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PubMed1992

Establishment of human squamous carcinoma cell lines highly and minimally sensitive to bleomycin and analysis of factors involved in the sensitivity.

Human squamous carcinoma cell lines that were highly and minimally sensitive to bleomycin were established from clinical specimens and designated as SCCKN and SCCTF, respectively. Although these cell lines showed a similar growth doubling time in vitro, SCCTF was approximately ten times less sensitive to bleomycin than SCCKN. The bleomycin high and low sensitivities were stable even at the 70-cell passage level in vitro. In addition, nude mouse tumors produced by SCCTF were less sensitive to bleomycin that those produced by SCCKN, and the ratio of the mean tumor weight in bleomycin-treated mice to that in control mice was 89.2% in SCCTF and 18.8% in SCCKN. As compared with SCCKN, SCCTF also was less sensitive to peplomycin (5-fold), mitomycin C (2.3-fold), cis-diamine dichloroplatinum (2.5-fold), and vincristine (6.5-fold). Analyses of low bleomycin sensitivity showed that SCCTF had an approximately 20% decreased cellular accumulation and retention of bleomycin, 1.2-fold increase of bleomycin hydrolase activity, elevated DNA repair activity, and increased poly(adenosine diphosphate-ribose) polymerase activity as compared with SCCKN.

Animals↗
PubMed1981

Isolation and preliminary characterization of bleomycin-resistant mutants from Chinese hamster ovary cells.

Stable mutants resistant to an anticancer antibiotic, bleomycin-A2, were selected in Chinese hamster ovary (CHO) cell either spontaneously or after ethylmethane sulfonate mutagenesis. Fluctuation analysis showed that bleomycin resistance occurs in CHO at a rate of 6.50--6.58 x 10(-7) mutations per cell per generation. Bleomycin-A2-resistant cell lines exhibited increased resistance to bleomycin analogs--bleomycin-A5, -B2, -B4, and pepleomycin. Colchicine, mitomycin C, and ultraviolet light irradiation inhibited colony formation equally in CHO cells and in bleomycin-resistant mutants. Cell-cell hybridization tests showed that bleomycin-resistance behaves as a dominant trait. Bleomycin-inactivating activity in the mutant cell extracts was three to fourfold higher than that in extracts of the parental CHO cell.

Animals↗
PubMed1997

Bleomycin induces strain-dependent alterations in the pattern of epithelial cell-specific marker expression in mouse lung.

Clinical use of the antineoplastic agent bleomycin is restricted due to pulmonary toxicity. Murine models of bleomycin-induced pulmonary fibrosis have been developed in an attempt to understand the mechanisms involved in the fibrotic process. Studies have shown that the alveolar epithelium is damaged early after bleomycin treatment. The purpose of this study was to evaluate the pattern of gene expression in airway and alveolar epithelial cells after bleomycin exposure in mice that vary in susceptibility to bleomycin-induced fibrosis. Surfactant protein C (SPC) and Clara cell-specific protein (CC10) mRNA were used as cell-specific markers of alveolar type II cells and airway Clara cells, respectively. Mice were treated with a single intratracheal dose of bleomycin and the pattern of SPC and CC10 transcripts was examined by in situ hybridization. The pattern of SPC mRNA 28 days after treatment was uniform in controls and resistant mice but exhibited a patchy appearance in sensitive mice. Bleomycin treatment also resulted in a strain-dependent loss of CC10 mRNA-expressing cells. In sensitive mice 28 days after treatment, SPC mRNA was ectopically expressed in the distal bronchiolar epithelium in a morphologically distinct cell type. Serial sections revealed that these cells either coexpressed CC10 mRNA or were located adjacent to CC10 mRNA-containing cells. This unique cell population may represent a progenitor cell type important in epithelial repair. The strain-dependent changes in CC10 and SPC gene expression after bleomycin treatment are suggestive of a role for the epithelium in pulmonary fibrosis versus repair.

Animals↗
PubMed1993

Bleomycin lung toxicity detected by technetium-99m diethylene triamine penta-acetic acid aerosol scintigraphy.

