large cell lymphoma

International Nuclear Information System (INIS)

Coleman, M.; Bernhardt, B.; Boyd, D.B.; Gerstein, G.

1986-01-01

This chapter describes a new combination chemotherapy program that was initiated at the New York Hospital-Cornell Medical Center for large cell lymphoma (LCL). The program, known as COPBLAM (Cyclophosphamide, Oncovin, Prednisone, Bleomycin, Adriamycin, Matulane) was an intensive multidrug regimen designed to maximize tumor cell kill. Some of the novel concepts and features are described. The treatment was fully successful in 60% of the 48 patients studied that were undergoing radiation therapy

C-type natriuretic peptide ameliorates pulmonary fibrosis by acting on lung fibroblasts in mice.

Science.gov (United States)

Kimura, Toru; Nojiri, Takashi; Hino, Jun; Hosoda, Hiroshi; Miura, Koichi; Shintani, Yasushi; Inoue, Masayoshi; Zenitani, Masahiro; Takabatake, Hiroyuki; Miyazato, Mikiya; Okumura, Meinoshin; Kangawa, Kenji

2016-02-19

Pulmonary fibrosis has high rates of mortality and morbidity; however, no effective pharmacological therapy has been established. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, selectively binds to the transmembrane guanylyl cyclase (GC)-B receptor and exerts anti-inflammatory and anti-fibrotic effects in various organs through vascular endothelial cells and fibroblasts that have a cell-surface GC-B receptor. Given the pathophysiological importance of fibroblast activation in pulmonary fibrosis, we hypothesized that the anti-fibrotic and anti-inflammatory effects of exogenous CNP against bleomycin (BLM)-induced pulmonary fibrosis were exerted in part by the effect of CNP on pulmonary fibroblasts. C57BL/6 mice were divided into two groups, CNP-treated (2.5 μg/kg/min) and vehicle, to evaluate BLM-induced (1 mg/kg) pulmonary fibrosis and inflammation. A periostin-CNP transgenic mouse model exhibiting CNP overexpression in fibroblasts was generated and examined for the anti-inflammatory and anti-fibrotic effects of CNP via fibroblasts in vivo. Additionally, we assessed CNP attenuation of TGF-β-induced differentiation into myofibroblasts by using immortalized human lung fibroblasts stably expressing GC-B receptors. Furthermore, to investigate whether CNP acts on human lung fibroblasts in a clinical setting, we obtained primary-cultured fibroblasts from surgically resected lungs of patients with lung cancer and analyzed levels of GC-B mRNA transcription. CNP reduced mRNA levels of the profibrotic cytokines interleukin (IL)-1β and IL-6, as well as collagen deposition and the fibrotic area in lungs of mice with bleomycin-induced pulmonary fibrosis. Furthermore, similar CNP effects were observed in transgenic mice exhibiting fibroblast-specific CNP overexpression. In cultured-lung fibroblasts, CNP treatment attenuated TGF-β-induced phosphorylation of Smad2 and increased mRNA and protein expression of α-smooth muscle actin and SM22�

Evolutionarily distant streptophyta respond differently to genotoxic stress

Czech Academy of Sciences Publication Activity Database

Vágnerová, Radka; Lukešová, Alena; Lukeš, Martin; Rožnovská, Petra; Holá, Marcela; Fulnečková, Jana; Fajkus, J.; Angelis, Karel

2017-01-01

Roč. 8, č. 11 (2017), č. článku 331. ISSN 2073-4425 R&D Projects: GA ČR GA16-01137S; GA MŠk(CZ) LQ1601; GA MŠk LTC17047 Institutional support: RVO:61389030 ; RVO:60077344 ; RVO:61388971 ; RVO:68081707 Keywords : Bleomycin * DNA damage and repair * Klebsormidium * Methyl methanesulfonate * Physcomitrella patens * Ultraviolet light * Zygnema Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Plant sciences, botany Impact factor: 3.600, year: 2016

An Innovative Cell Microincubator for Drug Discovery Based on 3D Silicon Structures

Directory of Open Access Journals (Sweden)

Francesca Aredia

2016-01-01

Full Text Available We recently employed three-dimensional (3D silicon microstructures (SMSs consisting in arrays of 3 μm-thick silicon walls separated by 50 μm-deep, 5 μm-wide gaps, as microincubators for monitoring the biomechanical properties of tumor cells. They were here applied to investigate the in vitro behavior of HT1080 human fibrosarcoma cells driven to apoptosis by the chemotherapeutic drug Bleomycin. Our results, obtained by fluorescence microscopy, demonstrated that HT1080 cells exhibited a great ability to colonize the narrow gaps. Remarkably, HT1080 cells grown on 3D-SMS, when treated with the DNA damaging agent Bleomycin under conditions leading to apoptosis, tended to shrink, reducing their volume and mimicking the normal behavior of apoptotic cells, and were prone to leave the gaps. Finally, we performed label-free detection of cells adherent to the vertical silicon wall, inside the gap of 3D-SMS, by exploiting optical low coherence reflectometry using infrared, low power radiation. This kind of approach may become a new tool for increasing automation in the drug discovery area. Our results open new perspectives in view of future applications of the 3D-SMS as the core element of a lab-on-a-chip suitable for screening the effect of new molecules potentially able to kill tumor cells.

Polycomb-group histone methyltransferase CLF is required for proper somatic recombination in Arabidopsis

Institute of Scientific and Technical Information of China (English)

Na Chen; Wang-Bin Zhou; Ying-Xiang Wang; Ai-Wu Dong; Yu Yu

2014-01-01

Homologous recombination (HR) is a key process during meiosis in reproductive cells and the DNA damage repair process in somatic cells. Although chromatin structure is thought to be crucial for HR, only a smal number of chromatin modifiers have been studied in HR regulation so far. Here, we investigated the function of CURLY LEAF (CLF), a Polycomb-group (PcG) gene responsible for histone3 lysine 27 trimethy-lation (H3K27me3), in somatic and meiotic HR in Arabidopsis thaliana. Although fluorescent protein reporter assays in pol en and seeds showed that the frequency of meiotic cross-over in the loss-of-function mutant clf-29 was not significantly different from that in wild type, there was a lower frequency of HR in clf-29 than in wild type under normal conditions and under bleomycin treatment. The DNA damage levels were compara-ble between clf-29 and wild type, even though several DNA damage repair genes (e.g. ATM, BRCA2a, RAD50, RAD51, RAD54,and PARP2) were expressed at lower levels in clf-29. Under bleomycin treatment, the expression levels of DNA repair genes were similar in clf-29 and wild type, thus CLF may also regulate HR via other mechanisms. These findings expand the current knowledge of PcG function and contribute to general interests of epigenetic regulation in genome stability regulation.

Serum inter-alpha-trypsin inhibitor and matrix hyaluronan promote angiogenesis in fibrotic lung injury.

Science.gov (United States)

Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S; Hollingsworth, John W; Jiang, Dianhua; Lancaster, Lisa H; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K; Noble, Paul W; Kimata, Koji; Schwartz, David A

2008-11-01

The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627).

Long-term recovery of spermatogenesis after radiotherapy in patients with testicular cancer.

Science.gov (United States)

Hansen, P V; Trykker, H; Svennekjaer, I L; Hvolby, J

1990-06-01

Gonadal function was evaluated before irradiation and by serial analyses after treatment in 27 patients with seminomas and 24 patients with nonseminomatous germ cell tumors of the testis. During subdiaphragmatic irradiation, a median testicular dose of 1.7 Gy (range, 1.2 to 4.8 Gy) reached the remaining testis. Twenty nonseminoma patients were treated with adjuvant chemotherapy using vincristine and bleomycin (OB) or cisplatin/dactinomycin, vinblastine, and bleomycin (P/DVB). After orchiectomy, 94% had spermatozoa in semen, 49% had a total sperm count exceeding the reference value (80 x 10(6], and in 67% serum follicle-stimulating hormone levels were normal. The corresponding estimated values 5 and 9 years after treatment were 61%, 13%, 14%, and 84%, 35%, 32%, respectively. A Cox regression analysis of recovery, with azoospermia used as an endpoint, showed that (1) recovery depended on the radiation dose, (2) adjuvant chemotherapy prolonged the recovery period, (3) recovery was decreased in patients with low pretreatment total sperm counts and in patients older than 25 years. A prognostic index was derived from the regression model and radiation dose-response curves were calculated (+/- chemotherapy). We conclude that a profound, dose-dependent impairment of spermatogenesis is caused by radiation scatter reaching the testis during subdiaphragmal irradiation. An effective gonadal shield should reduce the gonadal dose to a level low enough to preserve spermatogenesis in most patients.

Drug-induced Pulmonary Fibrosis

International Nuclear Information System (INIS)

Daba, Mohammad H.; Al-Arifi, Mohammad N; Gubar, Othman A.; El-Tahir, Kamal E.

2004-01-01

Pulmonary fibrosis is characterized by the accumulation of excessive connective tissue in the lungs. Its causes include chronic administration of some drugs for example bleomycin, cyclophosphamide, amiodarone, procainamide, penicillamine, gold and nitrofurantoin; exposure to certain environmental factors such as gases, asbestos and silica and bacterial or fungal infections. Some systemic diseases also predispose to the disease for example rheumatoid arthritis and systemic lupus erythematosus. The disease is associated with release of oxygen radicals and some mediators such as tumor necrosis factor-alpha TNF-alpha, transforming growth factor-beta Tbgf-beta, PDGF, If-I, Et-I and interleukins 1, 4, 8 and 13. The symptoms of the disease include dyspne a, non-productive cough, fever and damage to the lung cells. It is diagnosed with the aid of chest radiography, high resolution computed tomographic scanning and the result of pulmonary function tests. Drug-induced pulmonary fibrosis may involve release of free oxygen radicals and various cytokines for example Il-I beta and TNF-alpha via activation of nuclear transcription factor Nf-beta as in the case of bleomycin and mitomycin or via release of TGF-beta as in case of tamoxifen or via inhibition of macrophages and lymphocytes phospholipases as in the case of amiodarone with the resultant accumulation of phospholipids and reduction of the immune system. (author)

Modulation of pulmonary fibrosis by IL-13Rα2.

Science.gov (United States)

Lumsden, Robert V; Worrell, Julie C; Boylan, Denise; Walsh, Sinead M; Cramton, Jennifer; Counihan, Ian; O'Beirne, Sarah; Medina, Maria Fe; Gauldie, Jack; Fabre, Aurelie; Donnelly, Seamas C; Kane, Rosemary; Keane, Michael P

2015-04-01

Pulmonary fibrosis is a progressive and fatal disease that involves the remodeling of the distal airspace and the lung parenchyma, which results in compromised gas exchange. The median survival time once diagnosed is less than three years. Interleukin (IL)-13 has been shown to play a role in a number of inflammatory and fibrotic diseases. IL-13 modulates its effector functions via a complex receptor system that includes the IL-4 receptor (R) α, IL-13Rα1, and the IL-13Rα2. IL-13Rα1 binds IL-13 with low affinity, yet, when it forms a complex with IL-4α, it binds with much higher affinity, inducing the effector functions of IL-13. IL-13Rα2 binds IL-13 with high affinity but has a short cytoplasmic tail and has been shown to act as a nonsignaling decoy receptor. Transfection of fibroblasts and epithelial cells with IL-13Rα2 inhibited the IL-13 induction of soluble collagen, TGF-β, and CCL17. Adenoviral overexpression of IL-13Rα2 in the lung reduced bleomycin-induced fibrosis. Our work shows that overexpression of IL-13Rα2 inhibits the IL-13 induction of fibrotic markers in vitro and inhibits bleomycin-induced pulmonary fibrosis. In summary our study highlights the antifibrotic nature of IL-13Ra2. Copyright © 2015 the American Physiological Society.

Deletion of SMARCA4 impairs alveolar epithelial type II cells proliferation and aggravates pulmonary fibrosis in mice

Directory of Open Access Journals (Sweden)

Danyi Peng

2017-12-01

Full Text Available Alveolar epithelial cells (AECs injury and failed reconstitution of the AECs barrier are both integral to alveolar flooding and subsequent pulmonary fibrosis (PF. Nevertheless, the exact mechanisms regulating the regeneration of AECs post-injury still remain unclear. SMARCA4 is a part of the large ATP-dependent chromatin remodelling complex SWI/SNF, which is essential for kidney and heart fibrosis. We investigates SMARCA4 function in lung fibrosis by establishing PF mice model with bleomycin firstly and found that the expression of SMARCA4 was mainly enhanced in alveolar type II (ATII cells. Moreover, we established an alveolar epithelium-specific SMARCA4-deleted SP-C-rtTA/(tetO7-Cre/SMARCA4f/f mice (SOSM4Δ/Δ model, as well as a new SMARCA4-deleted alveolar type II (ATII-like mle-12 cell line. We found that the bleomycin-induced PF was more aggressive in SOSM4Δ/Δ mice. Also, the proliferation of ATII cells was decreased with the loss of SMARCA4 in vivo and in vitro. In addition, we observed increased proliferation of ATII cells accompanied by abnormally high expression of SMARCA4 in human PF lung sections. These data uncovered the indispensable role of SMARCA4 in the proliferation of ATII cells, which might affect the progression of PF.

Isolated Femoral Muscle and Bone Metastases Rarely Encountered in Testicular Seminoma

Directory of Open Access Journals (Sweden)

Serkan Degirmencioglu

2013-01-01

Full Text Available Isolated muscle and bone metastases are rarely encountered in patients with testicular seminomas. In the present study, a patient who was admitted with pain, loss of motion, and swelling in the right leg 20 months following surgery for stage I seminoma was presented. Hypermetabolic lesion was detected in the right femoral muscle and bone via positron emission tomography. After the presence of metastasis from seminoma was confirmed by biopsy, bleomycin, cisplatin, and etoposide, combination chemotherapy was administered to the patient.

Techniques for Optimizing Surgical Scars, Part 2: Hypertrophic Scars and Keloids.

Science.gov (United States)

Potter, Kathryn; Konda, Sailesh; Ren, Vicky Zhen; Wang, Apphia Lihan; Srinivasan, Aditya; Chilukuri, Suneel

2017-01-01

Surgical management of benign or malignant cutaneous tumors may result in noticeable scars that are of great concern to patients, regardless of sex, age, or ethnicity. Techniques to optimize surgical scars are discussed in this three-part review. Part 2 focuses on scar revision for hypertrophic and keloids scars. Scar revision options for hypertrophic and keloid scars include corticosteroids, bleomycin, fluorouracil, verapamil, avotermin, hydrogel scaffold, nonablative fractional lasers, ablative and fractional ablative lasers, pulsed dye laser (PDL), flurandrenolide tape, imiquimod, onion extract, silicone, and scar massage.

Ternary iron(II) complex with an emissive imidazopyridine arm from Schiff base cyclizations and its oxidative DNA cleavage activity

OpenAIRE

Mukherjee, Arindam; Dhar, Shanta; Nethaji, Munirathinam; Chakravarty, Akhil R

2005-01-01

The ternary iron(II) complex [Fe(L')(L")] $(PF_6)_3(1)$ as a synthetic model for the bleomycins, where L' and L" are formed from metal-mediated cyclizations of N,N -(2-hydroxypropane-1,3-diyl)bis(pyridine-2-aldimine)(L), is synthesized and structurally characterized by X-ray crystallography. In the six-coordinate iron(II) complex, ligands L' and L" show tetradentate and bidentate chelating modes of bonding. Ligand L' is formed from an intramolecular attack of the alcoholic OH group of L to o...

Loss of DNA topoisomerase I activity alters many cellular functions in Salmonella typhimurium

International Nuclear Information System (INIS)

Overbye, K.M.; Basu, S.K.; Margolin, P.

1983-01-01

In this paper is reported the absence of DNA topoisomerase I in S. typhimurium results in an increased level of the recBC DNase (exonuclease V) enzyme, an almost total abolition of both direct and indirect mutagenesis by alkylating agents, and altered characteristics in the formation of chromosomal tandem duplications. We also present evidence that modifications in DNA superhelicity may strongly affect the pattern of DNA degrafation initiated by treatment of recA mutant cells with bleomycin and mitomycin C. 43 references, 3 figures, 3 tables

The increase of microRNA-21 during lung fibrosis and its contribution to epithelial-mesenchymal transition in pulmonary epithelial cells.

Science.gov (United States)

Yamada, Mitsuhiro; Kubo, Hiroshi; Ota, Chiharu; Takahashi, Toru; Tando, Yukiko; Suzuki, Takaya; Fujino, Naoya; Makiguchi, Tomonori; Takagi, Kiyoshi; Suzuki, Takashi; Ichinose, Masakazu

2013-09-24

The excess and persistent accumulation of fibroblasts due to aberrant tissue repair results in fibrotic diseases such as idiopathic pulmonary fibrosis. Recent reports have revealed significant changes in microRNAs during idiopathic pulmonary fibrosis and evidence in support of a role for microRNAs in myofibroblast differentiation and the epithelial-mesenchymal transition in the context of fibrosis. It has been reported that microRNA-21 is up-regulated in myofibroblasts during fibrosis and promotes transforming growth factor-beta signaling by inhibiting Smad7. However, expression changes in microRNA-21 and the role of microRNA-21 in epithelial-mesenchymal transition during lung fibrosis have not yet been defined. Lungs from saline- or bleomycin-treated C57BL/6 J mice and lung specimens from patients with idiopathic pulmonary fibrosis were analyzed. Enzymatic digestions were performed to isolate single lung cells. Lung epithelial cells were isolated by flow cytometric cell sorting. The expression of microRNA-21 was analyzed using both quantitative PCR and in situ hybridization. To induce epithelial-mesenchymal transition in culture, isolated mouse lung alveolar type II cells were cultured on fibronectin-coated chamber slides in the presence of transforming growth factor-β, thus generating conditions that enhance epithelial-mesenchymal transition. To investigate the role of microRNA-21 in epithelial-mesenchymal transition, we transfected cells with a microRNA-21 inhibitor. Total RNA was isolated from the freshly isolated and cultured cells. MicroRNA-21, as well as mRNAs of genes that are markers of alveolar epithelial or mesenchymal cell differentiation, were quantified using quantitative PCR. The lung epithelial cells isolated from the bleomycin-induced lung fibrosis model system had decreased expression of epithelial marker genes, whereas the expression of mesenchymal marker genes was increased. MicroRNA-21 was significantly upregulated in isolated lung epithelial

The Usefulness Cytogenetic Biomarkers in Assessment of Occupational Exposure to Microwave Radiation

International Nuclear Information System (INIS)

Garaj-Vrhovac, V.; Kopjar, N.