In this study we investigated bleomycin-induced pulmonary toxicity in patients with germ-cell tumour by means of technetium-99m diethylene triamine penta-acetic acid aerosol scintigraphy. Twenty untreated patients who had no clinical or radiological evidence of pulmonary disease received four courses of etoposide, cisplatin and bleomycin chemotherapy. Aerosol lung scintigraphy and pulmonary function tests were performed in all patients before bleomycin treatment and after administration of 180 and 360 mg bleomycin. On the basis of the scintigrams the percentage decline in activity per minute (Kep) was evaluated, which represented an accurate parameter of lung membrane permeability. Pretreatment Kep values (0.891 +/- 0.286) were significantly lower than those obtained following 180 and 360 mg bleomycin treatment (1.176 +/- 0.336 and 1.389 +/- 0.477, respectively; P < 0.0005). The Kep values obtained with 180 and 360 mg bleomycin treatments were also significantly different (P < 0.005). In contrast, no significant change was observed in the results of pulmonary function tests. Our results demonstrate that evaluation of the pulmonary clearance of 99mTc-DTPA represents a useful means of monitoring the functional status of the lung epithelial membrane during bleomycin treatment. Further prospective studies are needed to assess the relationship between increase in permeability and development of lung toxicity in order to decide which patients should discontinue bleomycin therapy.

Adult↗
PubMed1987

Oxygen radical formation and DNA damage due to enzymatic reduction of bleomycin-Fe(III).

Aerobic incubations of bleomycin, FeCl3, DNA, NADPH, and isolated liver microsomal NADPH-cytochrome P-450 reductase resulted in NADPH and oxygen consumption and malondialdehyde formation, indicating that the deoxyribose moiety of DNA was split. All parameters measured depended on the active enzyme, bleomycin and FeCl3. In the absence of oxygen malondialdehyde formation was very low. When bleomycin, FeCl3 and the reductase were incubated with methional ethene (ethylene) was formed, suggesting that during the enzyme-catalyzed redox cycle of bleomycin-Fe(III/II) hydroxyl radicals were formed. Ethene formation also depended on oxygen, NADPH, the enzyme, bleomycin, and FeCl3. During aerobic incubations of bleomycin, FeCl3, NADPH, and isolated liver nuclei oxygen and NADPH were consumed and malondialdehyde was formed. Oxygen and NADPH consumption and malondialdehyde formation depended on bleomycin and FeCl3. In the absence of oxygen malondialdehyde was not formed. These results indicate that nuclear NADPH-cytochrome P-450 reductase redox cycles the bleomycin-Fe(III/II) complex and that the reduced complex activates oxygen, whereby hydroxyl radicals are formed which damage the deoxyribose of nuclear DNA.

Animals↗
PubMed1989

Lung lymphocytes in bleomycin-induced pulmonary disease.

Previous studies have not clearly defined the role of cell-mediated immunity in bleomycin-induced lung injury. In this report the functional activity of T lymphocytes obtained from minced lung preparations, bronchoalveolar lavage, and blood of rabbits treated with bleomycin was examined in cell proliferation and cell-mediated cytotoxicity assays. Four days after instillation of bleomycin (10 units/kg) into the right lung, histologic examination revealed mononuclear cell interstitial infiltrates and alveolar exudates. Right lung bronchoalveolar lavage (BAL) cell counts were similar in both groups, but the percentage of lymphocytes and neutrophils was elevated in bleomycin-treated groups (25% vs. 7% and 35% vs. 0% respectively; p less than 0.05). Spontaneous proliferation of cultured BAL and blood lymphocytes was similar in bleomycin-treated rabbits and controls. After 24 h of incubation with interleukin-2 (IL-2), BAL lymphocytes from bleomycin-treated rabbits had nearly a 4-fold greater proliferative response than lymphocytes from untreated rabbits. Concanavalin-A-dependent cell-mediated cytotoxicity (CDCMC) assays were performed to evaluate cytolytic lymphocyte activity. Spontaneous CDCMC activity was not detected in BAL fluid or in blood lymphocytes from either treated or control animals. After 24 h of incubation with IL-2, significant CDCMC activity was detected in lung lymphocytes from bleomycin-treated animals, but not in lung lymphocytes from control animals. These results indicate that stimulated lymphocytes are present in the lungs of rabbits 4 days after exposure to bleomycin.

Animals↗
PubMed2005

Increased expression of p53 and p21 (Waf1/Cip1) in the lesional skin of bleomycin-induced scleroderma.

Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive deposition of extracellular matrix in the affected skin as well as various internal organs, vascular injury and immune abnormality; however, the etiology of SSc remains still unknown. We previously established an experimental mouse model for scleroderma by repeated local injections of bleomycin, a DNA damaging agent. In this study, we examined the induction of apoptosis and the expression of p53, p21 (Waf1/Cip1), and proliferating cell nuclear antigen (PCNA) in the lesional skin following bleomycin exposure in this model. Dermal sclerosis was induced by alternate day's injections of bleomycin for 4 weeks. TUNEL assay showed that apoptotic cells began to appear at 1 week after bleomycin exposure, and were prominently detected at 3-4 weeks. Immunohistochemical examination showed increased expression of p53 and p21 mainly in the infiltrating mononuclear cells at 2 weeks after bleomycin treatment. Bleomycin treatment markedly enhanced PCNA expression at 1-2 weeks, mainly in mesenchyme, as compared with control phosphate buffered saline treatment. Reverse transcriptase-polymerase chain reaction analysis showed that the expression of p53 and p21 mRNA was concurrently upregulated at 1-2 weeks after bleomycin treatment. Taken together, coordinate increased levels of p53 and p21 preceded the maximal induction of apoptosis and dermal sclerosis. Our findings suggest that apoptotic processes are involved in the pathophysiology of bleomycin-induced scleroderma, which may be mediated, in part, by the upregulation of p53 and p21.

Animals↗
PubMed2000

Bleomycin increases steady-state levels of type I collagen, fibronectin and decorin mRNAs in human skin fibroblasts.

Bleomycin is a drug capable of inducing tissue fibrosis. In this study, the effects of bleomycin on gene expression of extracellular matrix encoding alpha1(I) collagen, fibronectin and decorin were determined in vitro in human dermal fibroblasts. Northern blot analysis showed that bleomycin upregulated alpha(I) collagen, fibronectin and decorin gene expression dose-dependently between 1 nM and 1 microM. Bleomycin at 100 nM upregulated alpha1(I) collagen, fibronectin and decorin mRNA expression with a peak at 6 h following stimulation in normal skin fibroblast monolayers. Bleomycin enhanced mRNA expression encoding these extracellular matrix proteins in both normal dermal and scleroderma fibroblasts. Concomitant stimulation with bleomycin and interferon-gamma (1,000 U/ml), a representative antifibrotic cytokine, decreased alpha1(I) collagen mRNA expression. Bleomycin also mildly upregulated mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) coordinately in normal skin fibroblasts. Our results indicate that bleomycin modulates gene expression of extracellular matrix proteins in dermal fibroblasts, and this effect may be mediated by TGF-beta and CTGF.

Anti-Bacterial Agents↗
PubMed1985

Bleomycin control of transplasma membrane redox activity and proton movement in HeLa cells.