2003-01-01

In recent years there has been growing interest in the health effects of the electromagnetic radiation's designated extremely low frequency (ELF) and radiofrequency radiation (RFR). Available data on cytogenetic consequences of microwave exposure on the induction of chromosome damage are contradictory, mostly because of different experimental conditions of in vitro and in vivo studies. It has been suggested that exposure to radiofrequency radiation may have genetic effects, which predispose to the development of cancer or birth defects. For the detection of early biological effects of DNA-damaging agents, well-established cytogenetic biomarkers are used. Comet assay was also successfully introduced detection of primary DNA damage and micronucleus assay for simultaneous detection of chromosome damage and spindle disfunction. The chromatid breakage assay, allowing selection of persons with a defect in DNA repair, is also an additional marker in human biomonitoring. Susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes may reflect the way a person deals with carcinogenic challenges. The objective of the present study the assessment of primary DNA damage, chromosome and spindle disfunctions as well as the mutagen sensitivity in peripheral blood leukocytes in radar-facility workers daily exposed to microwave radiation and corresponding control. As sensitive biomarkers three endpoints were chosen: the alkaline comet assay, micronucleus assay and chromatid breakage assay (bleomycin sensitivity test). A large number of experimental and epidemiological studies have been carried out to elucidate the possible health hazards associated with human exposure to ELF or RF electromagnetic fields. The results presented here indicate that the alkaline comet assay, as reliable biomarker of exposure, can be successfully applied in study of DNA damaging effects in microwave exposed subjects. The fact that the comet assay is a microdosimetric

Results of radiotherapy for cancer of head and neck region, 2

International Nuclear Information System (INIS)

Fujimura, Noriharu; Shinzato, Jintetsu; Watanabe, Keikichi; Habu, Kenjiro; Hirayama, Haruyuki

1988-01-01

From 1967 through 1985, 86 patients with cancer of the paranasal sinuses and 6 patients with cancer of the nasal cavity (excluding sarcoma) were treated by irradiation at the Department of Radiology, Kumamoto National Hospital. The mean age was 60.7. The rate of men to women was 1.2 : 1. The results were as follows ; 1) Fifty-nine patients (51 cases of maxillary sinus carcinoma, 4 of ethmoid sinus carcinoma, and 4 of cancer of the nasal cavity) were treated with antrostomy followed by radiotherapy and regional arterial infusion of 5-fluorouracil alone or a combination of 5-fluorouracil and bleomycin. In 11 cases of these, salvage with total maxillectomy was performed and 10 % of which were controlled for more than five years. In 9 cases of these, no case was salvaged with radiotherapy. An overall five-year survival rate was 32 %. 2) The survival rate of the postoperative irradiation (11 cases of maxillary sinus carcinoma, 1 of cancer of the nasal cavity) was 42 % at 2 and 4 years after the operations. 3) Twelve patients with cancer of the paranasal sinuses (11 cases of maxillary sinus carcinoma, 1 of ethmoid sinus carcinoma) survived more than five years. All of them were irradiated curatively with doses more than 40 Gy. In our series, there was no difference in long-term survival between 5-fluorouracil alone and a combination of 5-fluorouracil and bleomycin. (author)

Results of radiotherapy for cancer of head and neck region, 2. Cancer of the nasal cavity and paranasal sinuses

Energy Technology Data Exchange (ETDEWEB)

Fujimura, Noriharu; Shinzato, Jintetsu; Watanabe, Keikichi; Habu, Kenjiro; Hirayama, Haruyuki

1988-04-01

From 1967 through 1985, 86 patients with cancer of the paranasal sinuses and 6 patients with cancer of the nasal cavity (excluding sarcoma) were treated by irradiation at the Department of Radiology, Kumamoto National Hospital. The mean age was 60.7. The rate of men to women was 1.2 : 1. The results were as follows ; 1) Fifty-nine patients (51 cases of maxillary sinus carcinoma, 4 of ethmoid sinus carcinoma, and 4 of cancer of the nasal cavity) were treated with antrostomy followed by radiotherapy and regional arterial infusion of 5-fluorouracil alone or a combination of 5-fluorouracil and bleomycin. In 11 cases of these, salvage with total maxillectomy was performed and 10 % of which were controlled for more than five years. In 9 cases of these, no case was salvaged with radiotherapy. An overall five-year survival rate was 32 %. 2) The survival rate of the postoperative irradiation (11 cases of maxillary sinus carcinoma, 1 of cancer of the nasal cavity) was 42 % at 2 and 4 years after the operations. 3) Twelve patients with cancer of the paranasal sinuses (11 cases of maxillary sinus carcinoma, 1 of ethmoid sinus carcinoma) survived more than five years. All of them were irradiated curatively with doses more than 40 Gy. In our series, there was no difference in long-term survival between 5-fluorouracil alone and a combination of 5-fluorouracil and bleomycin.

Impaired diversity of the lung microbiome predicts progression of idiopathic pulmonary fibrosis.

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Takahashi, Youhei; Saito, Atsushi; Chiba, Hirofumi; Kuronuma, Koji; Ikeda, Kimiyuki; Kobayashi, Tomofumi; Ariki, Shigeru; Takahashi, Motoko; Sasaki, Yasushi; Takahashi, Hiroki

2018-02-27

Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe form of idiopathic interstitial pneumonias. Although IPF has not been thought to be associated with bacterial communities, recent papers reported the possible role of microbiome composition in IPF. The roles of microbiomes in respiratory functions and as clinical biomarkers for IPF remain unknown. In this study, we aim to identify the relationship between the microbial environment in the lung and clinical findings. Thirty-four subjects diagnosed with IPF were included in this analysis. The 16S rDNA was purified from bronchoalveolar lavage fluid obtained at the time of diagnosis and analyzed using next-generation sequencing techniques to characterize the bacterial communities. Furthermore, microbiomes from mice with bleomycin-induced lung fibrosis were analyzed. The most prevalent lung phyla were Firmicutes, Proteobacteria and Bacteroidetes. Decreased microbial diversity was found in patients with low forced vital capacity (FVC) and early mortality. Additionally, the diversity and relative abundance of Firmicutes, Streptococcaceae, and Veillonellaceae were significantly associated with FVC, 6-min walk distance, and serum surfactant protein D. Bleomycin-induced lung fibrosis resulted in decrease of diversity and alteration of microbiota in PCoA analysis. These results support the observations in human specimens. This study identified relationships between specific taxa in BALF and clinical findings, which were also supported by experiments in a mouse model. Our data suggest the possibility that loss of microbial diversity is associated with disease activities of IPF.

Male infertility in long-term survivors of pediatric cancer: A report from the Childhood Cancer Survivor Study

Science.gov (United States)

Wasilewski-Masker, K; Seidel, K D; Leisenring, W; Mertens, A C; Shnorhavorian, M; Ritenour, C W; Stovall, M; Green, D M; Sklar, C A; Armstrong, G T; Robison, L L; Meacham, L R

2014-01-01

Purpose The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors. Methods Within the Childhood Cancer Survivor Study, 1622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1622; 57.8%) and siblings (174/274; 63.5%) who tried to become pregnant. Relative risks (RR) and 95% confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided. Results Among those who provided self-report data, the prevalence of infertility was 46.0% in survivors versus 17.5% in siblings (RR=2.64, 95% CI 1.88-3.70, p infertility, 37% had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose score (AAD) ≥ 3 (RR= 2.13, 95% CI 1.69-2.68 for AAD ≥ 3 versus AADinfertility father their own children suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation. Implications for Cancer Survivors Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk. PMID:24711092

Male infertility in long-term survivors of pediatric cancer: a report from the childhood cancer survivor study.

Science.gov (United States)

Wasilewski-Masker, K; Seidel, K D; Leisenring, W; Mertens, A C; Shnorhavorian, M; Ritenour, C W; Stovall, M; Green, D M; Sklar, C A; Armstrong, G T; Robison, L L; Meacham, L R

2014-09-01

The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors. Within the Childhood Cancer Survivor Study, 1,622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1,622; 57.8 %) and siblings (174/274; 63.5 %) who tried to become pregnant. Relative risks (RR) and 95 % confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided. Among those who provided self-report data, the prevalence of infertility was 46.0 % in survivors versus 17.5 % in siblings (RR = 2.64, 95 % CI 1.88-3.70, p infertility, 37 % had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose (AAD) score ≥3 (RR = 2.13, 95 % CI 1.69-2.68 for AAD ≥3 versus AAD infertility father their own children, suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation. Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.

Serum Inter–α-Trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury

Science.gov (United States)

Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S.; Hollingsworth, John W.; Jiang, Dianhua; Lancaster, Lisa H.; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K.; Noble, Paul W.; Kimata, Koji; Schwartz, David A.

2008-01-01

Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-α-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627). PMID:18703791

[Suppressive Effects of Extract of Cedar Wood on Heat-induced Expression of Cellular Heat Shock Protein].

Science.gov (United States)

Miyakoshi, Junji; Matsubara, Eri; Narita, Eijiro; Koyama, Shin; Shimizu, Yoko; Kawai, Shuichi

2018-01-01

 In recent years, highly antimicrobial properties of cedar heartwood essential oil against the wood-rotting fungi and pathogenic fungi have been reported in several papers. Antimicrobial properties against oral bacteria by hinokitiol contained in Thujopsis have been also extensively studied. The relation of naturally derived components and human immune system has been studied in some previous papers. In the present study, we focused on Japanese cedar, which has the widest artificial afforestation site in the country among various tree species. Extract oil was obtained from mixture of sapwood and heartwood of about 40-year cedar grown in Oguni, Kumamoto, Japan. We examined the influence of extract components from Japanese cedar woods on the expression of heat shock protein 70 (Hsp70) during heating, and on the micronucleus formation induced by the treatment of bleomycin as a DNA damaging agent. Cell lines used in this study were human fetal glial cells (SVGp12) and human glioma cells (MO54). Remarkable suppression of the Hsp70 expression induced by heating at 43°C was detected by the treatment of cedar extract in both SVGp12 and MO54 cells. We also found that cedar extract had an inhibitory tendency to reduce the micronucleus formation induced by bleomycin. From these results, the extract components from Japanese cedar woods would have an inhibitory effect of the stress response as a suppression of the heat-induced Hsp70 expression, and might have a reductive effect on carcinogenicity.

Non-Hodgkin's lymphomas in Turkey: eighteen years' experience at the Hacettepe University.

Science.gov (United States)

Barista, I; Tekuzman, G; Firat, D; Baltali, E; Kansu, E; Kars, A; Ozisik, Y; Ruacan, S; Uzunalimoğlu, B; Karaağaoğlu, E

1994-12-01

In this retrospective study, 470 patients with non-Hodgkin's lymphoma (NHL) who had been followed in the Hacettepe University Medical Oncology Department between 1973 and 1990, were evaluated to establish their epidemiologic, clinical and therapeutic characteristics. Out of 470 patients, 302 (62.2%) were male and 168 (37.8%) were female. The ages ranged from 16 to 85, with a median of 44 years. Constitutional symptoms were present in 46.4% of the patients. According to the Working Formulation, low, intermediate, and high-grade lymphomas comprised 33.4%, 54.9%, and 12.7%, respectively. The most common extranodal presentation was gastrointestinal. The chemotherapy regimens most commonly used were CVP (cyclophosphamide, vincristine, prednisone), BCNOP (bleomycin, cyclophosphamide, mitoxantrone, vincristine, prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin). The response rates and the survival figures attained with these regimens were not statistically significantly different (P > 0.05). In the Cox multivariate model, pathologic grade, leukopenia, responsiveness to chemotherapy, bone marrow involvement and age were the important factors influencing the disease-free survival, while responsiveness to chemotherapy, age, presence of constitutional symptoms, pathologic grade, extranodal presentation and stage were the important factors influencing the overall survival. The distribution of NHL according to grade and stage was similar to that in western societies, while constitutional symptoms and lymphomas of the small intestine including immunoproliferative small intestinal disease were more common in Turkey.

Non‐Hodgkin's Lymphomas in Turkey: Eighteen Years’Experience at the Hacettepe University

Science.gov (United States)

Barista, Ibrahim; Tekuzman, Gülten; Firat, Dinçer; Baltali, Esmen; Kansu, Emin; Kars, Ayse; Özisik, Yavuz; Ruacan, Sevket; Uzunalimoglu, Bedri; Karaagaoglu, Ergun

1994-01-01

In this retrospective study, 470 patients with non‐Hodgkin's lymphoma (NHL) who had been followed in the Hacettepe University Medical Oncology Department between 1973 and 1990, were evaluated to establish their epidemiologic, clinical and therapeutic characteristics. Out of 470 patients, 302 (62.2%) were male and 168 (37.8%) were female. The ages ranged from 16 to 85, with a median of 44 years. Constitutional symptoms were present in 46.4% of the patients. According to the Working Formulation, low, intermediate, and high‐grade lymphomas comprised 33.4%, 54.9%, and 12.7%, respectively. The most common extranodal presentation was gastrointestinal. The chemotherapy regimens most commonly used were CVP (cyclophosphamide, vincristine, prednisone), BCNOP (bleomycin, cyclophosphamide, mitoxantrone, vincristine, prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and CHOP‐Bleo (cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin). The response rates and the survival figures attained with these regimens were not statistically significantly different (P > 0.05). In the Cox multivariate model, pathologic grade, leukopenia, responsiveness to chemotherapy, bone marrow involvement and age were the important factors influencing the disease‐free survival, while responsiveness to chemotherapy, age, presence of constitutional symptoms, pathologic grade, extranodal presentation and stage were the important factors influencing the overall survival. The distribution of NHL according to grade and stage was similar to that in western societies, while constitutional symptoms and lymphomas of the small intestine including immunoproliferative small intestinal disease were more common in Turkey. PMID:7531679

Influence of some radioprotective and radiosensitizing compounds on the replicative and repair induced DNA synthesis of rats spleen cells in vitro

International Nuclear Information System (INIS)

Goette, A.

1982-01-01

The effect of cysteine, dithiothreitol, N-ethylmaleimide, cytosinearabinoside, ethidiumbromide, bleomycine and diethyldithiocarbamate on the replicative and repair induced DNA synthesis in vitro was tested by using rats spleen cells. Besides the incorporation of a labeled DNA precursor (TdR- 3 H) the sedimentation of DNA in sucrose gradients was inquired. With respect to the DNA synthesis an uniform mechanism of action for the radioprotective substances can't be seen. Thymocytes and spleen cells seem to possess different systems of repair; this may be an explanation for their different sensibility against ionizing radiation. (orig./MG) [de

Multiple brain metastases - current management and perspectives for treatment with electrochemotherapy

DEFF Research Database (Denmark)

Linnert, Mette; Iversen, Helle Klingenberg; Gehl, Julie

2012-01-01

BACKGROUND: Due to the advanced oncological treatments of cancer, an overall increase in cancer incidence, and better diagnostic tools, the incidence of brain metastases is on the rise. This review addresses the current treatment options for patients with multiple brain metastases, presenting...... of the chemotherapeutic drug bleomycin by 300 times. Preclinical data are promising and the first patient has been treated in an ongoing clinical trial for patients with brain metastases. Perspectives for ECT in the brain include treatment of primary and secondary brain tumors as well as soft tissue metastases elsewhere....

Effects of the association of chemotherapy and radiotherapy on normal mouse skin

International Nuclear Information System (INIS)

Guigon, M.; Frindel, E.; Tubiana, M.; Hewitt, J.

1978-01-01

The effects of an association of chemotherapy and radiotherapy on the skin of mice were studied. The following drugs were tested; hydroxyurea, Methotrexate, and Bleomycin; they were injected at various times before irradiation. When hydroxyurea was injected 15 min before irradiation, the early and late cutaneous reactions were significantly lower than with irradiation alone. This protective effect corresponds to about 500 rad for an irradiation dose of 2500 rad. In the other protocols, we observed either no increase of the effect as a result of adjuvant chemotherapy (Methotrexate) or slightly increased reactions

Elektrokemoterapi til behandling af kutane metastaser

DEFF Research Database (Denmark)

Falk, Hanne; Matthiessen, Louise Wichmann; Dahlstrøm, Karin

2015-01-01

Cutaneous metastases occur in up to 9% of all patients with cancer and may cause discomfort and stigmatization. Electrochemotherapy is a local treatment using electric pulses to permeabilize cell membranes, enabling chemotherapy, such as bleomycin, to enter the cells and increase the cytotoxic...... effect by at least 300-fold. Electrochemotherapy is an efficient, once only treatment for cutaneous metastases with an objective response of 62-99%. Electrochemotherapy can reduce discomfort such as ulceration, oozing, bleeding and pain. Adverse events depend on the size of treatment area, but are very...

Assessing chemical mutagens: the risk to humans

International Nuclear Information System (INIS)

Brewen, J.G.

1978-01-01

Some topics discussed are as follows: chromosomal aberrations induced by x radiation, tritiated thymidine, maleic hydrazide, and nitrogen mustard; removal of pyrimidine dimers by photoreactivation in amphibian cells following uv radiation; effects of 4-nitroquinoline-oxide on leukocytes from XP and normal patients; DNA as a target for alkylating agents; sensitivity of spermatogonia to chemical mutagens; chromosomal aberrations induced by 8-ethoxycaffeine, methoxycaffeine, cytosine arabinoside, streptonigrin, bleomycin, and phleomycin; effects of MMS and triethylenemelamine on germ cells; and use of chromosomal aberrations for improving risk estimates for ionizing radiation

Theoretical, clinical and pharmacokinetic aspects of cancer chemotherapy administered by continuous infusion

International Nuclear Information System (INIS)

Sikic, B.I.

1986-01-01

This chapter reviews some of the theoretical and empirical aspects of the administration of anti-cancer drugs by continuous intravenous infusion in conjunction with radiation therapy. The variables contributing to schedule dependence of anti-cancer drugs are discussed. A table shows the improved therapeutic index of Bleomycin by continuous infusion in mice. The use of Cytarabine, a pyrimidine anti-metabolite which kills cells during S-phase or DNA synthesis, is examined. Fluorouracil and Doxorubicin are examined and several other drugs including vincristine, vinblastine, etoposide, and cisplatin are discussed

Results of radiotherapy with and without chemotherapy for esophageal cancer

International Nuclear Information System (INIS)

Hada, Yoshihiro

1986-01-01

From 1975 to 1983, a total of 51 cases of esophageal cancer with T2 ∼ T3 in TNM classification, were treated by radiotherapy alone or combined chemotherapy. All 51 patients received total dose of 60 ∼ 70 GY for 6 ∼ 8 weeks and 20 out of 51 were treated by radiotherapy plus chemotherapy (5FU or UFT and/or bleomycin or pepleomycin). The 2-year-survival rate was slightly better in patients treated by radiotherapy plus chemotherapy than in patients treated by radiotherapy alone, but this difference was not significant. (author)

Combined regional chemotherapy and radiation therapy in the treatment of epidermoid carcinoma in the oro-facial region

Energy Technology Data Exchange (ETDEWEB)

Danko, J; Satko, I [Komenskeho Univ., Bratislava (Czechoslovakia). Lekarska Fakulta; Durkovsky, J [Institute of Clinical Oncology, Bratislava (Czechoslovakia)

1979-01-01

Treatment was studied of oro-facial epidermoid carcinoma by combined chemo- and radiotherapy and eventual surgery. Cytostatic drugs were applied intraarterially. After a monocytostatic treatment trial with Methotrexate (MTX), a combined cytostatic program was developed alternating two cytostatic drugs, viz., MTX and Bleomycin (BLM). The usefulness of chemotherapy and its inclusion in the treatment of epidermoid carcinoma in the oro-facial region was found justified for combined therapy. The selected intraarterial administration, however, is not suitable for routine application. For this reason, the combination irradiation or surgical therapy with chemotherapy was adopted.

High endogenous activated protein C levels attenuates bleomycin-induced pulmonary fibrosis

NARCIS (Netherlands)

Lin, Cong; von der Thüsen, Jan; Isermann, Berend; Weiler, Hartmut; van der Poll, Tom; Borensztajn, Keren; Spek, Chris A.

2016-01-01

Coagulation activation accompanied by reduced anticoagulant activity is a key characteristic of patients with idiopathic pulmonary fibrosis (IPF). Although the importance of coagulation activation in IPF is well studied, the potential relevance of endogenous anticoagulant activity in IPF progression

Indium labelled bleomycin (111In-BLM) as a tumor localizing agent

International Nuclear Information System (INIS)

Akisada, Masayoshi; Hayashi, Sanshin.

1976-01-01

Both fundamental and clinical studies of 111 In-BLM were performed. The in vivo stability of the complex was ascertained by thin-layer-chromatography of urine. The blood clearance, ratio of 111 In-BLM in plasma to that in whole blood, and cumulative excretion curves of urine and stool were studied. The blood clearance curve showed that the first half time was 16 minutes and that more than 90% of the administered activity was cleared from the circulating blood in two days. Ratios of plasma activity to the whole blood was almost constant 100 hours after injection. Urinary and fecal excretion showed that 80% of the administered activity was excreted in 24 hours, mainly in the urine (less than 1.0% in the feces). There appeared to be an inverse relationship between urinary and fecal excretion. The effective and biological half time of the liver, heart, bone marrow at the level of L 4 and spleen were obtained by counting the activity externally using probes located at each corresponding site. The activity in the bone marrow and heart had a rather short effective half time. The clinical usefulness of 111 In-BLM as a tumor imaging agent was evaluated in 19 patients, with 12 malignant and 7 benign lesions in Mitsui Memorial Hospital. Each study with 111 In-BLM was combined with 67 Ga-citrate scintigrams. A new method for comparative analyses of two radiopharmaceuticals without using a computer is reported here since comparative evaluation by the naked eye was difficult to make. Clinical experience to date seems to be encouraging to the detection of malignancy, although some benign tumors showed marked uptake of 111 In-BLM. (Evans, J.)