Bleomycin, tallysomycin A, tallysomycin S10b and copper-bleomycin have been tested for their capacity to inhibit the transplasma membrane electron transport and associated proton release by HeLa cells. Transplasma membrane redox activity is measured using reduction of external ferricyanide by the cells. At 75 micrograms/ml bleomycin, tallysomycin A and tallysomycin S10b gave a maximum of 65% inhibition of the ferricyanide reduction rate; half-maximum inhibition was observed at 30 micrograms/ml. The copper-bleomycin complex was slightly more effective as an inhibitor with half-maximum inhibition at 20 micrograms/ml. Survival of cells after 1 hr of drug treatment was 50% at 25 micrograms/ml for bleomycin and copper-bleomycin and at 75 micrograms/ml for tallysomycin A. Tallysomycin A and tallysomycin S10b gave 75 to 83% inhibition of ferricyanide-induced proton extrusion, respectively at 50 micrograms/ml, whereas bleomycin and copper-bleomycin appeared to be slightly less effective with 50 to 60% inhibition, respectively, at 50 micrograms/ml. In all aspects studied, which included transplasma membrane ferricyanide reduction, ferricyanide-induced proton release, and cell survival, there were significant effects by these compounds on HeLa cells in the range of 25-50 micrograms/ml.

Bleomycin↗
PubMed1991

Inhibition of bleomycin-induced cellular DNA strand scission by 1,10-phenanthroline.

Inhibition by 1,10-phenanthroline of cellular DNA strand scission induced by the antitumor antibiotic bleomycin in Ehrlich ascites tumor cells was studied. DNA alkaline elution was performed on cells after 1-hr bleomycin treatments. Pretreatment for 24 hr with initial 1,10-phenanthroline concentrations of 0.2 nmol/10(5) cells, which depletes cells of ferritin iron by 80%, had no consistent effect on bleomycin strand breakage. However, simultaneous treatment with 3.1 nmol of 1,10-phenanthroline/10(5) cells and with bleomycin concentrations from 5 to 25 microM decreased both apparent double-stranded breaks and random breakage. When cells were treated with both 3.1 nmol of 1,10-phenanthroline/10(5) cells and 25 microM bleomycin, washed free of both drugs, and incubated at 35 degrees for 1 hr, the resulting breakage was equivalent to that found in cells treated with bleomycin only. When the combination treatment was extended to 4 hr, cell washing and reincubation resulted in increased strand scission, as compared with strand scission in cells treated with bleomycin only. Growth inhibition by bleomycin was not affected appreciably by temporary suppression of DNA strand breakage activity.

Animals↗
PubMed1985

Effects of intratracheal administration of bleomycin or saline in pair-fed and control-fed hamsters on daily food intake and on plasma levels of glucose, cortisol, and insulin, and lung levels of calmodulin, calcium, and collagen.

In the present study, the effects of intratracheal administration of bleomycin have been examined on daily food intake and on plasma levels of glucose, cortisol, and insulin, and on lung levels of calmodulin, calcium, and collagen in hamsters. Since bleomycin treatment caused nutritional deficiency leading to loss of body weight, we have included pair-fed and control-fed as control groups in order to rule out the nutritional deficiency-related effects on these measurements. Bleomycin-treated animals showed a dramatic decrease in daily food intake and body weight as compared to control-fed animals. Bleomycin-treated animals were hyperglycemic when compared to nutritionally comparable pair-fed animals and had plasma glucose levels similar to those of control-fed animals. Plasma cortisol levels in bleomycin-treated and pair-fed animals showed a time-dependent increasing trend, whereas plasma insulin levels in both groups tended to decrease. The lung levels of calmodulin and calcium in bleomycin-treated animals were significantly increased when compared with the pair-fed or control-fed group. Bleomycin-treated animals had significantly higher levels of lung collagen than pair-fed or control-fed at 7 and 13 days after treatment. The lung collagen content in pair-fed animals was significantly less than that of control-fed at 13 days. It was concluded that a disturbance in carbohydrate metabolism and increased lung levels of calmodulin and calcium might be somehow involved in fibroproliferative changes of the lung in bleomycin-treated animals.

Animals↗
PubMed1986

Bleomycin enhances the tyrosinase activity of human malignant melanoma cells in culture.

By application of bleomycin fine pigmentations on basal cell layers will appear in irritated parts of the skin. Therefore we investigated the effect of bleomycin on the tyrosinase activity. Bleomycin was determined to exhibit a strong cytostatic activity on human melanoma cells in culture (ED50 concentration = 0.21 microgram/ml) whereas the viability of the cells was not affected. Incubation of pigmented human melanoma cells in the presence of bleomycin containing culture medium (1-100 ng/ml) at 37 degrees C for different periods of time resulted in a marked increase of tyrosinase activity. The level of enzyme activity reached 140% if the controls were set to 100%. Direct addition of bleomycin to the crude cell extract produced no detectable stimulatory effect. There were no significant stimulation if the cells were grown with bleomycin in serum-free culture medium. The serum content influences the activity of tyrosinase in a marked degree. The serum concentration for half-maximal stimulation of tyrosinase was calculated to be 14.2%. Furthermore the inflammatory mediator histamine was found to stimulate tyrosinase in melanoma cells. There were no additional stimulatory effect if cells were incubated in the presence of both histamine and bleomycin. These results suggest that bleomycin is able to enhance tyrosinase activity in intact cell systems. Further a possible role of serum and/or inflammatory factors in the stimulatory process must be considered.

Basidiomycota↗
PubMed1985

The effect of endotoxin on bleomycin-induced lung fibrosis in the rat.

Bleomycin is a commonly used antineoplastic agent which produces dose- and time-dependent pneumonitis and fibrosis in humans. The mechanism of bleomycin-induced lung injury is uncertain. However, current data shows that bleomycin can generate reactive oxygen species such as superoxide and hydroxyl radicals. We therefore investigated whether intraperitoneal (i.p.) injection of endotoxin, a protectant for hyperoxia, could modulate the biochemical and morphological estimates of bleomycin-induced lung fibrosis in rats. However, pretreatment with multiple i.p. injections of endotoxin, combined with intratracheal bleomycin instillation, resulted in increased lung collagen content compared to bleomycin treatment alone and controls. Furthermore, morphological estimates of the severity of lung lesions present in the endotoxin-bleomycin treatment group were increased when compared with saline and endotoxin control lung lesions. These data indicate, in the current study design, that endotoxin did not reduce, but instead increased the severity of bleomycin-induced pulmonary fibrosis in rats. The mechanism for this increase in fibrosis may be the result of pre-existing endotoxin-induced cell injury.

Animals↗
PubMed1989

The effect of diclofenac acid (Voltaren) on bleomycin-induced pulmonary fibrosis in hamsters.

Bleomycin is an anti-neoplastic compound which produces a time- and dose-dependent pulmonary fibrosis. The mechanisms which cause this fibrosis are not known. However, the ability of bleomycin to modulate prostaglandin synthesis, degradation and circulating levels appears to be central to the fibrosis. Previous studies, which have attempt to modulate bleomycin-induced fibrosis by prevention of prostaglandin synthesis have conflicting results. Therefore, the present study was designed to determine the effects of diclofenac acid, a nonsteroidal anti-inflammatory compound, on the development of bleomycin-induced pulmonary fibrosis. Diclofenac acid pretreatment and daily injections prevented lung collagen accumulation after intratracheal bleomycin. In addition diclofenac acid treatment resulted in significantly lower lung collagen level after intratracheal bleomycin at 14 and 21 days when compared with bleomycin alone. These data indicate that diclofenac acid treatment inhibits bleomycin-induced lung fibrosis possible through the prevention of prostaglandins synthesis.

Animals↗
PubMed2005

Attenuation of bleomycin-induced lung fibrosis by oral sulfhydryl containing antioxidants in rats: erdosteine and N-acetylcysteine.