Region-specific role for Pten in maintenance of epithelial phenotype and integrity

Science.gov (United States)

Flodby, Per; Sunohara, Mitsuhiro; Castillo, Dan R.; McConnell, Alicia M.; Krishnaveni, Manda S.; Banfalvi, Agnes; Li, Min; Stripp, Barry; Zhou, Beiyun; Crandall, Edward D.; Minoo, Parviz

2017-01-01

Previous studies have demonstrated resistance to naphthalene-induced injury in proximal airways of mice with lung epithelial-specific deletion of the tumor-suppressor gene Pten, attributed to increased proliferation of airway progenitors. We tested effects of Pten loss following bleomycin injury, a model typically used to study distal lung epithelial injury, in conditional PtenSFTPC-cre knockout mice. Pten-deficient airway epithelium exhibited marked hyperplasia, particularly in small bronchioles and at bronchoalveolar duct junctions, with reduced E-cadherin and β-catenin expression between cells toward the luminal aspect of the hyperplastic epithelium. Bronchiolar epithelial and alveolar epithelial type II (AT2) cells in PtenSFTPC-cre mice showed decreased expression of epithelial markers and increased expression of mesenchymal markers, suggesting at least partial epithelial-mesenchymal transition at baseline. Surprisingly, and in contrast to previous studies, mutant mice were exquisitely sensitive to bleomycin, manifesting rapid weight loss, respiratory distress, increased early mortality (by day 5), and reduced dynamic lung compliance. This was accompanied by sloughing of the hyperplastic airway epithelium with occlusion of small bronchioles by cellular debris, without evidence of increased parenchymal lung injury. Increased airway epithelial cell apoptosis due to loss of antioxidant defenses, reflected by decreased expression of superoxide dismutase 3, in combination with deficient intercellular adhesion, likely predisposed to airway sloughing in knockout mice. These findings demonstrate an important role for Pten in maintenance of airway epithelial phenotype integrity and indicate that responses to Pten deletion in respiratory epithelium following acute lung injury are highly context-dependent and region-specific. PMID:27864284

Interferon-β lipofection I. Increased efficacy of chemotherapeutic drugs on human tumor cells derived monolayers and spheroids.

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Villaverde, M S; Gil-Cardeza, M L; Glikin, G C; Finocchiaro, L M E

2012-07-01

We evaluated the effect of hIFNβ gene transfer alone or in combination with different antineoplastic drugs commonly used in cancer treatment. Five human tumor-derived cell lines were cultured as monolayers and spheroids. Four cell lines (Ewing sarcomas EW7 and COH, melanoma M8 and mammary carcinoma MCF-7) were sensitive to hIFNβ gene lipofection. Although this effect appeared in both culture configurations, spheroids showed a relative multicellular resistance (insensitive colon carcinoma HT-29 excluded). EW7 and M8 hIFNβ-expressing cells were exposed to different concentrations of bleomycin, bortezomib, carboplatin, doxorubicin, etoposide, methotrexate, paclitaxel and vincristine in both configuration models. In chemotherapy-sensitive EW7 monolayers, the combination of hIFNβ gene and antineoplastic drugs displayed only additive or counteractive (methotrexate) effects, suggesting that cytotoxic mechanisms triggered by hIFNβ gene lipofection could be saturating the signaling pathways. Conversely, in chemotherapy-resistant EW7 spheroids or M8 cells, the combination of hIFNβ with drugs that mainly operate at the genotoxic level (doxorubicin, methotrexate and paclitaxel) presented only additive effects. However, drugs that also increase pro-oxidant species can complement the antitumor efficacy of the hIFNβ gene and clearly caused potentiated effects (bleomycin, bortezomib, carboplatin, etoposide and vincristine). The great bystander effect induced by hIFNβ gene lipofection could be among the main causes of its effectiveness, because only 1 or 2% of EW7 or M8 hIFNβ-expressing cells killed more than 60 or 80% of cell population, respectively.

Cross-sectional study comparing different therapeutic modalities for cystic lymphangiomas in children

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Hugo de Oliveira Olímpio

2014-08-01

Full Text Available OBJECTIVE: Here, we describe our experience with different therapeutic modalities used to treat cystic lymphangiomas in children in our hospital, including single therapy with OK-432, bleomycin and surgery, and a combination of the three modalities. METHODS: We performed a retrospective, cross-sectional study including patients treated from 1998 to 2011. The effects on macrocystic lymphangiomas and adverse reactions were evaluated. Twenty-nine children with cystic lymphangiomas without any previous treatment were included. Under general anesthesia, patients given sclerosing agents underwent puncture of the lesion (guided by ultrasound when necessary and complete aspiration of the intralesional liquid. The patients were evaluated with ultrasound and clinical examinations for a maximum follow-up time of 4 years. RESULTS: The proportions of patients considered cured after the first therapeutic approach were 44% in the surgery group, 29% in the bleomycin group and 31% in the OK-432 group. These proportions were not significantly different. Sequential treatment increased the rates of curative results to 71%, 74% and 44%, respectively, after the final treatment, which in our case was approximately 1.5 applications per patient. CONCLUSION: The results of this study indicate that most patients with cystic lymphangiomas do not show complete resolution after the initial therapy, regardless of whether the therapy is surgical or involves the use of sclerosing agents. To achieve complete resolution of the lesions, either multiple operations or a combination of surgery and sclerotherapy must be used and should be tailored to the characteristics of each patient.

Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice*

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Fan, Ming-Hui; Zhu, Qiang; Li, Hui-Hua; Ra, Hyun-Jeong; Majumdar, Sonali; Gulick, Dexter L.; Jerome, Jacob A.; Madsen, Daniel H.; Christofidou-Solomidou, Melpo; Speicher, David W.; Bachovchin, William W.; Feghali-Bostwick, Carol; Puré, Ellen

2016-01-01

Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2–4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent with in vitro studies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung. PMID:26663085

Experimental study on combination of chemotherapy and radiotherapy

International Nuclear Information System (INIS)

Tanaka, Juichi

1986-01-01

Recently, by applying multidrug therapy using cisplatin and bleomycin to the treatment of head and neck cancer, the response rate of chemotherapy has been markedly increased and thus, chemotherapy has taken an important part in the treatment of head and neck cancer. In this paper a clinical application of chemotherapy in combination with radiotherapy was evaluated from the point of the cure rate and also preservation of the structures and the functions of the head and neck region. In order to test the advantage or usefulness of initial chemotherapy followed by radiotherapy (= pre-radiation chemotherapy), the experimental study on combination of chemotherapy and radiotherapy was designed by using ICR mice and Ehrlich solid carcinoma. Cisplatin and peplomycin, a newly developed derivative of bleomycin, were used as chemotherapeutic agents. Tumor growth delay rate was chosen as a parameter to indicate the effectiveness. Results obtained are as follows. 1. Combination chemotherapy of cisplatin and peplomycin was more effective than each single agent on Ehrlich solid carcinoma. Synergistic effect was obtained by higher dose. So, the combination of cisplatin and peplomycin was proved to be eligible for pre-radiation chemotherapy. 2. Synergistic effect of chemotherapy and radiotherapy was observed when chemotherapy was used prior to radiotherapy on Ehrlich solid carcinoma. 3. Even their additional effect was not recognized when radiotherapy preceded to chemotherapy on Ehrlich solid carcinoma. 4. No severe toxic effect was seen in the mice. The experimental results made it clear that pre-radiation chemotherapy is beneficial to the treatment of head and neck cancer. (author)

Evidence-Based Scar Management: How to Improve Results with Technique and Technology.

Science.gov (United States)

Khansa, Ibrahim; Harrison, Bridget; Janis, Jeffrey E

2016-09-01

Scars represent the visible sequelae of trauma, injury, burn, or surgery. They may induce distress in the patient because of their aesthetically unpleasant appearance, especially if they are excessively raised, depressed, wide, or erythematous. They may also cause the patient symptoms of pain, tightness, and pruritus. Numerous products are marketed for scar prevention or improvement, but their efficacy is unclear. A literature review of high-level studies analyzing methods to prevent or improve hypertrophic scars, keloids, and striae distensae was performed. The evidence from these articles was analyzed to generate recommendations. Each intervention's effectiveness at preventing or reducing scars was rated as none, low, or high, depending on the strength of the evidence for that intervention. For the prevention of hypertrophic scars, silicone, tension reduction, and wound edge eversion seem to have high efficacy, whereas onion extract, pulsed-dye laser, pressure garments, and scar massage have low efficacy. For the treatment of existing hypertrophic scars, silicone, pulsed-dye laser, CO2 laser, corticosteroids, 5-fluorouracil, bleomycin, and scar massage have high efficacy, whereas onion extract and fat grafting seem to have low efficacy. For keloid scars, effective adjuncts to excision include corticosteroids, mitomycin C, bleomycin, and radiation therapy. No intervention seems to have significant efficacy in the prevention or treatment of striae distensae. Although scars can never be completely eliminated in an adult, this article presents the most commonly used, evidence-based methods to improve the quality and symptoms of hypertrophic scars, as well as keloid scars and striae distensae.

Metastatic nasopharyngeal carcinoma: clinical study and therapeutic results of 95 cases

International Nuclear Information System (INIS)

Khanfir, A.; Frikha, M.; Ghorbel, A.; Drira, M.M.; Karray, H.; Daoud, J.

2006-01-01

Purpose. -- The objective of this retrospective study was to discuss the epidemio-clinical criteria and the therapeutic results of metastatic nasopharyngeal carcinoma. Patients and methods. - The current study concerned 95 patients with histologically proven nasopharyngeal carcinoma who were metastatic at diagnosis or who had developed late metastasis. We reviewed the epidemio-clinical records of all the patients. Patients were treated with chemotherapy (BEC regimen: bleomycin, epirubicin and cisplatin or PBF regimen: bleomycin, 5-fluorouracil and cisplatin) and radiotherapy of pauci metastatic localizations (single or double) or bone metastasis with high risk of compression or fracture ±associated with locoregional radiotherapy for patients who were metastatic at diagnosis. Response was assessed according to the WHO criteria. Overall survival was calculated according to the Kaplan-Meier method. A long-term disease-free survival was defined from 36 months. Results. - There were 34 patients who were metastatic at diagnosis and 61 patients who had developed late metastasis. The mean age was 41.5 years (sex-ratio: 3.1). Bone metastases were the most frequent (83%). Objective and complete response rates were respectively 75% and 70%, and 32% and 16% for BEC and PBF regimens. Twenty-five patients received radiotherapy for pauci metastatic localizations, among whom 19 patients who were metastatic at diagnosis received locoregional irradiation. The overall survival probability was of 15% for three years. Eleven patients were long survivors (extremes: 36 and 134 months). Conclusion. - Therapeutic results were comparable to those reported in other series using platin combination chemotherapy. Radiotherapy of metastasis yielded to long-term survival. (authors)

IL-1 and IL-23 mediate early IL-17A production in pulmonary inflammation leading to late fibrosis.

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Paméla Gasse

Full Text Available BACKGROUND: Idiopathic pulmonary fibrosis is a devastating as yet untreatable disease. We demonstrated recently the predominant role of the NLRP3 inflammasome activation and IL-1β expression in the establishment of pulmonary inflammation and fibrosis in mice. METHODS: The contribution of IL-23 or IL-17 in pulmonary inflammation and fibrosis was assessed using the bleomycin model in deficient mice. RESULTS: We show that bleomycin or IL-1β-induced lung injury leads to increased expression of early IL-23p19, and IL-17A or IL-17F expression. Early IL-23p19 and IL-17A, but not IL-17F, and IL-17RA signaling are required for inflammatory response to BLM as shown with gene deficient mice or mice treated with neutralizing antibodies. Using FACS analysis, we show a very early IL-17A and IL-17F expression by RORγt(+ γδ T cells and to a lesser extent by CD4αβ(+ T cells, but not by iNKT cells, 24 hrs after BLM administration. Moreover, IL-23p19 and IL-17A expressions or IL-17RA signaling are necessary to pulmonary TGF-β1 production, collagen deposition and evolution to fibrosis. CONCLUSIONS: Our findings demonstrate the existence of an early IL-1β-IL-23-IL-17A axis leading to pulmonary inflammation and fibrosis and identify innate IL-23 and IL-17A as interesting drug targets for IL-1β driven lung pathology.

Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity.

Science.gov (United States)

Sato, Seidai; Shinohara, Shintaro; Hayashi, Shinya; Morizumi, Shun; Abe, Shuichi; Okazaki, Hiroyasu; Chen, Yanjuan; Goto, Hisatsugu; Aono, Yoshinori; Ogawa, Hirohisa; Koyama, Kazuya; Nishimura, Haruka; Kawano, Hiroshi; Toyoda, Yuko; Uehara, Hisanori; Nishioka, Yasuhiko

2017-09-15

Nintedanib, a tyrosine kinase inhibitor that is specific for platelet-derived growth factor receptors (PDGFR), fibroblast growth factor receptors (FGFR), and vascular endothelial growth factor receptors (VEGFR), has recently been approved for idiopathic pulmonary fibrosis. Fibrocytes are bone marrow-derived progenitor cells that produce growth factors and contribute to fibrogenesis in the lungs. However, the effects of nintedanib on the functions of fibrocytes remain unclear. Human monocytes were isolated from the peripheral blood of healthy volunteers. The expression of growth factors and their receptors in fibrocytes was analyzed using ELISA and Western blotting. The effects of nintedanib on the ability of fibrocytes to stimulate lung fibroblasts were examined in terms of their proliferation. The direct effects of nintedanib on the differentiation and migration of fibrocytes were also assessed. We investigated whether nintedanib affected the accumulation of fibrocytes in mouse lungs treated with bleomycin. Human fibrocytes produced PDGF, FGF2, and VEGF-A. Nintedanib and specific inhibitors for each growth factor receptor significantly inhibited the proliferation of lung fibroblasts stimulated by the supernatant of fibrocytes. Nintedanib inhibited the migration and differentiation of fibrocytes induced by growth factors in vitro. The number of fibrocytes in the bleomycin-induced lung fibrosis model was reduced by the administration of nintedanib, and this was associated with anti-fibrotic effects. These results support the role of fibrocytes as producers of and responders to growth factors, and suggest that the anti-fibrotic effects of nintedanib are at least partly mediated by suppression of fibrocyte function.

Histopathologic findings of radiotherapy combined with chemotherapy on head and neck cancer

International Nuclear Information System (INIS)

Sakaino, Koji; Matsumoto, Mitsuomi; Satake, Bunsuke; Takahashi, Keiichi; Makino, Sotaro

1979-01-01

We studied in this series about histopathologic changes in radiotherapy of squamous cell carcinoma of head and neck. Then we recognized that radiotherapy combined with chemotherapy is useful for radioresistant squamous cell carcinoma. In this series, we studied about cancer of the tongue as one of the keratinizing squamous cell carcinoma and used Bleomycin as a chemotherapeutic drug. We commented as follows: 1. Radiotherapy combined with chemotherapy had benefit decreasing of a period for radium therapy. 2. Severs complication was not occurred in this series, then this combined therapy was useful for aged or handicapped patient. (author)

Immortalization of Werner syndrome and progeria fibroblasts

International Nuclear Information System (INIS)

Saito, H.; Moses, R.E.

1991-01-01

Human fibroblast cells from two different progeroid syndromes, Werner syndrome (WS) and progeria, were established as immortalized cell lines by transfection with plasmid DNA containing the SV40 early region. The lineage of each immortalized cell line was confirmed by VNTR analysis. Each of the immortalized cell lines maintained its original phenotype of slow growth. DNA repair ability of these cells was also studied by measuring sensitivity to killing by uv or the DNA-damaging drugs methyl methansulfonate, bleomycin, and cis-dichlorodiamine platinum. The results showed that both WS and progeria cells have normal sensitivity to these agents

Radiation Interaction with Therapeutic Drugs and Cell Membranes

International Nuclear Information System (INIS)

Martin, Diana I.; Manaila, Elena N.; Matei, Constantin I.; Iacob, Nicusor I.; Ighigeanu, Daniel I.; Craciun, Gabriela D.; Moisescu, Mihaela I.; Savopol, Tudor D.; Kovacs, Eugenia A.; Cinca, Sabin A.; Margaritescu, Irina D.

2007-01-01

This transient permeabilized state of the cell membrane, named the 'cell electroporation' (CE) can be used to increase cells uptake of drugs that do not readily pass cell membrane, thus enabling their cytotoxicity. The anticancer drugs, such as bleomycin (BL) and cisplatin, are the most candidates for the combined use with ionizing and non-ionizing radiation fields. The methods and installations for the cell electroporation by electron beam (EB) and microwave (MW) irradiation are presented. The viability tests of the human leukocytes under EB and MW exposure with/without the BL in the cell cultures are discussed

Survival and Toxicity in Patients With Disseminated Germ CellCancer Aged 40 Years and Older

DEFF Research Database (Denmark)

Thomsen, Frederik B; Bandak, Mikkel; Thomsen, Maria F

2014-01-01

, etoposide and cisplatin (BEP). A control-group of 135 patients aged 18-35 years was randomly selected matched on year of BEP treatment. Cumulated doses of BEP as well as bone marrow toxicity, renal- and lung functions were recorded before, during and after termination of treatment. All patients were...... followed until death or October 1, 2011. RESULTS: The cumulated doses of BEP were comparable between the two groups, however, more patients aged ≥40 years were reduced in bleomycin doses based on a decrease in carbon monoxide diffusion capacity corrected for haemoglobin (P = 0.03). No differences between...

Preclinical validation of electrochemotherapy as an effective treatment for brain tumors

DEFF Research Database (Denmark)

Agerholm-Larsen, Birgit; Iversen, Helle K; Ibsen, Per

2011-01-01

treatment. Bleomycin was injected intracranially into male rats inoculated with rat glia-derived tumor cells 2 weeks before the application of the electrical field (32 pulses, 100 V, 0.1 ms, and 1 Hz). In this model, where presence of tumor was confirmed by magnetic resonance imaging (MRI) before treatment...... to the treated area, which MRI and histology showed to contain a fluid-filled cavity. In a long-range survival study, treatment side effects seemed to be minimal, with normal rat behavior observed after electrochemotherapy. Our findings suggest that electrochemotherapy may offer a safe and effective new tool...

Radiotherapy of esophageal cancer in combination with chemotherapy

International Nuclear Information System (INIS)

Jinnouchi, Shoshi; Koga, Kenji; Nishikawa, Kiyoshi; Kihara, Yasushi; Kusuhara, Toshiyuki; Watanabe, Katuji

1983-01-01

The significance of combination of chemotherapy in radiotherapy for esophageal cancer was evaluated in 32 patients. They were irradiated routinely in 5 times a weeks with a fraction dose of 200 rad by 10MV-X-ray linear accelerator. Combined drugs consist of Bleomycin or Pepleomycin in two-third and 5FU or FT-207 in one-third. There was statistically no significance between the results of radiation alone and combined chemotherapy, and the improvement of survival rate could not be obtained by combining chemotherapy. Some discussion on the causes of this unimprovement were made. (author)

Pediatric Hodgkin Lymphoma Treated at Cancer Institute, Chennai, India: Long-Term Outcome

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Dhanushkodi, Manikandan; Ganesan, Trivadi S.; Ganesan, Prasanth; Sundersingh, Shirley; Selvaluxmy, Ganesarajah; Swaminathan, Rajaraman; Rama, Ranganathan; Sagar, Tenali Gnana

2017-01-01

Purpose Pediatric Hodgkin lymphoma (HL) is a highly curable malignancy. Outcomes for pediatric HL may vary between developed and developing countries for multiple reasons. This study was conducted to ascertain the outcomes of children with HL at our center and to identify risk factors for recurrent disease. Methods We analyzed the outcomes of 172 consecutive, previously untreated patients with pediatric HL presenting at our center from 2001 to 2010. Patients were treated with either adriamycin, bleomycin, vinblastine, and dacarbazine or adriamycin, bleomycin, vinblastine, cyclophosphamide, vincristine, prednisone, and procarbazine chemotherapy initially, and radiation to bulky sites or a single site of residual disease when appropriate. Results The median duration of follow-up was 77 months. The median age of the patients was 10 years; 127 (74%) of the 172 patients were male. The extent of disease was stage I and II in 59% of the patients. B symptoms were present in 32% of the patients, and 27% had bulky disease. The most common histologic subtype was mixed cellularity (45%). The 5-year overall survival (OS) and progression-free survival (PFS) of the entire cohort were 92.9% and 83.1%, respectively. The 5-year OS rates for patients with stage I, II, III, and IV were 96%, 94.7%, 84%, and 69.8%, respectively. On univariate analysis, advanced stage, response on interim radiologic assessment, and presence of B symptoms significantly predicted inferior PFS and OS. On multivariate analysis, only interim radiologic response significantly predicted PFS (P < .001) and OS (P < .001). Conclusion Overall, the outcomes of patients treated at our center are comparable to those observed in other centers in India and globally. PMID:29094094

Pediatric Hodgkin Lymphoma Treated at Cancer Institute, Chennai, India: Long-Term Outcome

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Venkatraman Radhakrishnan

2017-10-01

Full Text Available Purpose: Pediatric Hodgkin lymphoma (HL is a highly curable malignancy. Outcomes for pediatric HL may vary between developed and developing countries for multiple reasons. This study was conducted to ascertain the outcomes of children with HL at our center and to identify risk factors for recurrent disease. Methods: We analyzed the outcomes of 172 consecutive, previously untreated patients with pediatric HL presenting at our center from 2001 to 2010. Patients were treated with either adriamycin, bleomycin, vinblastine, and dacarbazine or adriamycin, bleomycin, vinblastine, cyclophosphamide, vincristine, prednisone, and procarbazine chemotherapy initially, and radiation to bulky sites or a single site of residual disease when appropriate. Results: The median duration of follow-up was 77 months. The median age of the patients was 10 years; 127 (74% of the 172 patients were male. The extent of disease was stage I and II in 59% of the patients. B symptoms were present in 32% of the patients, and 27% had bulky disease. The most common histologic subtype was mixed cellularity (45%. The 5-year overall survival (OS and progression-free survival (PFS of the entire cohort were 92.9% and 83.1%, respectively. The 5-year OS rates for patients with stage I, II, III, and IV were 96%, 94.7%, 84%, and 69.8%, respectively. On univariate analysis, advanced stage, response on interim radiologic assessment, and presence of B symptoms significantly predicted inferior PFS and OS. On multivariate analysis, only interim radiologic response significantly predicted PFS (P < .001 and OS (P < .001. Conclusion: Overall, the outcomes of patients treated at our center are comparable to those observed in other centers in India and globally.

Pyrrhocoricin, a proline-rich antimicrobial peptide derived from insect, inhibits the translation process in the cell-free Escherichia coli protein synthesis system.

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Taniguchi, Masayuki; Ochiai, Akihito; Kondo, Hiroshi; Fukuda, Shun; Ishiyama, Yohei; Saitoh, Eiichi; Kato, Tetsuo; Tanaka, Takaaki

2016-05-01

Previous studies have shown that pyrrhocoricin, a proline-rich antimicrobial peptide (PrAMP), killed sensitive species in a dose-dependent manner by specifically binding to DnaK. Here, on the basis of the finding that DnaK-deficient Escherichia coli strains are susceptible to PrAMPs, we used pyrrhocoricin to investigate internal targets other than DnaK. Using conventional antibiotics (bleomycin, streptomycin, and fosfomycin) that have known modes of action, first, we validated the availability of an assay using a cell-free rapid translation system (RTS), which is an in vitro protein synthesis system based on E. coli lysate, for evaluating inhibition of protein synthesis. We found that, similarly to bleomycin and streptomycin, pyrrhocoricin inhibited GFP synthesis in RTS in a concentration-dependent manner. In addition, blockage of transcription and translation steps in RTS was individually estimated using RT-PCR after gene expression to determine mRNA products and using sodium dodecyl sulfate-polyacrylamide gel electrophoresis to determine the amounts of GFP expressed from purified mRNA, respectively. The results demonstrated that this inhibition of GFP synthesis by pyrrhocoricin did not occur at the transcription step but rather at the translation step, in a manner similar to that of GFP synthesis by streptomycin, an inhibitor of the translation step by causing misreading of tRNA. These results suggest that RTS is a powerful assay system for determining if antimicrobial peptides inhibit protein synthesis and its transcription and/or translation steps. This is the first study to have shown that pyrrhocoricin inhibited protein synthesis by specifically repressing the translation step. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Nonpalpable testicular pure seminoma with elevated serum alpha-fetoprotein presenting with retroperitoneal metastasis: a case report.

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Iwatsuki, Shoichiro; Naiki, Taku; Kawai, Noriyasu; Etani, Toshiki; Iida, Keitaro; Ando, Ryosuke; Nagai, Takashi; Okada, Atsushi; Tozawa, Keiichi; Sugiyama, Yosuke; Yasui, Takahiro

2016-05-05

Patients with a primary pure seminoma in the testis who have elevated serum alpha-fetoprotein are rare and should be treated as patients with nonseminomatous germ cell tumors. However, nonpalpable testicular tumors in this condition have never been reported. We describe a case of nonpalpable pure testicular seminoma with elevated serum alpha-fetoprotein presenting retroperitoneal metastasis. A 29-year-old Asian man was referred to our hospital with right flank pain. Computed tomography showed a mass located between his aorta and inferior vena cava, but a testicular tumor was not detected. His serum levels of lactate dehydrogenase, alpha-fetoprotein, and DUPAN-2 were high. Although no tumor or nodule was palpable in his testis, ultrasonography revealed multiple low echoic lesions in his right testicular parenchyma. He was diagnosed with right testicular cancer with retroperitoneal lymph node metastasis and underwent right high orchiectomy. A pathological examination revealed pure seminoma and no nonseminomatous components were found in the specimen. Three courses of induction systemic chemotherapy (cisplatin, etoposide, and bleomycin) normalized his serum alpha-fetoprotein and DUPAN-2 levels. Three additional courses of chemotherapy (etoposide and bleomycin) were performed, and treatment was completed with laparoscopic retroperitoneal lymph node dissection. Pathology of the dissected specimen showed fibrous and necrotic tissue with no viable cells. He is alive without recurrence 54 months after orchiectomy. We report a case of pure testicular seminoma with elevated serum alpha-fetoprotein and DUPAN-2 presenting retroperitoneal metastasis. We recommend an ultrasound examination of bilateral testes when large retroperitoneal tumors are detected in young men, even if a mass is not palpable in the scrotum.

Downregulation of B-myb promotes senescence via the ROS-mediated p53/p21 pathway, in vascular endothelial cells.

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Zhou, Zhihui; Yin, Yanlin; Chang, Qun; Sun, Guanqun; Lin, Jiahui; Dai, Yalei

2017-04-01

To reveal whether B-myb is involved in preventing senescence of vascular endothelial cells, and if so, to identify possible mechanisms for it. C57/BL6 male mice and primary human aortic endothelial cells (HAECs) were used. Bleomycin was applied to induce stress-related premature senescence. B-myb knockdown was achieved using an siRNA technique and cell senescence was assessed using the senescence-associated β-galactosidase (SA-β-gal) assay. Intracellular reactive oxygen species (ROS) production was analysed using an ROS assay kit and cell proliferation was evaluated using KFluor488 EdU kit. Capillary tube network formation was determined by Matrigel assay. Expressions of mRNA and protein levels were detected by real-time PCR and western blotting. B-myb expression significantly decreased, while p53 and p21 expressions increased in the aortas of aged mice. This expression pattern was also found in replicative senescent HAECs and senescent HAECs induced by bleomycin. B-myb knockdown resulted in upregulation of p22 phox , ROS accumulation and cell senescence of HAECs. Downregulation of B-myb significantly inhibited cell proliferation and capillary tube network formation and activated the p53/p21 signalling pathway. Blocking ROS production or inhibiting p53 activation remarkably attenuated SA-β-gal activity and delayed cell senescence induced by B-myb-silencing. Downregulation of B-myb induced senescence by upregulation of p22 phox and activation of the ROS/p53/p21 pathway, in our vascular endothelial cells, suggesting that B-myb may be a novel candidate for regulating cell senescence to protect against endothelial senescence-related cardiovascular diseases. © 2016 John Wiley & Sons Ltd.

Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages.

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Redente, Elizabeth F; Keith, Rebecca C; Janssen, William; Henson, Peter M; Ortiz, Luis A; Downey, Gregory P; Bratton, Donna L; Riches, David W H

2014-04-01

Idiopathic pulmonary fibrosis (IPF) is a relentless, fibrotic parenchymal lung disease in which alternatively programmed macrophages produce profibrotic molecules that promote myofibroblast survival and collagen synthesis. Effective therapies to treat patients with IPF are lacking, and conventional therapy may be harmful. We tested the hypothesis that therapeutic lung delivery of the proinflammatory cytokine tumor necrosis factor (TNF)-α into wild-type fibrotic mice would reduce the profibrotic milieu and accelerate the resolution of established pulmonary fibrosis. Fibrosis was assessed in bleomycin-instilled wild-type and TNF-α(-/-) mice by measuring hydroxyproline levels, static compliance, and Masson's trichrome staining. Macrophage infiltration and programming status was assessed by flow cytometry of enzymatically digested lung and in situ immunostaining. Pulmonary delivery of TNF-α to wild-type mice with established pulmonary fibrosis was found to reduce their fibrotic burden, to improve lung function and architecture, and to reduce the number and programming status of profibrotic alternatively programmed macrophages. In contrast, fibrosis and alternative macrophage programming were prolonged in bleomycin-instilled TNF-α(-/-) mice. To address the role of the reduced numbers of alternatively programmed macrophages in the TNF-α-induced resolution of established pulmonary fibrosis, we conditionally depleted macrophages in MAFIA (MAcrophage Fas-Induced Apoptosis) mice. Conditional macrophage depletion phenocopied the resolution of established pulmonary fibrosis observed after therapeutic TNF-α delivery. Taken together, our results show for the first time that TNF-α is involved in the resolution of established pulmonary fibrosis via a mechanism involving reduced numbers and programming status of profibrotic macrophages. We speculate that pulmonary delivery of TNF-α or augmenting its signaling pathway represent a novel therapeutic strategy to resolve

The downregulation of microRNA let-7a contributes to the excessive expression of type I collagen in systemic and localized scleroderma.

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Makino, Katsunari; Jinnin, Masatoshi; Hirano, Ayaka; Yamane, Keitaro; Eto, Mitsuhiko; Kusano, Takamitsu; Honda, Noritoshi; Kajihara, Ikko; Makino, Takamitsu; Sakai, Keisuke; Masuguchi, Shinichi; Fukushima, Satoshi; Ihn, Hironobu

2013-04-15

Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3'-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.

CT appearance of amiodarone-induced pneumonitis

International Nuclear Information System (INIS)

Nicholson, A.A.; Hayward, C.

1989-01-01

Basal peripheral pleuroparenchymal opacities are described on CT of early cryptogenic fibrosing alveolitis, asbestosis and bleomycin pneumonitis. These diseases may be caused by free radical effects on phospholipid metabolism causing cell wall damage. Amiodarone hydrochloride alters phospholipid synthesis metabolically. Amiodarone pneumonitis might be expected to show similar CT appearances. Sixteen patients who have developed new respiratory symptoms while taking amiodarone have been scanned prone and supine and at inspiration and expiration by means of a scanner with 2-mm sections at 1-cm intervals. All have been previously healthy nonsmokers with no relevant occupational history. Previous chest radiographs have been normal. Results are presented

Lung Surfactant Protein D (SP-D) Response and Regulation During Acute and Chronic Lung Injury

DEFF Research Database (Denmark)

Gaunsbaek, Maria Quisgaard; Rasmussen, Karina Juhl; Beers, Michael F.

2013-01-01

in three murine models of lung injury, using a validated ELISA technology for estimation of SP-D levels. METHODS: Mice were exposed to lipopolysaccharide, bleomycin, or Pneumocystis carinii (Pc) and sacrificed at different time points. RESULTS: In lipopolysaccharide-challenged mice, the level of SP...... injury, with a sustained increment during chronic inflammation compared with acute inflammation. A quick upregulation of SP-D in serum in response to acute airway inflammation supports the notion that SP-D translocates from the airways into the vascular system, in favor of being synthesized systemically....... The study also confirms the concept of using increased SP-D serum levels as a biomarker of especially chronic airway inflammation....

S100A4 amplifies TGF-β-induced fibroblast activation in systemic sclerosis

DEFF Research Database (Denmark)

Tomcik, Michal; Palumbo-Zerr, Katrin; Zerr, Pawel

2015-01-01

(SSc). METHODS: The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4...... or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4(-/-) mice were protected from bleomycin-induced skin fibrosis with reduced dermal...

Burned-out seminoma revealed by solitary rib bone metastasis

Energy Technology Data Exchange (ETDEWEB)

Nishisho, Toshihiko; Miyagi, Ryo; Sairyo, Koichi [Tokushima University Graduate School, Department of Orthopedics, Institute of Biomedical Sciences, Tokushima-city, Tokushima (Japan); Sakaki, Mika [Saitama Medical University International Medical Center, Department of Pathology, Hidaka-city, Saitama (Japan); Takao, Shoichiro [Tokushima University Graduate School, Department of Radiology, Institute of Biomedical Sciences, Tokushima-city, Tokushima (Japan)

2017-10-15

Burned-out tumor is a rare phenomenon in which a testicular tumor regresses in the primary lesion and progresses in a metastatic lesion. We report the case of a 30-year-old male with burned-out seminoma revealed by open biopsy of solitary 10th rib bone metastasis. He underwent inguinal orchiectomy, which revealed hyalinization, indicating a spontaneously regressed testicular tumor. Chemotherapy for seminoma was administered in three cycles of bleomycin + etoposide + cisplatin therapy. The chemotherapy was effective, and wide resection of the rib was subsequently performed. No postoperative chemotherapy was performed, and there has been no evidence of recurrence for 3 years postoperatively. (orig.)

Radio-isotope uptake by tumours. Introduction to their clinical use

International Nuclear Information System (INIS)

Blanchon, P.

1975-01-01

Before each group of authors exposes his results, present tendencies and progress in research may be briefly recalled. The object is to make to clinicians, a technique which is both reliable and relatively easy to perform. The improvements are due to ease of recording with the gamma-camera, and, apart from Hg 197, the introduction of new radio-isotopes: Ga 67, bleomycin labelled with Co 57 and Cu 67 without a carrier. Tumours which escape detection have thus become rare and the specificity of the methods is reinforced. But the difficulties due to possible fixation on advanced inflammatory lesions have not yet been totally overcome [fr

Diagnostic possibilities in lymphatic node diseases

International Nuclear Information System (INIS)

Radeva, M.

1994-01-01

A brief review of lymphoscintigraphy applied in Bulgarian medical practice is presented. The most widely used radiopharmaceuticals are listed: 9 m Tc-colloid and 113 In-colloid; 67 Ga-citrate, 75 Se-methionine, 51 Cr-bleomycin, 201 Tl-chloride; monoclonal antibodies labelled with 125 I, 131 I, 111 In, 99 Tc. Some pathological changes occurring during indirect colloid lymphoscintigraphy re mentioned. Except for diagnostic purposes, lymphoscintigraphy is also used in following up the development of malignant lymphomas. A combination of indirect lymphoscintigraphy with succeeding radioimmunoscintigraphy of lymph nodes gives maximal reliable and precise data about the disease process and its distribution. 9 refs. (orig.)

Comparison of biomolecule desorption yields for low and high energy primary ions

International Nuclear Information System (INIS)

Kamensky, I.; Hakansson, P.; Sundqvist, B.; McNeal, C.J.; MacFarlane, R.

1982-01-01

Ion induced desorption yields of molecular ions from samples of cesium iodide, glycylglycine, ergosterol, bleomycin and a trinucleoside diphosphate have been studied using primary beams of 54 MeV 63 Cu 9+ and 3 keV 133 Cs + . Mass analysis was performed with a time-of-flight technique. Each sample was studied with the same spectrometer for both low and high energy primary ions and without opening of the vacuum chamber in between the measurements. The results show that fast heavy ions give larger yields for all samples studied and that the yield ratios for high to low energy desorption increase with the mass of the sample molecule. (orig.)

Resistance Training Does Not Protect Against Increases in Plasma Cytokine Levels Among Germ Cell Cancer Patients During and After Chemotherapy

DEFF Research Database (Denmark)

Christensen, Jesper Frank; Tolver, Anders; Andersen, J.L.

2014-01-01

Abstract Context: Testicular germ cell cancer (GCC) patients treated with cisplatin-etoposide-bleomycin chemotherapy (BEP) have excellent prognosis but have an increased risk of late-occurring morbidities, which may be associated with changes in the inflammatory profile. Objective: The objective...... of the study was to explore plasma cytokine concentrations in GCC patients randomized to resistance training or usual care during BEP, in comparison with healthy controls. Design/Setting: This was a randomized controlled trial in GCC patients enrolled from an oncology clinic, including a healthy reference......). Changes in TNF-α correlated with pulmonary toxicity (P BEP display consistently elevated levels of systemic inflammatory markers compared with healthy...

Novel form of miR-29b suppresses bleomycin-induced pulmonary fibrosis.

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Yuko Yamada

Full Text Available MicroRNA 29b (miR-29b replacement therapy is effective for suppressing fibrosis in a mouse model. However, to develop clinical applications for miRNA mimics, the side effects of nucleic acid drugs have to be addressed. In this study, we focused on miRNA mimics in order to develop therapies for idiopathic pulmonary fibrosis. We developed a single-stranded RNA, termed "miR-29b Psh-match," that has a unique structure to avoid problems associated with the therapeutic uses of miRNAs. A comparison of miR-29b Psh-match and double-stranded one, termed "miR-29b mimic" indicated that the single-stranded form was significantly effective towards fibrosis according to both in vivo and in vitro experiments. This novel form of miR-29b may become the foundation for developing an effective therapeutic drug for pulmonary fibrosis.

Clinical evaluation of tumor scintigraphy with sup(99m) Tc-bleomycin, (2)

International Nuclear Information System (INIS)

Odori, Teruo

1979-01-01

A comparative study with tumor scintigraphy using sup(99m) Tc-BLM and 67 Ga-citrate ( 67 Ga), bone scintigraphy and angiography was performed on various bone and soft tissue tumors. sup(99m) Tc-BLM was found to have an advantage over 67 Ga in sensitivity and specifity for malignant tumors. sup(99m) Tc-BLM also well delineated the extent of the malignant lesions; with particular usefullness in assessing the extent of the lesions of aggressive fibromatosis for the diagnosis and treatment. Bone scintigrams with phosphate compounds (sup(99m) Tc-PC) delineated the bone lesions clearly, reflecting the increased bone reaction. The combined study with sup(99m) Tc-PC and sup(99m) Tc-BLM made it very easy to define the nature and the extent of the lesions. Angiography was found to be an excellent preoperative means which delineated the extent of the lesions of bone and soft tissue and identify the nature. The combination study with sup(99m) Tc-BLM and angiography was proved to have the best sensivity (100%) and specifity (88%) in identifying the malignent tumors. (author)

Angiotensin-converting enzyme: an indicator of bleomycin-induced pulmonary toxicity in humans?

DEFF Research Database (Denmark)

Sørensen, Peter G; Rømer, F K; Cortes, Dina

1984-01-01

or radiological evidence of pulmonary damage. While the static and dynamic lung function parameters were unchanged, carbon monoxide diffusion capacity (DLCO) decreased significantly (P less than 0.01) during a total of 126 days of pulsed regimen, indicating damage to the alveolar-endothelial membrane. S-ACE...... was unchanged within each treatment course but increased significantly (P less than 0.05) from the initial value to the last treatment course. Two months after cessation of treatment S-ACE returned to pretreatment values. Although the changes were modest they might mirror treatment-associated endothelial damage....

Differentiating inflamed and normal lungs by the apparent reaction rate constants of lactate dehydrogenase probed by hyperpolarized (13)C labeled pyruvate.