Antioxidant therapy may be useful in diseases with impaired oxidant antioxidant balance such as lung fibrosis. The effects of sulfhydryl-containing antioxidant agents N-acetylcysteine (NAC) and erdosteine on the bleomycin-induced lung fibrosis were compared in rats. The animals were divided into four groups: Vehicle + vehicle, vehicle + bleomycin (2.5 U/kg), bleomycin + (10 mg/kg), and bleomycin + NAC (3 mmol/kg). Bleomycin administration resulted in prominent lung fibrosis as measured by lung hydroxyproline content and lung histology which is almost completely prevented by erdosteine and NAC. Hydroxyproline content was 18.7 +/- 3.5 and 11.2 +/- 0.6 mg/g dried tissue in bleomycin and saline treated rats, respectively (P < 0.001), and this level was 11.3 +/- 1.2 and 13.8 +/- 1.2 mg/g dried tissue in erdosteine and NAC pretreated, respectively. Erdosteine and NAC significantly reduced depletion of glutathione peroxidase, and prevented increases in myeloperoxidase activities, nitric oxide, and malondialdehyde levels in lung tissue produced by bleomycin. Data presented here indicate that erdosteine and NAC similarly prevented bleomycin-induced lung fibrosis and their antioxidant effects were also similar in this experiment.

Acetylcysteine↗
PubMed2006

Resveratrol alleviates bleomycin-induced lung injury in rats.

Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance such as pulmonary fibrosis. This study was designed to examine the effects of resveratrol, an antioxidant agents, against bleomycin-induced pulmonary fibrosis and oxidative damage. Wistar albino rats were administered a single dose of bleomycin (5 mg/kg; via the tracheal cannula) followed by either saline or resveratrol (10 mg/kg; orally) for 14 days. The effect of resveratrol on pulmonary oxidative damage was studied by cell count and analysis of cytokine levels (TGF-beta, TNF-alpha, IL-1beta and IL-6) in the bronchoalveolar lavage fluid (BALF) and biochemical measurements of malondialdehyde (MDA), an end product of lipid peroxidation; glutathione (GSH), a key antioxidant; and myeloperoxidase (MPO) activity, an index of neutrophil infiltration, in the lung tissue. Bleomycin-induced lung fibrosis was determined by lung collagen contents and also microscopically. Bleomycin caused a significant decrease in lung GSH, which was accompanied with significant increases in MDA level, MPO activity, and collagen contents of the lung tissue concomitant with increased levels of the pro-inflammatory mediators and cell count in BALF. On the other hand, resveratrol treatment reversed all these biochemical indices as well as histopathological alterations induced by bleomycin. The results demonstrate the role of oxidative mechanisms in bleomycin-induced pulmonary fibrosis, and resveratrol, by its antioxidant properties, ameliorates oxidative injury and fibrosis due to bleomycin. Thus, an effective supplement with resveratrol as an adjuvant therapy may be a very promising agent in alleviating the side effects of bleomycin, an effective chemotherapeutic agent.

Administration, Oral↗
PubMed2005

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

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)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha 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-kappaB) activation and secrete IL-8 in response to bleomycin; (2) the acquired ability of HEK293 to exhibit NF-kappaB 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-kappaB 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.

Antimetabolites, Antineoplastic↗
PubMed2004

The selective effect of genistein on the toxicity of bleomycin in normal lymphocytes and HL-60 cells.

This study was carried out to find whether genistein might enhance bleomycin induced cytotoxicity in human leukemia (HL-60) while protecting normal blood lymphocytes. Despite the excellent chemotherapeutic effect of bleomycin, its cytotoxicity and genotoxicity in normal cells remains a major problem in chemotherapy. Genistein, one of the major Soy isoflavones, is particularly effective in quenching free radicals generated by toxic agents. In this study, the protective and enhancement effects of genistein on bleomycin induced cytotoxicity in HL-60 cells and blood lymphocytes were demonstrated. HL-60 cells were treated with various concentrations of genistein for 3 h followed by treatment with various concentrations of bleomycin during the G1 phase. Pretreatment of genistein increased micronuclei (MN) frequency and DNA damage as a result of bleomycin treatment. However, when human lymphocytes were pretreated with genistein prior to bleomycin treatment during the G2 or G0 phase, the frequencies of bleomycin induced MN was decreased. Although the extent of bleomycin induced DNA damage determined by single cell gel electrophoresis was increased through the pretreatment of genistein in HL-60 cells, it was decreased in normal lymphocytes. The result of this study may therefore provide great impact on the potential activity of genistein as a therapeutic agent.

Antibiotics, Antineoplastic↗