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Xu, He N; Kadlececk, Stephen; Shaghaghi, Hoora; Zhao, Huaqing; Profka, Harilla; Pourfathi, Mehrdad; Rizi, Rahim; Li, Lin Z

2016-02-01

Clinically translatable hyperpolarized (HP) (13)C-NMR can probe in vivo enzymatic reactions, e.g., lactate dehydrogenase (LDH)-catalyzed reaction by injecting HP (13)C-pyruvate into the subject, which is converted to (13)C labeled lactate by the enzyme. Parameters such as (13)C-lactate signals and lactate-to-pyruvate signal ratio are commonly used for analyzing the HP (13)C-NMR data. However, the biochemical/biological meaning of these parameters remains either unclear or dependent on experimental settings. It is preferable to quantify the reaction rate constants with a clearer physical meaning. Here we report the extraction of the kinetic parameters of the LDH reaction from HP (13)C-NMR data and investigate if they can be potential predictors of lung inflammation. Male Sprague-Dawley rats (12 controls, 14 treated) were used. One dose of bleomycin (2.5 U/kg) was administered intratracheally to the treatment group. The lungs were removed, perfused, and observed by the HP-NMR technique, where a HyperSense dynamic nuclear polarization system was used to generate the HP (13)C-pyruvate for injecting into the lungs. A 20 mm (1)H/(13)C dual-tuned coil in a 9.4-T Varian vertical bore NMR spectrometer was employed to acquire the (13)C spectral data every 1 s over a time period of 300 s using a non-selective, 15-degree radiofrequency pulse. The apparent rate constants of the LDH reaction and their ratio were quantified by applying ratiometric fitting analysis to the time series data of (13)C labeled pyruvate and lactate. The apparent forward rate constant kp =(3.67±3.31)×10(-4) s(-1), reverse rate constant kl =(4.95±2.90)×10(-2) s(-1), rate constant ratio kp /kl =(7.53±5.75)×10(-3) for the control lungs; kp =(11.71±4.35)×10(-4) s(-1), kl =(9.89±3.89)×10(-2) s(-1), and kp /kl =(12.39±4.18)×10(-3) for the inflamed lungs at the 7(th) day post treatment. Wilcoxon rank-sum test showed that the medians of these kinetic parameters of the 7-day cohort were significantly

Connective tissue growth factor/CCN2-null mouse embryonic fibroblasts retain intact transforming growth factor-β responsiveness

International Nuclear Information System (INIS)

Mori, Yasuji; Hinchcliff, Monique; Wu, Minghua; Warner-Blankenship, Matthew; Lyons, Karen M.; Varga, John

2008-01-01

Background: The matricellular protein connective tissue growth factor (CCN2) has been implicated in pathological fibrosis, but its physiologic role remains elusive. In vitro, transforming growth factor-β (TGF-β) induces CCN2 expression in mesenchymal cells. Because CCN2 can enhance profibrotic responses elicited by TGF-β, it has been proposed that CCN2 functions as an essential downstream signaling mediator for TGF-β. To explore this notion, we characterized TGF-β-induced activation of fibroblasts from CCN2-null (CCN2 -/- ) mouse embryos. Methods: The regulation of CCN2 expression was examined in vivo in a model of fibrosis induced by bleomycin. Cellular TGF-β signal transduction and regulation of collagen gene expression were examined in CCN2 -/- MEFs by immunohistochemistry, Northern, Western and RT-PCR analysis, immunocytochemistry and transient transfection assays. Results: Bleomycin-induced skin fibrosis in the mouse was associated with substantial CCN2 up-regulation in lesional fibroblasts. Whereas in vitro proliferation rate of CCN2 -/- MEFs was markedly reduced compared to wild type MEFs, TGF-β-induced activation of the Smad pathways, including Smad2 phosphorylation, Smad2/3 and Smad4 nuclear accumulation and Smad-dependent transcriptional responses, were unaffected by loss of CCN2. The stimulation of COL1A2 and fibronectin mRNA expression and promoter activity, and of corresponding protein levels, showed comparable time and dose-response in wild type and CCN2 -/- MEFs, whereas stimulation of alpha smooth muscle actin and myofibroblast transdifferentiation showed subtle impairment in MEFs lacking CCN2. Conclusion: Whereas endogenous CCN2 plays a role in regulation of proliferation and TGF-β-induced myofibroblast transdifferentiation, it appears to be dispensable for Smad-dependent stimulation of collagen and extracellular matrix synthesis in murine embryonic fibroblasts

Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension.

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Avouac, Jerome; Konstantinova, Irena; Guignabert, Christophe; Pezet, Sonia; Sadoine, Jeremy; Guilbert, Thomas; Cauvet, Anne; Tu, Ly; Luccarini, Jean-Michel; Junien, Jean-Louis; Broqua, Pierre; Allanore, Yannick

2017-11-01

To evaluate the antifibrotic effects of the pan-peroxisome proliferator-activated receptor (PPAR) agonist IVA337 in preclinical mouse models of pulmonary fibrosis and related pulmonary hypertension (PH). IVA337 has been evaluated in the mouse model of bleomycin-induced pulmonary fibrosis and in Fra-2 transgenic mice, this latter being characterised by non-specific interstitial pneumonia and severe vascular remodelling of pulmonary arteries leading to PH. Mice received two doses of IVA337 (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. IVA337 demonstrated at a dose of 100 mg/kg a marked protection from the development of lung fibrosis in both mouse models compared with mice receiving 30 mg/kg of IVA337 or vehicle. Histological score was markedly reduced by 61% in the bleomycin model and by 50% in Fra-2 transgenic mice, and total lung hydroxyproline concentrations decreased by 28% and 48%, respectively, as compared with vehicle-treated mice. IVA337 at 100 mg/kg also significantly decreased levels of fibrogenic markers in lesional lungs of both mouse models. In addition, IVA337 substantially alleviated PH in Fra-2 transgenic mice by improving haemodynamic measurements and vascular remodelling. In primary human lung fibroblasts, IVA337 inhibited in a dose-dependent manner fibroblast to myofibroblasts transition induced by TGF-β and fibroblast proliferation mediated by PDGF. We demonstrate that treatment with 100 mg/kg IVA337 prevents lung fibrosis in two complementary animal models and substantially attenuates PH in the Fra-2 mouse model. These findings confirm that the pan-PPAR agonist IVA337 is an appealing therapeutic candidate for these cardiopulmonary involvements. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Modulation of CD11c+ lung dendritic cells in respect to TGF-β in experimental pulmonary fibrosis.

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Chakraborty, Kaustav; Chatterjee, Soumya; Bhattacharyya, Arindam

2017-09-01

Idiopathic pulmonary fibrosis (IPF) is a deadly, progressive lung disease with very few treatment options till now. Bleomycin-induced pulmonary fibrosis (BIPF) is a commonly used mice model in IPF research. TGF-β1 has been shown to play a key role in pulmonary fibrosis (PF). Dendritic cell (DC) acts as a bridge between innate and adaptive immune systems. The coexistence of chronic inflammation sustained by mature DCs with fibrosis suggests that inflammatory phenomenon has key importance in the pathogenesis of pulmonary fibrosis. Here, we investigated the modulation of DCs phenotypic maturation, accumulation in lung tissue, and expression of other lung DC subsets in respect to TGF-β in PF. First, we established BIPF model in mice and blocked TGF-β expression by the use of inhibitor SB431542. Accumulation of lung CD11c+ DCs is significantly higher in both inflammatory and fibrotic phases of the disease but that percentages got reduced in the absence of TGF-β. TGF-β initiates up-regulation of costimulatory molecules CD86 and CD80 in the inflammatory phases of the disease but not so at fibrotic stage. Expression of lung DC subset CD11c+CD103+ is significantly increased in inflammatory phase and also in fibrotic phase of BIPF. Blocking of TGF-β causes decreased expression of CD11c+CD103+ DCs. Another important lung DC subset CD11c+CD11b+ expression is suppressed by the absence of TGF-β after bleomycin administration. CD11c+CD103+ DCs might have anti-inflammatory as well as anti-fibrotic nature in PF. All these data demonstrate differential modulation of CD11c+ lung DCs by TGF-β in experimental PF. © 2017 International Federation for Cell Biology.

Targeting of TAM Receptors Ameliorates Fibrotic Mechanisms in Idiopathic Pulmonary Fibrosis.

Science.gov (United States)

Espindola, Milena S; Habiel, David M; Narayanan, Rohan; Jones, Isabelle; Coelho, Ana L; Murray, Lynne A; Jiang, Dianhua; Noble, Paul W; Hogaboam, Cory M

2018-06-01

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung remodeling, which progressively abolishes lung function in an RTK (receptor tyrosine kinase)-dependent manner. Gas6 (growth arrest-specific 6) ligand, Tyro3 (TYRO3 protein tyrosine kinase 3), and Axl (anexelekto) RTK expression and activity are increased in IPF. To determine if targeting these RTK pathways would inhibit fibroblast activation and the development of pulmonary fibrosis. Quantitative genomic, proteomic, and functional analyses were used to determine Gas6/TAM (Tyro3, Axl, and Mertk [MER proto-oncogene, tyrosine kinase]) RTK expression and activation in tissues and fibroblasts from normal and IPF lungs. The profibrotic impact of these RTK pathways were also examined in bleomycin-induced pulmonary fibrosis and in SCID/Bg mice that developed pulmonary fibrosis after the intravenous administration of primary IPF fibroblasts. Gas6, Axl, and Tyro3 were increased in both rapidly and slowly progressive IPF compared with normal lung samples and fibroblasts. Targeting these pathways with either specific antibodies directed at Gas6 or Axl, or with small-molecule TAM inhibitors indicated that the small molecule-mediated targeting approach was more efficacious in both in vitro and in vivo studies. Specifically, the TAM receptor inhibitor R428 (also known as BGB324) significantly inhibited the synthetic, migratory, and proliferative properties of IPF fibroblasts compared with the other Gas6/TAM receptor targeting agents. Finally, loss of Gas6 expression decreased lung fibrotic responses to bleomycin and treatment with R428 inhibited pulmonary fibrosis in humanized SCID/Bg mice. Gas6/TAM receptor activity contributes to the activation of pulmonary fibroblasts in IPF, suggesting that targeting this RTK pathway might be an effective antifibrotic strategy in this disease.

The antiviral drug tenofovir, an inhibitor of Pannexin-1-mediated ATP release, prevents liver and skin fibrosis by downregulating adenosine levels in the liver and skin.

Directory of Open Access Journals (Sweden)

Jessica L Feig

Full Text Available Fibrosing diseases are a leading cause of morbidity and mortality worldwide and, therefore, there is a need for safe and effective antifibrotic therapies. Adenosine, generated extracellularly by the dephosphorylation of adenine nucleotides, ligates specific receptors which play a critical role in development of hepatic and dermal fibrosis. Results of recent clinical trials indicate that tenofovir, a widely used antiviral agent, reverses hepatic fibrosis/cirrhosis in patients with chronic hepatitis B infection. Belonging to the class of acyclic nucleoside phosphonates, tenofovir is an analogue of AMP. We tested the hypothesis that tenofovir has direct antifibrotic effects in vivo by interfering with adenosine pathways of fibrosis using two distinct models of adenosine and A2AR-mediated fibrosis.Thioacetamide (100mg/kg IP-treated mice were treated with vehicle, or tenofovir (75mg/kg, SubQ (n = 5-10. Bleomycin (0.25U, SubQ-treated mice were treated with vehicle or tenofovir (75mg/kg, IP (n = 5-10. Adenosine levels were determined by HPLC, and ATP release was quantitated as luciferase-dependent bioluminescence. Skin breaking strength was analysed and H&E and picrosirus red-stained slides were imaged. Pannexin-1expression was knocked down following retroviral-mediated expression of of Pannexin-1-specific or scrambled siRNA.Treatment of mice with tenofovir diminished adenosine release from the skin of bleomycin-treated mice and the liver of thioacetamide-treated mice, models of diffuse skin fibrosis and hepatic cirrhosis, respectively. More importantly, tenofovir treatment diminished skin and liver fibrosis in these models. Tenofovir diminished extracellular adenosine concentrations by inhibiting, in a dose-dependent fashion, cellular ATP release but not in cells lacking Pannexin-1.These studies suggest that tenofovir, a widely used antiviral agent, could be useful in the treatment of fibrosing diseases.

Synsepalum dulcificum extracts exhibit cytotoxic activity on human colorectal cancer cells and upregulate c-fos and c-jun early apoptotic gene expression

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Jichang Seong

2018-01-01

Full Text Available Objective: To explore cytotoxicity of Synsepalum dulcificum (S. dulcificum Daniell (Sapotaceae on human colon cancer (HCT-116 and HT-29, human monocytic leukemia (THP-1 and normal (HDFn cell lines, and its effect on the expression of early apoptotic genes, c-fos and c-jun. Methods: Leaf, stem and berry of S. dulcificum were separately extracted by using 2 solvents, 10% ethanol (EtOH and 80% methanol (MeOH. PrestoBlue® cell viability assay and qRT-PCR assay were conducted to examine the above objectives respectively. Results: Stem MeOH, stem EtOH, and berry EtOH extracts of S. dulcificum were cytotoxic to HCT-116 and HT-29 human colon cancer cells. For HCT-116, IC50 values of these 3 extracts were not significantly different (P>0.05 from that of the positive control bleomycin (IC50 of 33.57 μg/mL, while for HT-29, IC50 values of these 3 extracts were significantly lower (P<0.05 than that of bleomycin (IC50 of 25.24 μg/mL. None of the extracts were cytotoxic to the THP-1 monocytic leukemia cells and HDFn normal human dermal fibroblasts. For both HCT-116 and HT-29, these extracts significantly up-regulated (P<0.05 the expression of c-fos and c-jun compared to the untreated negative control. Conclusions: The results of this study suggest that cytotoxicity of stem MeOH, stem EtOH, and berry EtOH extracts of S. dulcificum on HCT-116 and HT-29 colon cancer cells is due to the induced apoptosis which is caused by the up-regulation of the expression of early apoptotic genes, c-fos and c-jun.

Second malignancies after chemotherapy and radiotherapy for Hodgkin disease.

Science.gov (United States)

Chronowski, Gregory M; Wilder, Richard B; Levy, Larry B; Atkinson, Edward N; Ha, Chul S; Hagemeister, Fredrick B; Barista, Ibrahim; Rodriguez, Maria A; Sarris, Andreas H; Hess, Mark A; Cabanillas, Fernando; Cox, James D

2004-02-01

The purpose of this preliminary study was to determine the incidence of second malignancies after combined-modality therapy for adults with Hodgkin disease and relate it to the details of initial treatment. We retrospectively studied 286 patients ranging in age from 16 to 88 years with stage I or II Hodgkin disease who were treated between 1980 and 1995 with chemotherapy followed 3 to 4 weeks later by radiotherapy. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone was used in 161 cases, mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) in 67 cases, Adriamycin, bleomycin, vinblastine, and dacarbazine in 19 cases, lomustine, vinblastine, procarbazine, and prednisone/doxorubicin, bleomycin, dacarbazine, and lomustine in 18 cases, and other chemotherapeutic regimens in the remaining 21 cases. The median radiotherapy dose was 40 Gy given in 20 daily 2-Gy fractions. Median follow-up of surviving patients was 7.4 years. There were 2,230 person-years of observation. Significantly increased relative risks (RR) were observed for acute myeloid leukemia (RR, 69.3; 95% CI, 14.3-202.6) and melanoma (RR, 7.3; 95% CI, 1.5-21.3). The 5-, 10-, and 15-year actuarial risks of acute myeloid leukemia were 0.8%, 1.3%, and 1.3%, respectively. Patients treated with MOPP had the highest 15-year actuarial risk of leukemia (1.6%). The 5-, 10-, and 15-year actuarial risks of solid tumors were 1.9%, 9.3%, and 16.8%, respectively. Consolidative radiotherapy to both sides of the diaphragm resulted in a trend toward an increased risk of solid tumors relative to radiotherapy to only one side of the diaphragm (p = 0.08). In an effort to reduce the risk of second malignancies, we have stopped using the alkylating agents nitrogen mustard and procarbazine and elective paraaortic and splenic radiotherapy after chemotherapy.

An elevated serum beta-2-microglobulin level is an adverse prognostic factor for overall survival in patients with early-stage Hodgkin disease.

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Chronowski, Gregory M; Wilder, Richard B; Tucker, Susan L; Ha, Chul S; Sarris, Andreas H; Hagemeister, Fredrick B; Barista, Ibrahim; Hess, Mark A; Cabanillas, Fernando; Cox, James D

2002-12-15

The relative importance of prognostic factors in patients with early-stage Hodgkin disease remains controversial. The purpose of this study was to evaluate prognostic factors among patients who received chemotherapy before radiotherapy. From 1987 to 1995, 217 consecutive patients ranging in age from 16 to 88 years (median, 28 years) with Ann Arbor Stage I (n = 55) or II (n = 162) Hodgkin disease underwent chemotherapy before radiotherapy at a single center. Most were treated on prospective studies. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone (NOVP), doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), cyclophosphamide, vinblastine, procarbazine, prednisone, doxorubicin, bleomycin, dacarbazine, and CCNU (CVPP/ABDIC), or other chemotherapeutic regimens were given to 160, 18, 15, 10, and 14 patients, respectively. The median radiotherapy dose was 40 Gy. Serum beta-2-microglobulin (beta-2M) levels ranged from 1.0 to 4.1 mg/L (median, 1.7 mg/L; upper limit of normal, 2.0 mg/L). We studied univariate and multivariate associations between survival and the following clinical features: serum beta-2M level above 1.25 times the upper limit of normal (n = 12), male gender (n = 113), hypoalbuminemia (n = 11), and bulky mediastinal disease (n = 94). Follow-up of surviving patients ranged from 0.9 to 13.4 years (median, 6.6 years) and 92% were observed for 3.0 or more years. Nineteen patients have died. Only elevation of the serum beta-2M level was an independent adverse prognostic factor for overall survival (P = 0.0009). The prognostic significance of a simple, widely available, and inexpensive blood test, beta-2M, has not been studied routinely in patients with Hodgkin disease and should be tested prospectively in large, cooperative group trials. Copyright 2002 American Cancer Society.DOI 10.1002/cncr.10998

Two cycles of cisplatin-based chemotherapy for low-volume stage II seminoma: results of a retrospective, single-center case series.

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Pichler, Renate; Leonhartsberger, Nicolai; Stöhr, Brigitte; Horninger, Wolfgang; Steiner, Hannes

2012-01-01

To report on the oncological outcome and toxicity of patients treated with 2 cycles of cisplatin-based chemotherapy for low-volume metastatic stage II seminoma. We retrospectively identified a case series of 15 patients with seminoma stage IIA (26.7%) and IIB (73.3%) who underwent chemotherapy consisting of 2 cycles of cisplatin, etoposide and bleomycin (PEB) (cisplatin 20 mg/m(2) on days 1-5, etoposide 100 mg/m(2) on days 1-5, bleomycin 30 mg on days 1, 8 and 15) according to patient preference (refusing a 3rd cycle of PEB) or institutional practice in the last decades. Complete staging before chemotherapy was available in all patients. Patient age, the side and diameter of the primary tumor, the size of the lymph nodes before and after chemotherapy, acute and late toxicity of chemotherapy, the incidence of second malignancies, the relapse-free rate and cancer-specific mortality were recorded. Chemotherapy was well tolerated and no episode of febrile neutropenia occurred. Thrombocytopenia grade 4 was not seen in any patient, while leukopenia grade 4 was observed in 4 (26.6%) patients. The mean (range) lymph node size decreased significantly from 2.54 cm (1.1-4.0) before chemotherapy to 0.75 cm (0.4-2.2) after chemotherapy (p < 0.001). After a median (range) follow-up of 60 (13-185) months, no patient had relapsed, no patient had died as a result of seminoma and second malignancy was seen in only 1 (6.6%) patient. These excellent long-term results from a retrospective case series of 2 cycles of PEB in stage IIA/IIB seminoma patients represent a hint for further research with a view to reducing treatment burden. However, these incidental findings should be studied in prospective trials prior to drawing any conclusions. Copyright © 2013 S. Karger AG, Basel.

Modifying effects of pre-existing fibrosis in rats exposed to aerosols of 239PuO2. II

International Nuclear Information System (INIS)

Lundgren, D.L.; Mauderly, J.L.; Gillett, N.A.; Hahn, F.F.

1988-01-01

We have initiated a study using rats to determine the modifying effects of pre-existing pulmonary fibrosis on the retention and biological effects of inhaled 239 PuO 2 . Pulmonary fibrosis was induced by intratracheal instillation of 8.5 IU/kg body weight of bleomycin at 45 to 49 days before inhalation exposure to an aerosol of 239 PuO 2 . The clearance of 239 Pu from the lungs of rats was decreased significantly (p 239 Pu, apparently by entrapping the particles in fibrotic areas of the lung. The life span of the rats with pulmonary fibrosis was decreased by up to 25% compared with control rats having similar initial lung burdens of 239 Pu. (author)

Cross-sensitivity of X-ray-hypersensitive cells derived from LEC strain rats to DNA-damaging agents

International Nuclear Information System (INIS)

Okui, T.; Endoh, D.; Arai, S.; Isogai, E.; Hayashi, M.

1996-01-01

The cross-sensitivity of X-ray-hypersensitive lung fibroblasts from LEC strain (LEC) rats to other DNA-damaging agents was examined. The LEC cells were 2- to 3-fold more sensitive to bleomycin (BLM) that induces DNA double-strand breaks, and to a cross-linking agent, mitomycin C, than the cells from WKAH strain (WKAH) rats, while they were slightly sensitive to alkylating agents, ethyl nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine, but not to UV-irradiation. Although no difference was observed in the initial yields of DNA double-strand breaks induced by BLM between LEC and WKAH cells, the repair process of DNA double-strand breaks was significantly slower in LEC cells than in WKAH cells

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics.

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Garg, Abhishek D; More, Sanket; Rufo, Nicole; Mece, Odeta; Sassano, Maria Livia; Agostinis, Patrizia; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2017-01-01

The expression "immunogenic cell death" (ICD) refers to a functionally unique form of cell death that facilitates (instead of suppressing) a T cell-dependent immune response specific for dead cell-derived antigens. ICD critically relies on the activation of adaptive responses in dying cells, culminating with the exposure or secretion of immunostimulatory molecules commonly referred to as "damage-associated molecular patterns". Only a few agents can elicit bona fide ICD, including some clinically established chemotherapeutics such as doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin. In this Trial Watch, we discuss recent progress on the development of ICD-inducing chemotherapeutic regimens, focusing on studies that evaluate clinical efficacy in conjunction with immunological biomarkers.

Evaluation of tumor dissemination in esophageal cancer patients using radionuclide method

International Nuclear Information System (INIS)

Gabuniya, R.I.; Bogdasarov, Yu.B.; Zajtseva, T.I.; Labunets, I.N.; Ryndin, V.D.

1986-01-01

Scintigraphy with 67 Ga-citrate and 111 In-bleomycin was conducted in 32 esophageal cancer patients, 4 patients with benign esophageal tumors and in 3 patients with scarryulcerous esophagitis. A raised accumulation of the radiopharmaceutical (RP) in the esophagus, in 4 cases in the retroperitoneal paraaortic lymph nodes in which a metastatis image was confirmed at computerized tomography and diagnostic laparotomy, was observed in all cancer patients. No regularities in the intensity of the accumulation of both radiopharmaceuticals in the esophageal tumor with relation to its histological structure were detected. The advantage of the above radiopharmaceuticals is a possibility to use them for the detection of tumor dissemination and distant metastases in esophageal cancer

Gamma-ray induced inhibition of DNA synthesis in ataxia telangiectasia fibroblasts is a function of excision repair capacity

International Nuclear Information System (INIS)

Smith, P.J.; Paterson, M.C.

1980-01-01

The extent of the deficiency in γ-ray induced DNA repair synthesis in an ataxia telangiectasia (AT) human fibroblast strain was found to show no oxygen enhancement, consistent with a defect in the repair of base damage. Repair deficiency, but not repair proficiency, in AT cells was accompanied by a lack of inhibition of DNA synthesis by either γ-rays or the radiomimetic drug bleomycin. Experiments with 4-nitroquinoline 1-oxide indicated that lack of inhibition was specific for radiogenic-type damage. Thus excision repair, perhaps by DNA strand incision or chromatin modification, appears to halt replicon initiation in irradiated repair proficient cells whereas in repair defective AT strains this putatively important biological function is inoperative

A comparative study of preoperative B-V-M-M chemotherapy and irradiation in advanced squamous cell cancer of the oral cavity

International Nuclear Information System (INIS)

Olasz, L.; Kwashie, F.; Herzegh, P.; Bruncsics, Z.; Hrovath, A.; Kiralyfalvi, L.

1996-01-01

From January 1976, 50 patients with squamous cell cancer of the head and neck were treated with telecobalt preoperative irradiation followed by appropriate surgery. Another group of 50 patients, who matched in risk factors and stage of disease, were treated with preoperative chemotherapy and surgery. Chemotherapy consisted of bleomycin, vincristine, mitolactol and methotrexate. All patients received 3 courses. Surgery was performed 2-3 weeks post-chemotherapy or 4-6 weeks post-radiotherapy. Forty four percent of the patients in the radiotherapy group showed recurrences, while 30% of the patients had recurrence in the chemotherapy group. The overall 3-year survival rate was 66% in the chemotherapy group and 57% in the radiation therapy group, with no statistical difference. (author)

[A case of lung abscess during chemotherapy for testicular tumor].

Science.gov (United States)

Hayashi, Yujiro; Miyago, Naoki; Takeda, Ken; Yamaguchi, Yuichiro; Nakayama, Masashi; Arai, Yasuyuki; Kakimoto, Ken-ichi; Nishimura, Kazuo

2014-05-01

32-year-old man was seen in a clinic because of prolonged cough and slight-fever. Chest X-ray showed multiple pulmonary nodules, and multiple lung and mediastinal lymph node metastases from right testicular tumor was suspected by positron emission tomography/CT (PET/CT) scan. He was diagnosed with right testicular germ cell tumor (embryonal carcinoma + seminoma, pT2N1M1b), and classified into the intermediate risk group according to International Germ Cell Cancer Collaborative Group. He underwent 4 cycles of chemotherapy with bleomycin, etoposide and cisplatin (BEP therapy). During BEP therapy, sputum with foul odor appeared and chest CT scan revealed lung abscess with a necrotic lesion of metastatic tumor. The lung abscess was treated successfully with antibiotics.

Dynamic response of plant genome to ultraviolet radiation and other genotoxic stresses

International Nuclear Information System (INIS)

Molinier, Jean; Oakeley, Edward J.; Niederhauser, Olivier; Kovalchuk, Igor; Hohn, Barbara

2005-01-01

Oligonucleotide microarray technology was used to identify genes, which are responding after exposure to UV-C radiation and to other agents causing genotoxic stress. The effect of these conditions on recombinational DNA repair was monitored in parallel. Global changes in gene expression were investigated in Arabidopsis wild-type plants challenged with UV-C, bleomycin, another abiotic agent and xylanase, a biotic factor, all leading to elevated homologous recombination frequencies. The comparison of the expression profile of each treatment allowed defining genes specifically involved in the dynamic response to UV. In the future, the potential roles of such genes in the different forms of stress recognition, signal transduction, and their roles in DNA repair processes will be assessed by using reverse genetic tools available for Arabidopsis thaliana

Photothermal enhancement of chemotherapy mediated by gold-silica nanoshell-loaded macrophages: in vitro squamous cell carcinoma study

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Madsen, Steen J.; Shih, En-Chung; Peng, Qian; Christie, Catherine; Krasieva, Tatiana; Hirschberg, Henry

2016-01-01

Moderate hyperthermia (MHT) has been shown to enhance the effects of chemotherapeutic agents in a wide variety of cancers. The purpose of this study was to investigate the combined effects of commonly used chemotherapeutic agents with MHT induced by near-infrared (NIR) activation of gold nanoshell (AuNS)-loaded macrophages (Ma). AuNS-loaded murine Ma combined with human FaDu squamous cells, in hybrid monolayers, were subjected to three cytotoxic drugs (doxorubicin, bleomycin, cisplatin) with or without NIR laser irradiation. For all three drugs, efficacy was increased by NIR activation of AuNS-loaded Ma. The results of this in vitro study provide proof-of-concept for the use of AuNS-loaded Ma for photothermal enhancement of the effects of chemotherapy on squamous cell carcinoma.

Hyperthermia and chemotherapy agent

International Nuclear Information System (INIS)

Roizin-Towle, L.; Hall, E.J.

1981-01-01

The use of chemotherapeutic agents for the treatment of cancer dates back to the late 19th century, but the modern era of chemotherapy drugs was ushered in during the 1940's with the development of the polyfunctional alkylating agent. Since then, numerous classes of drugs have evolved and the combined use of antineoplastic agents with other treatment modalities such as radiation or heat, remains a large relatively unexplored area. This approach, combining local hyperthermia with chemotherapy agents affords a measure of targeting and selective toxicity not previously available for drugs. In this paper, the effects of adriamycin, bleomycin and cis-platinum are examined. The adjuvant use of heat may also reverse the resistance of hypoxic cells noted for some chemotherapy agents

Simultaneous demonstration of UV-type and ionizing radiation-type DNA repair by the nucleoid sedimentation technique

International Nuclear Information System (INIS)

Aldenhoff, P.; Sperling, K.

1984-01-01

The nucleoid sedimentation technique is one of the most sensitive methods for measuring DNA excision repair. With this technique, it is shown that both UV- and ionizing radiation-type repair (the latter induced by bleomycin) can be discriminated in HeLa and normal diploid cells using 1-β-D-arabinofuranosylcytosine. The latter compound inhibits UV-type repair synthesis, and thus causes DNA breaks due to enzymic incision to persist, but has no effect on rejoining DNA after ionizing radiation-type damage. It was then possible to prove that 4-nitroquinoline-1-oxide induces both types of lesions which are repaired simultaneously. This effect could be demonstrated in HeLa and normal human diploid cells in a single experimental set-up. (Auth.)

Effects of Long-Term Exposure to 60 GHz Millimeter-Wavelength Radiation on the Genotoxicity and Heat Shock Protein (Hsp Expression of Cells Derived from Human Eye

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Shin Koyama

2016-08-01

Full Text Available Human corneal epithelial (HCE-T and human lens epithelial (SRA01/04 cells derived from the human eye were exposed to 60 gigahertz (GHz millimeter-wavelength radiation for 24 h. There was no statistically significant increase in the micronucleus (MN frequency in cells exposed to 60 GHz millimeter-wavelength radiation at 1 mW/cm2 compared with sham-exposed controls and incubator controls. The MN frequency of cells treated with bleomycin for 1 h provided positive controls. The comet assay, used to detect DNA strand breaks, and heat shock protein (Hsp expression also showed no statistically significant effects of exposure. These results indicate that exposure to millimeter-wavelength radiation has no effect on genotoxicity in human eye cells.

Beneficial effect of intralesionally injected 5-fluorouracil on basal cell epithelioma associated with radiodermatitis

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Hata, Seiichiro (Osaka Univ. (Japan). Faculty of Medicine)

1984-06-01

A 81-year-old male had perioral radiodermatitis of 50 years' duration which was associated with Bowen's disease and basal cell epitheliomas since age 59 years. One of those basal cell epitheliomas treated with topical 5-FU and bleomycin ointments increased to form an ulcer of 25 x 15mm in size nearby the right side of nose, accompanying with a fistule to the oral cavity while he hesitated to visit the hospital. 5-FU was intralesionally injected into the tumor. After the injections in total dose of 6,550mg the ulcer got epithelized and the biopsy could not reveal the tumor cell. The case proves the effectiveness of intralesional injection of 5-FU for basal cell epithelioma which avoids the surgical excision.

Anti-Ma2-associated encephalitis with normal FDG-PET: a case of pseudo-Whipple's disease.

Science.gov (United States)

Castle, James; Sakonju, Ai; Dalmau, Josep; Newman-Toker, David E

2006-10-01

A 39-year-old man presented with a history of several months of progressive personality changes, social withdrawal, bradykinesia, mutism, dysphagia, worsening gait, and difficulty with daily living activities. Examination revealed an atypical parkinsonian appearance with incomplete supranuclear ophthalmoplegia and an unusual oculomotor disorder characterized by both low-amplitude, intermittent opsoclonus, and slow, nystagmoid intrusions. Routine laboratory testing, autoimmune and infectious serologies, brain MRI, lumbar puncture, electroencephalogram, whole-body CT scan, paraneoplastic serologies, small bowel biopsy, 18F-fluorodeoxyglucose positron emission tomography CT scan, brain biopsy, and testicular ultrasound. Anti-Ma2 paraneoplastic encephalitis in association with metastatic testicular cancer; initially misdiagnosed as CNS Whipple's disease. Corticosteroids, intravenous immunoglobulins, orchiectomy, muscle relaxants, mycophenolate mofetil, plasmapheresis, and bleomycin, etoposide and platinum chemotherapy.

Adaptive response induced by occupational exposures to ionizing radiation

International Nuclear Information System (INIS)

Barquinero, J.F.; Caballin, M.R.; Barrios, L.; Murtra, P.; Egozcue, J.; Miro, R.; Ribas, M.

1997-01-01

We have found a significant decreased sensitivity to the cytogenetic effects of ionizing radiation (IR) and bleomycin (BLM) in lymphocytes from individuals occupationally exposed to IR when compared with a control population. These results suggest that occupational exposures to IR can induce adaptive response that can be detected by a subsequent treatment by IR or by BLM. However, no correlation between the results obtained with both treatments was observed. A great heterogeneity in the frequencies of chromatid aberrations induced by BLM was observed. The study of the influence of different harvesting times showed that there was no correlation with the frequencies of chromatid breaks. Our results indicate that the use of BLM to detect adaptive response has several difficulties at the individual level. (author)

Relationship between radiation effect for carcinoma of the esophagus and x-ray findings before and after radiotherapy

International Nuclear Information System (INIS)

Morita, Kozo; Obata, Yasunori; Watanabe, Michiko; Karasawa, Kazuo; Takagi, Iwao

1980-01-01

From 1970 through 1978, 95 patients with carcinoma of the esophagus were treated with irradiation alone and/or combined with the administration of Bleomycin, preoperatively. On the basis of the histological analysis of the surgical specimen, the relationship between radiation effect for the primary tumor and the x-ray findings before and after the radiotherapy was investigated. The radiotherapy was the most effective for the superficial and tumorous type on the x-ray findings before treatment. The tumorous protruded subtype in the serrated type was more radiosensitive than the ulcerative subtype. The same tendency was also observed in the spiral type. The narrowing of the esophagus (funnelled type) and the ulceration were the most unsuitable signs for the radiotherapy. (author)

Radiologically guided percutaneous pleurodesis of malignant pleural effusion

International Nuclear Information System (INIS)

Morrison, M.C.; Mueller, P.R.; Saini, S.; Hahn, P.F.; Lee, M.J.; Cortell, E.; Girard, M.; Goldberg, M.; Simeone, J.F.

1990-01-01

This paper reports that in patients with symptomatic malignant pleural effusion. US-guided placement of small-bore catheters for pleurodesis presents an alternative to traditional surgical management. Catheters ranging in size from 7-F to 16-F (n = 17), or greater than 16-F (n = 5), were placed intrapleurally under US guidance in 22 patients with symptomatic malignant pleural effusion. Pleur-E-Vac suction was applied until tube drainage was less than 100 mL/d. Tetracycline (1--2 g/100 mL of normal saline solution) or bleomycin (45--100 U/50 mL of 5% dextrose) was then instilled and left in the pleural space for 1--3 hours. The chest tube was removed when output was less than 20 mL/d

Sulfur amino acid metabolism in doxorubicin-resistant breast cancer cells

International Nuclear Information System (INIS)

Ryu, Chang Seon; Kwak, Hui Chan; Lee, Kye Sook; Kang, Keon Wook; Oh, Soo Jin; Lee, Ki Ho; Kim, Hwan Mook; Ma, Jin Yeul; Kim, Sang Kyum

2011-01-01

Although methionine dependency is a phenotypic characteristic of tumor cells, it remains to be determined whether changes in sulfur amino acid metabolism occur in cancer cells resistant to chemotherapeutic medications. We compared expression/activity of sulfur amino acid metabolizing enzymes and cellular levels of sulfur amino acids and their metabolites between normal MCF-7 cells and doxorubicin-resistant MCF-7 (MCF-7/Adr) cells. The S-adenosylmethionine/S-adenosylhomocysteine ratio, an index of transmethylation potential, in MCF-7/Adr cells decreased to ∼ 10% relative to that in MCF-7 cells, which may have resulted from down-regulation of S-adenosylhomocysteine hydrolase. Expression of homocysteine-clearing enzymes, such as cystathionine beta-synthase, methionine synthase/methylene tetrahydrofolate reductase, and betaine homocysteine methyltransferase, was up-regulated in MCF-7/Adr cells, suggesting that acquiring doxorubicin resistance attenuated methionine-dependence and activated transsulfuration from methionine to cysteine. Homocysteine was similar, which is associated with a balance between the increased expressions of homocysteine-clearing enzymes and decreased extracellular homocysteine. Despite an elevation in cysteine, cellular GSH decreased in MCF-7/Adr cells, which was attributed to over-efflux of GSH into the medium and down-regulation of the GSH synthesis enzyme. Consequently, MCF-7/Adr cells were more sensitive to the oxidative stress induced by bleomycin and menadione than MCF-7 cells. In conclusion, our results suggest that regulating sulfur amino acid metabolism may be a possible therapeutic target for chemoresistant cancer cells. These results warrant further investigations to determine the role of sulfur amino acid metabolism in acquiring anticancer drug resistance in cancer cells using chemical and biological regulators involved in sulfur amino acid metabolism. - Research highlights: → MCF-7/Adr cells showed decreases in cellular GSH

Neoadjuvant and adjuvant chemotherapy of cervical cancer: mature results of the phase 2 PBM-PFU protocol.

Science.gov (United States)

McCaffrey, Rebecca; Bahtiyar, Mert; Kohorn, Ernest I; Chambers, Joseph T; Schwartz, Peter E; Chambers, Setsuko K

2011-04-01

The mature results of the neoadjuvant and adjuvant chemotherapy arms of the nonrandomized, phase 2 Yale University cisplatin, bleomycin, methotrexate, and 5-FU protocol are presented. Sixty-seven patients were prospectively accrued with a median follow-up of 5.4 years, and standard parameters of toxicity and efficacy were studied. Both univariate and multivariate analyses were applied. The 5-year disease-free survival of 78% for the 25 patients in the adjuvant group, of which 80% had high-risk features including positive margins, parametria, and lymph nodes and 28% had adenocarcinomas, was comparable to recent relevant literature. Only 64% of patients in this group received consolidation radiation therapy, which did not impact on survival. Only 12% of patients recurred distantly. Notably, those who received 4 months or more of chemotherapy had prolonged survival (P = 0.012). In the neoadjuvant group, chemotherapy response rate among 42 patients (with stages 1B-IIIB cancer) was 79% (50% partial response, 29% complete response), and no patient progressed. In the subgroup of 22 patients who underwent surgery after chemotherapy, 59% had nonsquamous histology. Forty-five percent of patients with stage IIB cancer were deemed operable after chemotherapy. Ninety-five percent received postoperative radiation therapy. There was a 9% pathologic complete response rate, with positive lymph nodes found in 27%. Notably, those who received 3 months or less of chemotherapy had improved overall survival (P = 0.030). Survival rates of these 22 patients at 3 and 5 years were 73% and 63%, respectively. Although not randomized, these survival rates were similar to those achieved with chemoradiation. Although there are several logistical/design features of the cisplatin, bleomycin, methotrexate, and 5-FU regimen that are not in line with the current chemotherapy era, our experience with this well-tolerated regimen can serve as a proof of principle. Our data suggests that both neoadjuvant

Basal cell carcinoma: 10-year experience with electrochemotherapy.

Science.gov (United States)

Campana, Luca G; Marconato, Roberto; Valpione, Sara; Galuppo, Sara; Alaibac, Mauro; Rossi, Carlo R; Mocellin, Simone

2017-05-31

Electrochemotherapy (ECT), by combining manageable cytotoxic agents with short electric pulses, represents an effective palliative skin-directed therapy. The accumulated evidence indicates that ECT stands out as a safe and well-tolerated alternative treatment for patients with multiple or large basal cell carcinoma (BCC), who are not suitable for conventional treatments. However, long-term data and shared indications are lacking. In this observational study, we retrospectively analyzed 84 prospectively collected patients with multiple, recurrent or locally advanced BCC who were not candidate for standard therapies and received bleomycin-based ECT according to the European Standard Operative Procedures of ECT, from 2006 to 2016. Disease extent was local, locally advanced and metastatic in 40 (48%), 41 (49%) and 3 (3%), respectively. Forty-four (52%) individuals had multiple BCCs. Grade 3 skin toxicity after ECT was observed in 6% of cases. Clearance rate was 50% (95% CI 39-61%). Primary presentation (p = 0.004), tumor size <3 cm (p < 0.001), well-defined borders (p = 0.021), absence of tumor ulceration (p = 0.001), non-aggressive BCC histology (p = 0.046) and age ≤69 years were associated with higher complete response rate. In patients with local BCC, the clearance rate was 72.5 and 85% after one or two ECT cycles, respectively. In the laBCC group, 32 patients (78%) achieved an objective response. Five-year recurrence rate for local and laBCC was 20 and 38%, respectively (p ≤ 0.001). One or two ECT cycles with bleomycin may be a valuable palliative treatment in well-selected patients with multiple BCCs and favorable tumor features. Validation of predictive factors will be imperative to match patients with optimal ECT treatment modalities. Management of laBCC with ECT warrants further investigation. Trial registration ISRCTN14633165 Registered 24 March 2017 (retrospectively registered).

Fibrocytes in the Fibrotic Lung: Altered Phenotype Detected by Flow Cytometry

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Charles eReese

2014-06-01

Full Text Available Fibrocytes are bone marrow hematopoietic-derived cells that also express a mesenchymal cell marker (commonly collagen I and participate in fibrotic diseases of multiple organs. Given their origin, they or their precursors must be circulating cells before recruitment into target tissues. While most previous studies focused on circulating fibrocytes, here we focus on the fibrocyte phenotype in fibrotic tissue. The study’s relevance to human disease is heightened by use of a model in which bleomycin is delivered systemically, recapitulating several features of human scleroderma including multi-organ fibrosis not observed when bleomycin is delivered directly into the lungs. Using flow cytometry, we find in the fibrotic lung a large population of CD45high fibrocytes (called Region I rarely found in vehicle-treated control mice. A second population of CD45+ fibrocytes (called Region II is observed in both control and fibrotic lung. The level of CD45 in circulating fibrocytes is far lower than in either Region I or II lung fibrocytes. The chemokine receptors CXCR4 and CCR5 are expressed at higher levels in Region I than in Region II and are present at very low levels in all other lung cells including CD45+/collagen I- leucocytes. The collagen chaperone HSP47 is present at similar high levels in both Regions I and II, but at a higher level in fibrotic lung than in control lung. There is also a major population of HSP47high/CD45- cells in fibrotic lung not present in control lung. CD44 is present at higher levels in Region I than in Region II and at much lower levels in all other cells including CD45+/collagen I- leucocytes. When lung fibrosis is inhibited by restoring caveolin-1 activity using a caveolin-1 scaffolding domain peptide (CSD, a strong correlation is observed between fibrocyte number and fibrosis score. In summary, the distinctive phenotype of fibrotic lung fibrocytes suggests that fibrocyte differentiation occurs primarily within the

Assessment of lymph node tumour from CT scans: how good is diameter and visual assessment

International Nuclear Information System (INIS)

Kumar, Pratik; Rehani, M.M.; Anand, Vikram; Raina, Vinod; Rao, Keshava

1995-01-01

The evaluation response of tumours requires quantification of tumour mass in terms of volume or maximum diameter. In normal practice changes in maximum diameter of tumour are assessed visually on follow-up CT films. This may lead to erroneous results. Twenty one patients of testicular cancer in stage II A to II D with retroperitoneal lymphadenopathy were scanned by CT for 3 to 5 times during the course of treatment. Tumour size was assessed in terms of diameter as per practice followed routinely. A very important observation was that actual measurement of diameter instead of visual assessment resulted in change of stage of cancer in 42.8% (9 out of 21) cases. Moreover, in 6 out of these 21 cases (28%) there occurred a change in stage from II C to II D which assumes significance due to change in treatment protocol from BEP (Bleomycin, Etoposide, Cisplatinum) to BOP-VIP (Bleomycin, Vincristin, Cisplatinum , VP-16, Ifosfamide, Cisplatinum). Tumour volume estimated on the basis of visual method differed considerably from the calculated one. In 16 out of 21 scans, the difference was between 6.4% to 42.9%. The acceptable difference of 5% was seen only in 4 out of 21 cases indicating the importance of volume measurement. The method of volume estimation was validated and found to be within ± 5% of actual volume. The correlation between diameter and volume shows that tumours with similar range of diameter have 20% to 100% more volume. Many times increase in diameter was found associated with actually reduced tumour volume, difference being as much as 515%. This has not been documented earlier in clinical situations. Thus, the study underscores the role of measuring the diameter of tumour for staging and highlights the need for actual volume estimation rather than depending on maximum transverse diameter alone in follow-up studies. (author). 9 refs., 4 figs., 4 tabs

Detection of the pyrogen in the radiopharmaceuticals using Limulus test and inhibitory factors in the gelation reaction

International Nuclear Information System (INIS)

Murata, Hajime; Iio, Masahiro; Yamada, Hideo; Chiba, Kazuo; Kobayashi, Masayoshi.

1975-01-01

To examine the sensitivities of the Limulus test and the inhibitory factors in radiopharmaceuticals, the following procedures were employed. Twenty commonly used radiopharmaceuticals were examined by Limulus Lysate (Pre-gel). In order to detect the inhibitory factors, several doses of endotoxin (E. coli) were added to the radiopharmaceuticals before the Limulus test was made and the results were compared with control results using saline solution of endotoxin. When the pH of the reaction solution lay out of a suitable range (6.0-7.5), the pH was adjusted by Tris-HCl buffer before the reaction. The sensitivity of the Limulus test control using Pre-gel was positive at a concentration of 10 -3 μg/ml of endotoxin. The Limulus test was sensitive and without inhibitory reactions for sup(99m)TcO 4 -, sup(99m)Tc-albumin, sup(99m)Tc-MAA, sup(99m)Tc-Sn-colloid, 131 I-hippurate, Na 131 I, Na 2 51 CrO 4 , 67 Ga-citrate and 57 Co-bleomycin as they were supplied. 111 In-DTPA, sup(99m)Tc-phytate, sup(99m)Tc-pyrophosphate, sup(99m)Tc-DTPA, 131 I-PVP, 59 FeCl 3 , Na-phosphate ( 32 P), 198 Au-colloid and 75 Se-selenomethionine needed to have their pH adjusted to avoid inhibition. Benzyl alcohol in the radiopharmaceutical showed an inhibitory effect at a concentration greater than 1%. Commonly used 169 Yb-DTPA which was evaluated by this test had a sensitivity of 2.5 x 10 -3 μg/ml due to addition of a small amount of benzyl alcohol. 131 I-BSP showed intense inhibition in gelation reaction. Contaminations of endotoxin were detected in sup(99m)Tc-albumin, sup(99m)Tc-Sn-colloid, 131 I-hippurate, Na 131 I, Na 2 51 CrO 4 , 198 Au-colloid, 57 Co-bleomycin and 75 Se-selenomethionine. (auth.)

Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

International Nuclear Information System (INIS)

Hoppe, Bradford S.; Flampouri, Stella; Zaiden, Robert; Slayton, William; Sandler, Eric; Ozdemir, Savas; Dang, Nam H.; Lynch, James W.; Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P.

2014-01-01

Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on 18 F-Fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes were similar

Involved-Node Proton Therapy in Combined Modality Therapy for Hodgkin Lymphoma: Results of a Phase 2 Study

Energy Technology Data Exchange (ETDEWEB)

Hoppe, Bradford S., E-mail: bhoppe@floridaproton.org [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Flampouri, Stella [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States); Zaiden, Robert [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Jacksonville, Florida (United States); Slayton, William [Department of Pediatrics, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Sandler, Eric [Department of Pediatrics, Division of Hematology/Oncology Nemours Children' s Clinic, Jacksonville, Florida (United States); Ozdemir, Savas [Department of Radiology, Division of Functional and Molecular Imaging, University of Florida College of Medicine, Jacksonville, Florida (United States); Dang, Nam H.; Lynch, James W. [Department of Medicine, Division of Hematology and Oncology, University of Florida College of Medicine, Gainesville, Florida (United States); Li, Zuofeng; Morris, Christopher G.; Mendenhall, Nancy P. [Radiation Oncology, University of Florida Proton Therapy Institute, Jacksonville, Florida (United States)

2014-08-01

Purpose: This study describes the early clinical outcomes of a prospective phase 2 study of consolidative involved-node proton therapy (INPT) as a component of combined-mode therapy in patients with stages I to III Hodgkin lymphoma (HL) with mediastinal involvement. Methods and Materials: Between September 2009 and June 2013, 15 patients with newly diagnosed HL received INPT after completing chemotherapy in an institutional review board-approved protocol comparing the dosimetric impact of PT with those of three-dimensional conformal radiation therapy (3DCRT) and intensity modulated RT. Based on {sup 18}F-Fluorodeoxyglucose positron emission tomography/computed tomography ({sup 18}F-FDG PET/CT) response, 5 children received 15 to 25.5 cobalt Gy equivalent (CGE) of INPT after receiving 4 cycles of Adriamycin, Bleomycin, Vincristine, Etoposide, Prednisone, Cyclophosphamide or Vincristine, adriamycin, methotrexate, Prednisone chemotherapy, and 10 adults received 30.6 to 39.6 CGE of INPT after 3 to 6 cycles of Adriamycin, Bleomycine, Vinblastine, Dacarbazine. Patients were routinely evaluated for toxicity during and after treatment, using Common Terminology Criteria for Adverse Events, version 3.0, and for relapse by physical examination and routine imaging. Relapse-free survival (RFS) and event-free survival (EFS) rates were calculated using the Kaplan-Meier method from the time of diagnosis. Results: The median follow-up was 37 months (range, 26-55). Two events occurred during follow-up: 1 relapse (inside and outside the targeted field) and 1 transformation into a primary mediastinal large B cell lymphoma. The 3-year RFS rate was 93%, and the 3-year EFS rate was 87%. No acute or late grade 3 nonhematologic toxicities were observed. Conclusions: Although decades of follow-up will be needed to realize the likely benefit of PT in reducing the risk of radiation-induced late effects, PT following chemotherapy in patients with HL is well-tolerated, and disease outcomes

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

Energy Technology Data Exchange (ETDEWEB)

Gunther, Jillian R. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Fanale, Michelle A. [Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Reddy, Jay P. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Akhtari, Mani [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Department of Radiation Oncology, The University of Texas Medical Branch at Galveston, Galveston, Texas (United States); Smith, Grace L.; Pinnix, Chelsea C.; Milgrom, Sarah A.; Yehia, Zeinab Abou; Allen, Pamela K.; Osborne, Eleanor M. [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Mawlawi, Osama [Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States); Dabaja, Bouthaina S., E-mail: bdabaja@mdanderson.org [Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas (United States)

2016-09-01

Purpose: The German Hodgkin Study Group HD11 trial validated 4 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by involved field radiation therapy (IFRT) for early unfavorable Hodgkin lymphoma (HL) patients. However, practitioners often recommend 6 cycles followed by RT, especially for bulky disease. We compared patient outcomes after treatment with 4 or 6 cycles of ABVD followed by RT (IFRT and involved site RT [ISRT]). Methods and Materials: We identified 128 patients treated for early unfavorable HL (GHSG criteria) between 2000 and 2013. Clinical outcomes (overall survival [OS] and freedom from relapse [FFR]) were estimated using Kaplan-Meier analysis. Toxicities were evaluated. Results: The median follow-up time was 5.0 years. Patients received 4 (70 patients, 55%) or 6 (58 patients, 45%) cycles of chemotherapy. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4-cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6-cycle group. For patients receiving 4 and 6 cycles, the 6-year OS was 100% and 97% (P=.35), respectively, and the 6 year FFR was 100% and 98% (P=.28), respectively. More patients received 6 cycles if they were treated before 2010 (HD11 report) (P=.01) and if they had bulky disease (P<.01). Sixty-eight percent of patients received ISRT. The 6-year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P=.58). More patients experienced bleomycin pulmonary toxicity in the 6-cycle group (20% vs 31%, P=.16). For patients with bulky disease, the 4-year FFR was similar with receipt of 4 (100%) or 6 (98%) cycles (P=.48) and IFRT (100%) or ISRT (98%) (P=.52). There were no deaths among patients with bulky disease. Conclusions: Patients with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by ISRT. Six cycles of chemotherapy does not appear superior for disease control, even for bulky disease.

Treatment of Early-Stage Unfavorable Hodgkin Lymphoma: Efficacy and Toxicity of 4 Versus 6 Cycles of ABVD Chemotherapy With Radiation

International Nuclear Information System (INIS)

Gunther, Jillian R.; Fanale, Michelle A.; Reddy, Jay P.; Akhtari, Mani; Smith, Grace L.; Pinnix, Chelsea C.; Milgrom, Sarah A.; Yehia, Zeinab Abou; Allen, Pamela K.; Osborne, Eleanor M.; Mawlawi, Osama; Dabaja, Bouthaina S.

2016-01-01

Purpose: The German Hodgkin Study Group HD11 trial validated 4 cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy followed by involved field radiation therapy (IFRT) for early unfavorable Hodgkin lymphoma (HL) patients. However, practitioners often recommend 6 cycles followed by RT, especially for bulky disease. We compared patient outcomes after treatment with 4 or 6 cycles of ABVD followed by RT (IFRT and involved site RT [ISRT]). Methods and Materials: We identified 128 patients treated for early unfavorable HL (GHSG criteria) between 2000 and 2013. Clinical outcomes (overall survival [OS] and freedom from relapse [FFR]) were estimated using Kaplan-Meier analysis. Toxicities were evaluated. Results: The median follow-up time was 5.0 years. Patients received 4 (70 patients, 55%) or 6 (58 patients, 45%) cycles of chemotherapy. Bulky disease was present in 22 patients (31%; 0 stage IA, 3 stage IB, 19 stage IIA) of the 4-cycle group and 42 patients (72%; 5 stage IA, 3 stage IB, 34 stage IIA) of the 6-cycle group. For patients receiving 4 and 6 cycles, the 6-year OS was 100% and 97% (P=.35), respectively, and the 6 year FFR was 100% and 98% (P=.28), respectively. More patients received 6 cycles if they were treated before 2010 (HD11 report) (P=.01) and if they had bulky disease (P<.01). Sixty-eight percent of patients received ISRT. The 6-year FFR was 99% and 100% for patients receiving ISRT and IFRT, respectively (P=.58). More patients experienced bleomycin pulmonary toxicity in the 6-cycle group (20% vs 31%, P=.16). For patients with bulky disease, the 4-year FFR was similar with receipt of 4 (100%) or 6 (98%) cycles (P=.48) and IFRT (100%) or ISRT (98%) (P=.52). There were no deaths among patients with bulky disease. Conclusions: Patients with early unfavorable HL have excellent outcomes with 4 cycles of ABVD chemotherapy followed by ISRT. Six cycles of chemotherapy does not appear superior for disease control, even for bulky disease.

Secondary leukemia associated with a conventional dose of etoposide: review of serial germ cell tumor protocols.

Science.gov (United States)

Nichols, C R; Breeden, E S; Loehrer, P J; Williams, S D; Einhorn, L H

1993-01-06

Case reports have suggested that treatment with high-dose etoposide can result in development of a unique secondary leukemia. This study was designed to estimate the risk of developing leukemia for patients receiving conventional doses of etoposide along with cisplatin and bleomycin. We reviewed the records at Indiana University of all untreated patients entering clinical trials using etoposide at conventional doses (cumulative dose, 2000 mg/m2 or less) for germ cell cancer between 1982 and 1991. The records of all patients who received a chemotherapy regimen containing etoposide, ifosfamide, or cisplatin after failing to respond to primary chemotherapy were also reviewed. Between 1982 and 1991, 538 patients entered serial clinical trials with planned cumulative etoposide doses of 1500-2000 mg/m2 in combination with cisplatin plus either ifosfamide or bleomycin. Of these 538 patients, 348 received an etoposide combination as initial chemotherapy and 190 received etoposide as part of salvage treatment. To date, 315 patients are alive, with median follow-up of 4.9 years, and 337 patients have had follow-up beyond 2 years. Two patients (0.37%) developed leukemia. One developed acute undifferentiated leukemia with a t(4;11) (q21;q23) cytogenetic abnormality 2.0 years after starting etoposide-based therapy, and one developed acute myelomonoblastic leukemia with no chromosome abnormalities 2.3 years after beginning chemotherapy. During this period, several hundred patients were treated with etoposide-based chemotherapy and did not enter clinical trials. Three of these patients are known to have developed hematologic abnormalities, including one patient with acute monoblastic leukemia with a t(11;19)(q13;p13) abnormality. Secondary leukemia after treatment with a conventional dose of etoposide does occur, but the low incidence does not alter the risk-to-benefit ratio of etoposide-based chemotherapy in germ cell cancer. The reports of leukemia associated with high doses of

Pharmacological targeting of protease-activated receptor 2 affords protection from bleomycin-induced pulmonary fibrosis

NARCIS (Netherlands)

C. Lin (Cong); J. von der Thusen (Jan); J. Daalhuisen (Joost); M. Ten Brink (Marieke); B. Crestani (Bruno); T. van der Poll (Tom); K. Borensztajn (Keren); C. Arnold Spek (C.)

2015-01-01

textabstractIdiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed

Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis

NARCIS (Netherlands)

Lin, Cong; von der Thüsen, Jan; Daalhuisen, Joost; ten Brink, Marieke; Crestani, Bruno; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

2015-01-01

Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2

Calcium Electroporation

DEFF Research Database (Denmark)

Frandsen, Stine Krog; Gibot, Laure; Madi, Moinecha

2015-01-01

BACKGROUND: Calcium electroporation describes the use of high voltage electric pulses to introduce supraphysiological calcium concentrations into cells. This promising method is currently in clinical trial as an anti-cancer treatment. One very important issue is the relation between tumor cell kill...... efficacy-and normal cell sensitivity. METHODS: Using a 3D spheroid cell culture model we have tested the effect of calcium electroporation and electrochemotherapy using bleomycin on three different human cancer cell lines: a colorectal adenocarcinoma (HT29), a bladder transitional cell carcinoma (SW780......), and a breast adenocarcinoma (MDA-MB231), as well as on primary normal human dermal fibroblasts (HDF-n). RESULTS: The results showed a clear reduction in spheroid size in all three cancer cell spheroids three days after treatment with respectively calcium electroporation (p

Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.

Science.gov (United States)

Gadjeva, V; Koldamova, R

2001-01-01

A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), using ethyl nitrite for nitrosation of the intermediate spin-labeled ureas has been described. In vitro synergistic effects of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (3b) on the cytotoxicity of bleomycin and farmorubicin were found in human lymphoid leukemia tumor cells. We measured the tissue distribution of 3b in organ homogenates of C57BL mice by an electron paramagnetic resonance method. The spin-labeled nitrosourea was mainly localized in the lungs. Our results strongly support the development and validation of a new approach for synthesis of less toxic nitrosourea derivatives as potential synergists of antitumor drugs.

Neoadjuvant chemotherapy in locally advanced cervical cancer: two randomised studies

International Nuclear Information System (INIS)

Kumar, L.; Grover, R.; Pokharel, Y.H.; Chander, S.; Kumar, S.; Singh, R.; Rath, G.K.; Kochupillai, V.

1998-01-01

The results of two studies looking at the place of neo-adjuvant chemotherapy in the treatment of locally advanced cervical cancer being treated with radiotherapy are presented. Between August 1990 and January 1992, 184 patients with squamous cell carcinoma of the cervix, FIGO stage II B IVA were randomised (study 1) to receive either two cycles of bleomycin, ifosfamide-mesna and cisplatin (BIP) chemotherapy (CT) followed by radiotherapy (RT). Three patients died of CT toxicity - two in study 1 and one in study 2. Cystitis, proctitis and local skin reaction after RT occurred equally in the two groups in both the studies. The neo-adjuvant chemotherapy prior to radiotherapy demonstrated a high response rate, but this did not translate into improved overall survival compared to those patients receiving radiotherapy alone

Effects of artichoke (Cynara scolymus) leaf and bloom head extracts on chemically induced DNA lesions in Drosophila melanogaster.

Science.gov (United States)

Jacociunas, Laura Vicedo; Dihl, Rafael Rodrigues; Lehmann, Mauricio; de Barros Falcão Ferraz, Alexandre; Richter, Marc François; da Silva, Juliana; de Andrade, Heloísa Helena Rodrigues

2014-03-01

The genotoxicity of bloom head (BHE) and leaf (LE) extracts from artichoke (Cynara scolymus L.), and their ability to modulate the mutagenicity and recombinogenicity of two alkylating agents (ethyl methanesulfonate - EMS and mitomycin C - MMC) and the intercalating agent bleomycin (BLM), were examined using the somatic mutation and recombination test (SMART) in Drosophila melanogaster. Neither the mutagenicity nor the recombinogenicity of BLM or MMC was modified by co- or post-treatment with BHE or LE. In contrast, co-treatment with BHE significantly enhanced the EMS-induced genotoxicity involving mutagenic and/or recombinant events. Co-treatment with LE did not alter the genotoxicity of EMS whereas post-treatment with the highest dose of LE significantly increased this genotoxicity. This enhancement included a synergistic increase restricted to somatic recombination. These results show that artichoke extracts promote homologous recombination in proliferative cells of D. melanogaster.

Effects of ionizing radiation on cells from Fanconi's anemia patients

International Nuclear Information System (INIS)

Duckworth-Rysiecki, G.; Taylor, A.M.

1985-01-01

The lymphocytes from some Fanconi's anemia patients appeared to be more radiosensitive than normal as measured by the number of X-ray-(or bleomycin-) induced chromosome aberrations seen following G2 treatment. Fibroblasts from the same patients, however, all showed the same degree of colony survival as normals following exposure to gamma-rays [Do, 1.13 +/- 0.072 (S.E.) Gy and 1.14 +/- 0.077 Gy for Fanconi's anemia and normal fibroblasts, respectively]. The lack of increased radiosensitivity in Fanconi's fibroblasts was also observed by the same degree of inhibition of DNA synthesis as seen in normals following gamma-irradiation. The results show clearly that there is no increase in radiosensitivity common to all cell types from Fanconi's patients, although an apparent increase in chromosomal radiosensitivity may be seen in the lymphocytes from an occasional patient

Treatment-related risk factors for premature menopause following Hodgkin lymphoma

DEFF Research Database (Denmark)

De Bruin, Marie L; Huisbrink, Jeannine; Hauptmann, Michael

2008-01-01

We conducted a cohort-study among 518 female 5-year Hodgkin lymphoma (HL) survivors, aged 14 to 40 years (median: 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40...... years. After a median follow up of 9.4 years, 97 women had reached menopause before age 40 years. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared with radiotherapy alone. Treatment with MOPP (mechlorethamine, vincristine, procarbazine, prednisone......)/ABV (doxorubicine, bleomycine, vinblastine) significantly increased the risk of premature menopause (hazard ratio [HR]: 2.9), although to a lesser extent than MOPP treatment (HR: 5.7). Alkylating agents, especially procarbazine (HR: 8.1) and cyclophosphamide (HR: 3.5), showed the strongest associations. Ten years...

Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer

DEFF Research Database (Denmark)

Kier, Maria G; Hansen, Merete K; Lauritsen, Jakob

2016-01-01

radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL). Main Outcomes and Measures: Cumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls. Results: The study......Importance: Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options....... Objective: To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens. Design, Setting, and Participants: This study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular...

An improved brine shrimp larvae lethality microwell test method.

Science.gov (United States)

Zhang, Yi; Mu, Jun; Han, Jinyuan; Gu, Xiaojie

2012-01-01

This article described an improved brine shrimp larvae lethality microwell test method. A simply designed connecting vessel with alternative photoperiod was used to culture and collect high yield of active Artemia parthenogenetica nauplii for brine shrimp larvae lethality microwell test. Using this method, pure A. parthenogenetica nauplii suspension was easily cultured and harvested with high density about 100-150 larvae per milliliter and the natural mortality was reduced to near zero by elimination of unnecessary artificial disturbance. And its sensitivity was validated by determination of LC(50)-24 h of different reference toxicants including five antitumor agents, two pesticides, three organic pollutants, and four heavy metals salts, most of which exhibited LC(50)-24 h between 0.07 and 58.43 mg/L except for bleomycin and mitomycin C with LC(50)-24 h over 300 mg/L.

Contribution of sup(99m)Tc labelled sodium pyrophosphate bone scintigraphy to the diagnosis of bone metastases

International Nuclear Information System (INIS)

Remi, J.-P.

1976-01-01

Bone scintigraphy, by its ease of application and the use of short-lived isotopes, has revolutionised the conditions of bone metastase diagnosis. Scintigraphy possesses two advantages, the possibility it offers of exploring the whole skeleton at once and its extreme simplicity. This technique should therefore find its place at the very beginning of the bone examination, an attitude which also has dosimetric repercussions: a 'whole skeleton' examination delivers 170 mrad to the marrow, whereas spinal and pelvic X-rays deliver 325 mrad. Unfortunately the sup(99m)Tc-labelled sodium pyrophosphate bone scintigraphy is not specific to any given lesion. Diagnosis can only be improved by the appearance of tracers taken up specifically on the neoplasic tissue, as is already the case of 131 I for thyroid cancer metastases. Labelled bleomycine and 67 Ga have so far given disappointing results [fr

Clinical impact of FDG-PET/CT in the planning of radiotherapy for early-stage Hodgkin lymphoma

DEFF Research Database (Denmark)

Hutchings, Martin; Loft, Annika; Hansen, Mads

2007-01-01

BACKGROUND: Early-stage Hodgkin lymphoma (HL) has excellent survival rates but carries a high risk of late treatment-related adverse effects. Modern, individualised therapeutic strategies require an accurate determination of the extent of the disease. This study investigated the potential impact...... of 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography/computerised tomogrpahy (FDG-PET/CT) in the planning of involved field radiotherapy (IFRT). PATIENTS AND METHODS: Thirty patients received staging FDG-PET/CT before therapy, and IFRT after a short course of ABVD (adriamycin, bleomycin......, vinblastine, dacarbazine) chemotherapy. IFRT planning was performed using only the CT data from the FDG-PET/CT scan. Later, the IFRT planning was performed anew using the FDG-PET/CT data as basis for contouring. RESULTS: In 20 out of 30 patients, the radiotherapy (RT) course was unaffected by the addition...

Multi-modality treatment in males with advanced malignant germ cell tumours

International Nuclear Information System (INIS)

Fossaa, S.D.; Klepp, O.; Ous, S.; Lien, H.; Stenwig, J.T.; Abeler, V.; Eliasson, G.; Hoest, H.

1984-01-01

After chemotherapy with cis-platinum, vinblastine and bleomycin, 33 surgical prosedures were performed in 29 patients with advanced malignant germ-cell tumours. The tumour masses could be completely resected macroscopially in 26 patients. Patients with fibros/necrosis or completely resected mature teratoma had an excellent prognosis, whereas only 5 of the 11 patients with vital malignant tumour survived in spite of second-line treatment with chemotherapy/radiotherapy. Preoperatively elevated serum levels of AFP, β-HCG and/or LDH indicated the presence of residual germ cell tumour. Eight of 14 patients were rendered tumour-free by radiotherapy given as second- or third-line treatment. In general, tumour masses, remaining after cis-platinum-based induction chemotherapy should be resected as completely as possible even in the case of mature teratoma or fibrosis/necrosis. Radiotherapy should be considered as second -and thirdline treatment

Principia of cancer therapy, 19. Effects of per rectum carmofur on radiotherapeutic efficacy of rectal carcinomas

Energy Technology Data Exchange (ETDEWEB)

Mishina, Hitoshi; Okuyama, Shinichi

1987-12-01

Radiotherapy combined with bleomycin in oil and tegafur and/or carmofur has already been shown markedly effective in those patients having rectal cancer as studied histologically (Okuyama et al. Tohoku J. Exp. Med. 143 : 503, 1984) as well as clinically (Hariu et al. Jap. Assoc. Gastrenterol. Surg., Hiroshima, 1983). In search for attainment of better effectiveness, carmofur suppositories were developed. Their pharmacokinetic analysis revealed a ten-time increment in the blood concentration of 5-FU as compared with tegafur suppositories. The clinical results in terms of reduction in tumor size, CEA titers and survival appeared to be improved. Histological studies on the surgical materials seemed promising, too. The probable clinical significance of carmofur suppositories may be that pre-operative radiotherapy of rectal cancers, and possibly those patients having their metastases to the liver organ be greatly expedited.

Principia of cancer therapy, 19

International Nuclear Information System (INIS)

Mishina, Hitoshi; Okuyama, Shinichi

1987-01-01

Radiotherapy combined with bleomycin in oil and tegafur and/or carmofur has already been shown markedly effective in those patients having rectal cancer as studied histologically (Okuyama et al. Tohoku J. Exp. Med. 143 : 503, 1984) as well as clinically (Hariu et al. Jap. Assoc. Gastrenterol. Surg., Hiroshima, 1983). In search for attainment of better effectiveness, carmofur suppositories were developed. Their pharmacokinetic analysis revealed a ten-time increment in the blood concentration of 5-FU as compared with tegafur suppositories. The clinical results in terms of reduction in tumor size, CEA titers and survival appeared to be improved. Histological studies on the surgical materials seemed promising, too. The probable clinical significance of carmofur suppositories may be that pre-operative radiotherapy of rectal cancers, and possibly those patients having their metastases to the liver organ be greatly expedited. (author)

Targeting protease activated receptor-1 with P1pal-12 limits bleomycin-induced pulmonary fibrosis

NARCIS (Netherlands)

Lin, Cong; Duitman, Janwillem; Daalhuisen, Joost; ten Brink, Marieke; von der Thüsen, Jan; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

2014-01-01

Idiopathic pulmonary fibrosis is the most devastating fibrotic diffuse parenchymal lung disease which remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. Protease-activated receptor (PAR)-1 is a G-protein-coupled receptor that mediates critical

57Co-bleomycin kinetics in normal and tumour-bearing mice after systemic and local administration

International Nuclear Information System (INIS)

Bier, J.; Benders, P.; Bitter, K.; Wenzel, M.

1979-01-01

In tumour-free and tumour-bearing mice the body clearance and organ distribution of 57 Co-BLM was measured at different time intervals after i.v., sc, and it. administration of the drug. No significant difference could be demonstrated in body clearance following different doses and routes of application of labelled BLM in tumour-free and tumour-bearing mice. The organ distribution studies showed higher concentrations following iv. compared to sc. or it of 57 Co-BLM: however, the activity in the ipsilateral injection sites was significantly increased after sc. and it. injection. In tumour-bearing mice the activity in the lymph nodes draining injection site was as high as that seen in the draining lymph modes following iv. injection. However, on the contralateral side, the lymph mode concentration was significantly reduced after it injection. These results indicate on the basis of organ distribution of 57 Co-BLM a rational basis for it treatment of malignant tumours. (orig.) [de

Electrochemotherapy with bleomycin of different types of cutaneous tumours in a ferret (Mustela putorius furo

Directory of Open Access Journals (Sweden)

Racnik Jozko

2017-12-01

Full Text Available Mast cell tumour, sebaceous gland adenoma, and less common squamous papilloma are skin tumours in ferrets (Mustela putorius furo, and early excisional surgery is usually the treatment of choice. The aim of our study was to investigate the effectiveness of electrochemotherapy (ECT, a new, minimally invasive non-surgical method, as first treatment option of different types of ferret skin tumours located on surgically difficult sites.

miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1.

Directory of Open Access Journals (Sweden)

Christian Lacks Lino Cardenas

Full Text Available As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF, remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls. In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that

Detection of the pyrogen in the radiopharmaceuticals using Limulus test and inhibitory factors in the gelation reaction

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Murata, H; Iio, M; Yamada, H; Chiba, K [Tokyo Metropolitan Geriatric Medical Center (Japan); Kobayashi, M

1975-08-01

To examine the sensitivities of the Limulus test and the inhibitory factors in radiopharmaceuticals, the following procedures were employed. Twenty commonly used radiopharmaceuticals were examined by Limulus Lysate (Pre-gel). In order to detect the inhibitory factors, several doses of endotoxin (E. coli) were added to the radiopharmaceuticals before the Limulus test was made and the results were compared with control results using saline solution of endotoxin. When the pH of the reaction solution lay out of a suitable range (6.0-7.5), the pH was adjusted by Tris-HCl buffer before the reaction. The sensitivity of the Limulus test control using Pre-gel was positive at a concentration of 10/sup -3/ ..mu..g/ml of endotoxin. The Limulus test was sensitive and without inhibitory reactions for sup(99m)TcO/sub 4/-, sup(99m)Tc-albumin, sup(99m)Tc-MAA, sup(99m)Tc-Sn-colloid, /sup 131/I-hippurate, Na/sup 131/I, Na/sub 2//sup 51/CrO/sub 4/, /sup 67/Ga-citrate and /sup 57/Co-bleomycin as they were supplied. /sup 111/In-DTPA, sup(99m)Tc-phytate, sup(99m)Tc-pyrophosphate, sup(99m)Tc-DTPA, /sup 131/I-PVP, /sup 59/FeCl/sub 3/, Na-phosphate (/sup 32/P), /sup 198/Au-colloid and /sup 75/Se-selenomethionine needed to have their pH adjusted to avoid inhibition. Benzyl alcohol in the radiopharmaceutical showed an inhibitory effect at a concentration greater than 1%. Commonly used /sup 169/Yb-DTPA which was evaluated by this test had a sensitivity of 2.5 x 10/sup -3/ ..mu..g/ml due to addition of a small amount of benzyl alcohol. /sup 131/I-BSP showed intense inhibition in gelation reaction. Contaminations of endotoxin were detected in sup(99m)Tc-albumin, sup(99m)Tc-Sn-colloid, /sup 131/I-hippurate, Na/sup 131/I, Na/sub 2//sup 51/CrO/sub 4/, /sup 198/Au-colloid, /sup 57/Co-bleomycin and /sup 75/Se-selenomethionine.

Hodgkin's lymphoma-related vanishing bile duct syndrome: A case report and literature review

Directory of Open Access Journals (Sweden)

Kiong-Ming Wong

2013-11-01

Full Text Available We report the case of a 38-year-old man who developed vanishing bile duct syndrome in association with Hodgkin's lymphoma. He was noted to have cervical lymphadenopathy and marked elevation of total serum bilirubin at diagnosis. He achieved complete remission with normalization of serum bilirubin after eight courses of Adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed with autologous hematopoietic cell transplantation. Consecutive liver biopsies performed at diagnosis and at the stage of complete remission revealed the disappearance and regeneration of interlobular bile ducts, respectively. Our case provides pathological evidence that Hodgkin's lymphoma-related vanishing bile duct syndrome is a reversible bile duct injury disease. Bilirubin is a reliable serum marker to monitor the treatment response of these cases. The mechanism to develop hyperbilirubinemia with vanishing bile duct in such a case of Hodgkin's lymphoma remains to be studied. A literature review was carried out.

Intralesional copper wire retention and pingyangmycin injection: an effective combinational therapy for complex venous malformation in soft tissue.

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Yuan, S-M; Hong, Z-J; Jiang, H-Q; Wang, J; Hu, X-B

2014-04-01

Complex venous malformations (VMs) may extensively involve the soft tissue. The treatment remains a challenge till now. Here we introduce a combinational therapy of copper wires and pingyangmycin (bleomycin A5,PYM). Copper wires were retained in VMs by repeated penetration with a straight needle. Subsequently, PYM solution was injected into the lesion. Eight to 10 days later, copper wires were removed. The dressing was changed every day until the puncture pores healed. Magnetic resonance imaging scanning was performed to observe the change of VMs. From January 2001 to December 2011, 56 patients were treated. During the follow-up period, most of the VMs shrunk obviously. The symptoms were relieved or disappeared. The complications included local pain, temporary paraesthesia and moderate fever, which disappeared quickly after the removal of copper wires. This combinational therapy is a safe and effective approach for the complex VMs in soft tissue.

Novel types of DNA-sugar damage in neocarzinostatin cytotoxicity and mutagenesis

International Nuclear Information System (INIS)

Goldberg, I.H.

1986-01-01

Although a number of antitumor antibiotics interact with DNA to form covalent adducts with the bases, relatively few damage DNA by interacting with the deoxyribose moiety. Neocarzinostatin (NCS), a member of a family of macromolecular antibiotics obtained from filtrates of Streptomyces, is such an agent. Many of the biochemical and cellular effects of NCS resemble those of ionizing radiation. Most, possibly all, of the DNA lesions caused by NCS appear to result from the direct attack of an activated form of the drug on the deoxyribose of DNA. This is to be contrasted with ionizing radiation or the antibiotic bleomycin, that damage DNA deoxyribose through the intervention of a reduced form of oxygen. This paper describes the nature of the interaction between the active component of NCS and DNA, on the mechanism of the ensuing deoxyribose damage, and on some of the biological consequences of these actions. 24 refs., 7 figs

A case of radiation-induced squamous cell carcinoma of an 87-year-old physician

International Nuclear Information System (INIS)

Tanaka, Eiichiro; Takatsuka, Sumiko; Takenouchi, Tatsuya

2005-01-01

We reported a case of radiation-induced squamous cell carcinoma on the bilateral middle finger of an 87-year-old physician. He had exposed his hands to radiation without defense when he took an X-ray photograph. Squamous papules and ulcers occurred on both of his hands 10-years ago. The ulcer on the right middle finger enlarged rapidly after a one-month duration. A biopsy specimen showing squamous cell carcinoma derived from chronic radiation dermatitis, and disarticulation at the proximal interpharyngeal joint (PIP) joint of the right middle finger was performed. Six month later, hyperkeratotic tumor newly occurred on the opposite middle finger, and were operated on in the same way. The remaining lesions of chronic radiation dermatitis were treated by topical bleomycin hydrochloride. Since medical workers carelessly exposed their skin to radiation several decades ago, attention to late occurrence of radiation-induced skin cancer is needed. (author)

Prognostic value of baseline metabolic tumor volume in early stage Hodgkin's lymphoma in the standard arm of H10 trial

DEFF Research Database (Denmark)

Cottereau, Anne Ségolène; Versari, Annibale; Loft, Annika

2018-01-01

and compared to baseline characteristics, staging classifications and iPET2. A total of 258 patients were eligible, 101 favorable and 157 unfavorable. The median follow-up was 55 months, with 27 PFS and 12 OS events. TMTV was prognosticator of PFS (p...We tested baseline PET/CT as a measure of total tumor burden in order to better identify high risk patients in early-stage Hodgkin's lymphoma (HL). Stage I-II HL patients enrolled in the standard arm (combined modality treatment) of the H10 trial (NCT00433433) with available baseline PET...... and interim PET (iPET2) after two cycles of doxorubicine, bleomycin, vinblastine, dacarbazine were included. Total metabolic tumor volume (TMTV) was measured on baseline PET. IPET2 findings were reported negative (DS1-3) or positive (DS4-5) with the Deauville scale. The prognostic value of TMTV was evaluated...

A link between double-strand break-related repair and V(D)J recombination: the scid mutation

International Nuclear Information System (INIS)

Hendrickson, E.A.; Qin, X.Q.; Bump, E.A.; Schatz, D.G.; Oettinger, M.; Weaver, D.T.

1991-01-01

We show here that mammalian site-specific recombination and DNA-repair pathways share a common factor. The effects of DNA-damaging agents on cell lines derived from mice homozygous for the scid (severe combined immune deficiency) mutation were studied. Surprisingly, all scid cell lines exhibited a profound hypersensitivity to DNA-damaging agents that caused double-strand breaks (x-irradiation and bleomycin) but not to other chemicals that caused single-strand breaks or cross-links. Neutral filter elution assays demonstrated that the x-irradiation hypersensitivity could be correlated with a deficiency in repairing double-strand breaks. These data suggest that the scid gene product is involved in two pathways: DNA repair of random double-strand breaks and the site-specific and lymphoid-restricted variable-(diversity)-joining [V(D)J] DNA rearrangement process. We propose that the scid gene product performs a similar function in both pathways and may be a ubiquitous protein

Selective vancomycin detection using optical fibre long period gratings functionalised with molecularly imprinted polymer nanoparticles.

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Korposh, Sergiy; Chianella, Iva; Guerreiro, Antonio; Caygill, Sarah; Piletsky, Sergey; James, Stephen W; Tatam, Ralph P

2014-05-07

An optical fibre long period grating (LPG) sensor modified with molecularly imprinted polymer nanoparticles (nanoMIPs) for the specific detection of antibiotics is presented. The operation of the sensor is based on the measurement of changes in refractive index induced by the interaction of nanoMIPs deposited onto the cladding of the LPG with free vancomycin (VA). The binding of nanoMIPs to vancomycin was characterised by a binding constant of 4.3 ± 0.1 × 10(-8) M. The lowest concentration of analyte measured by the fibre sensor was 10 nM. In addition, the sensor exhibited selectivity, as much smaller responses were obtained for high concentrations (∼700 μM) of other commonly prescribed antibiotics such as amoxicillin, bleomycin and gentamicin. In addition, the response of the sensor was characterised in a complex matrix, porcine plasma, spiked with 10 μM of VA.

Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy.

Science.gov (United States)

Pol, Jonathan; Vacchelli, Erika; Aranda, Fernando; Castoldi, Francesca; Eggermont, Alexander; Cremer, Isabelle; Sautès-Fridman, Catherine; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

2015-04-01

The term "immunogenic cell death" (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona fide ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers.