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PubMed2002

Characterization of bleomycin lung injury by nuclear magnetic resonance: correlation between NMR relaxation times and lung water and collagen content.

The response of the NMR relaxation times (T(1), CPMG T(2), and Hahn T(2)) to bleomycin-induced lung injury was studied in excised, unperfused rat lungs. NMR, histologic, and biochemical (collagen content measurement) analyses were performed 1, 2, 4, and 8 weeks after intratracheal instillation of saline (control lungs) or 10 U/kg bleomycin sulfate. The control lungs showed no important NMR, water content, histologic, or collagen content changes. The spin-spin relaxation times for the fast and intermediate components of the CPMG decay (T(2f) and T(2i), respectively) increased 1 week after bleomycin injury (acute inflammatory stage) and then progressively decreased during the following 2-8 weeks (i.e., with the development of the chronic, fibrotic stage of the injury). The slow component (T(2s)) showed no significant changes. The response of T(1) and the slow component of the Hahn T(2) was, on the whole, similar to that of CPMG T(2f) and T(2i). T(1) changes were very small. Lung water content increased 1 week after injury. Histologic and biochemical assessment of collagen showed that collagen content was close to control at 1 week, but markedly increased at 2, 4, and 8 weeks. T(1) and T(2) data were directly correlated with lung water content and inversely correlated with collagen content. Our results indicate that NMR relaxation time measurements (particularly T(2)) reflect the structural changes associated with bleomycin injury. The prolonged T(2) relaxation times observed in the acute stage are related to the presence of edema, whereas the subsequent decrease in these values marks the stage of the collagen deposition (fibrotic stage). CPMG-T(2) and Hahn-T(2) measurements can be valuable as a potentially noninvasive method for characterizing bleomycin-induced lung injury and pathologically related lung disorders.

Animals↗
PubMed1992

N-nitrosoheptamethyleneimine-induced pulmonary and esophageal carcinogenesis and effects of concomitant treatment with bleomycin in rats.

The combination effects of bleomycin with N-nitrosoheptamethyleneimine (NHMI) or dihydroxy-di-N-propylnitrosamine (DHPN) on pulmonary carcinogenesis were investigated. Male F344 rats were given NHMI (20 or 40 ppm) or DHPN (200 ppm) in the drinking water and intraperitoneally injected with bleomycin (1 mg/kg) once a week for 18 weeks and then killed at week 24. Many rats treated with NHMI died before the termination of the experiment due to toxicity or development of advanced esophageal carcinomas, considered to be the main cause of death. Detailed histological examination performed on rats killed at week 24 revealed no statistically significant effects of bleomycin on NHMI or DHPN induction of neoplastic lesions in the lung or esophagus, although pulmonary carcinomas were only found in two rats treated with NHMI plus bleomycin. Under the present experimental conditions, NHMI exerted stronger carcinogenic activity in the esophagus than in the lung, and no obvious modifying effects of simultaneously administered bleomycin were evident on NHMI- or DHPN-induced pulmonary carcinogenesis.

Adenoma↗
PubMed1993

Structural basis for the sequence selectivity of DNA cleavage by bleomycins.

DNA strand scission by the bleomycin analogs talisomycin S10b and a novel fluorescent mimic, fluoromycin, has been characterized and compared with that of bleomycin A2. Both analogs were found to have essentially the same sequence specificity for DNA strand scission as bleomycin A2. As observed with bleomycin A2, the preferred sites of DNA cleavage by talisomycin S10b and fluoromycin were 5'-GpT-3' and 5'-GpC-3'. These results suggest that the DNA sequence selectivity of bleomycins remains unaltered upon modification of the C-terminal domain.

Base Sequence↗
PubMed1993

Identification of a plasma membrane protein that specifically binds bleomycin.

In this paper, the association of radiolabelled bleomycin on the plasma membrane of DC-3F cells is shown to be saturable, displaying classical features of a ligand-receptor binding. This association corresponds to the presence of 140,000 to 400,000 binding sites at the surface of the cells with a half-saturating concentration of 5 microM. Moreover, using a gel electrophoresis procedure to separate membrane proteins incubated with radiolabelled bleomycin, we demonstrate the existence of a membrane protein of about 250kDa able to specifically bind bleomycin. This membrane bleomycin-binding protein could play a major part in the association of bleomycin with the cells and in its further internalization, a process that has not been elucidated yet.

Animals↗
PubMed1993

A new brain tumour therapy combining bleomycin with in vivo electropermeabilization.

The potentials of in vivo electropermeabilization in combination with bleomycin in brain tumor treatment have been explored. In the brain of normal Fischer 344 rats, 2 electrodes were placed 5 mm apart. Electropermeabilization was performed with 8 to 12 exponential 400 V pulses with a time constant of 325 microseconds. Some animals were given bleomycin i.v., 1mg/kg b.w., 4 minutes before electric pulses delivery. No adverse effects were recorded during the observation of the animals during the following month. The effect of bleomycin and electropermeabilization upon tumour growth was studied in rats with glioma cells (RG2) implanted in the head of the right caudate nucleus. Treatment was given at different time intervals after the implantation of tumor cells and the effect upon survival was studied. Bleomycin alone did not prolong the survival of the animals. On the contrary, bleomycin plus electropermeabilization on the 10th, 11th or 12th day after inoculation increased the survival time to almost double that of untreated animals. We conclude that this treatment may be of value in brain tumour therapy.

Animals↗
PubMed1999

Anti-sclerotic effect of transforming growth factor-beta antibody in a mouse model of bleomycin-induced scleroderma.

Recent studies have demonstrated the evidence of the crucial role of transforming growth factor-beta (TGF-beta) in the pathogenesis of tissue fibrosis; however, its precise role has not been fully elucidated. Administration of anti-TGF-beta antibody is shown to be effective for inhibiting lung fibrosis induced by bleomycin in an experimental animal model. We have recently established a mouse model for scleroderma by repeated injections of bleomycin. In this study, we examined whether the suppression of TGF-beta leads to the improvement of dermal sclerotic lesion by using this model. We induced dermal sclerosis in C3H mice by subcutaneous injections of bleomycin (100 microg/ml) for 3 weeks, and separate groups of mice were also injected with bleomycin with either anti-TGF-beta antibody (10 microg/ml) or control normal rabbit serum for 3 weeks. Thus treated skins were harvested and analyzed for histological sclerosis, serum cytokine, and influx of mast cells and eosinophils, both of which are known to release fibrogenic cytokines or several mediators responsible for tissue fibrosis. The result showed that anti-TGF-beta antibody caused a significant reduction in cutaneous sclerosis characterized by histological features and hydroxyproline contents. Examination of tissue sections also revealed a significant suppression of influx of mast cells and eosinophils. Serum interleukin-4 (IL-4) and IL-6 levels determined by enzyme-linked immunosorbent assay exhibited a significant reduction after anti-TGF-beta antibody treatment. Our results suggest that administration of an antibody against TGF-beta is useful in preventing experimental dermal sclerosis induced by bleomycin and raises a possibility of the therapeutic approach of anti-TGF-beta antibody in scleroderma.

Animals↗
PubMed2001

All-trans-retinoic acid (ATRA) is of no benefit in bleomycin-induced lung injury.

All-trans-retinoic acid (ATRA) has anti-fibrotic and antiinflammatory properties, and may be useful as a therapeutic agent in lung fibrosis. To test this hypothesis we investigated the effect of ATRA on bleomycin-induced lung fibrosis in Sprague-Dawley rats. Treatment groups included: (1) a single intratracheal (i.t.) instillation of bleomycin and daily intraperitoneal (i.p.) injection of 0.5 mg/kg per day ATRA; (2) i.t. bleomycin and i.p. ATRA, 2 mg/kg per day, (3) i.t. bleomycin and i.p. diluent (cottonseed oil); (4) i.t. saline and i.p. ATRA, 0.5 mg/kg per day, (5) i.t. saline and i.p. ATRA, 2 mg/kg per day; and (6) i.t. saline and i.p. diluent. Animals were studied 14 days after i.t. instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semi-quantitative morphological index of lung injury, and by biochemical analysis of lung hydroxyproline content. Overt signs of lung injury were apparent in bleomycin-treated rats by all measures. These changes were not affected by treatment with ATRA at either dose. This study does not support the use of ATRA to prevent or ameliorate lung fibrosis.

Animals↗
PubMed1992

Superoxide anion production by rat neutrophils at various stages of bleomycin-induced lung injury.

This study investigated the level of activation of neutrophils isolated from rats at various stages of bleomycin-induced lung injury. Neutrophils were collected from blood and bronchoalveolar lavage (BAL) fluid and their superoxide anion (O2-)-generating capacity measured in response to phorbol myristate acetate (PMA) and opsonized zymosan (OZ) stimulation. When stimulated with PMA, BAL neutrophils isolated from animals 3 days after bleomycin treatment had a significantly greater capacity to produce O2- than BAL neutrophils from animals 7 days after bleomycin treatment. The O2- levels of 7 day BAL neutrophils more closely resembled the resting levels obtained with circulating neutrophils from both control and bleomycin-treated animals. There were no differences observed in any of the neutrophils when stimulated with OZ. Myeloperoxidase levels were measured in plasma and BAL and found to be elevated only in plasma at 7 days after bleomycin. These data demonstrate that neutrophil activation does occur in this model and that the activation appears to be transient, in response to specific stimuli and compartmentalized between the lung and blood.

Animals↗
PubMed1985

Evaluation of bleomycin, chlorozotocin, MGBG, and bruceantin in patients with advanced soft tissue sarcoma, bone sarcoma, or mesothelioma.

Patients with objectively measurable soft tissue sarcoma, bone sarcoma, or mesothelioma who had failed at least one prior chemotherapy regimen received either bleomycin (20 U/M2 i.v. day 1 each week), chlorozotocin (150 mg/M2 i.v. q6 weeks), MGBG (500 mg/M2 i.v. each week, escalated in 50 mg/M2 weekly increments to a maximum dose of 700 mg/M2), or bruceantin (5.5 mg/M2 days 1, 8, 15, and 22, with cycles repeated every 6 weeks). One hundred eighty patients were evaluable: 53 on bleomycin, 51 on chlorozotocin, 38 on MGBG, and 38 on bruceantin. Two partial responses resulted from bleomycin, and one each from chlorozotocin and MGBG. Both responders on bleomycin had mesothelioma. Seventy-four percent of the patients were of ECOG performance status 0 or 1, and over half on each arm had moderate or worse toxicity. At these doses and schedules, none of the four drugs tested was active against previously treated sarcomas. Bleomycin, however, should be considered for further evaluation in mesothelioma patients.

Adolescent↗
PubMed1985

A pharmacokinetic evaluation of IM administration of bleomycin oil suspension.

Bleomycin oil suspension was given IM twice daily to four patients, and bleomycin saline solution infused to three patients with cervical carcinoma. The serum levels of bleomycin were followed for 12 h by radioimmunoassay. Both regimens revealed comparable side effects. Only minor responses were seen. Bleomycin oil suspension produced prolonged levels of bleomycin in serum.

Bleomycin↗
PubMed1982

Bleomycin clinical pharmacology by radioimmunoassay.

Bleomycin pharmacokinetics were studied by radioimmunoassay in 11 patients who received 7-30 U intravenously (IV) and eight patients who received 4-30 U subcutaneously (SC). For patients who received IV bleomycin plasma disappearance was biphasic, with a mean initial half-life of 0.26 h and a terminal half-life of 2.3 h. Mean plasma drug clearance was 67.8 ml/min/m2 and the volume of distribution was 13.2 l/m2. Urinary excretion accounted for 63.9% of the drug in 24 h. After SC administration peak plasma levels occurred in 1.1 h, with a mean elimination half-life of 4.3 h. Mean plasma drug clearance was 60.5 ml/min/m2 and the volume of distribution was 19.2 l/m2. Bleomycin plasma clearance correlated well with serum creatinine (r2 = 0.72). Bleomycin has a rapid plasma elimination and urinary excretion. Bleomycin bioavailability after SC administration appears comparable to that seen after IV administration as determined by the areas under the plasma disappearance curves. Prolonged plasma levels are seen after SC injection, suggesting this route of administration can produce plasma concentrations comparable to those attained with continuous IV infusions.

Adolescent↗
PubMed1993

Bleomycin injury of the lung in a mast-cell-deficient model.

Lung mast cell hyperplasia and fibrosis is induced by bleomycin lung injury. The role of the mast cell in this process of injury and resultant fibrosis is unclear. Mutant mi/mi mice, profoundly mast-cell-deficient, were treated with intraperitoneal bleomycin and demonstrated minimal acute inflammatory and chronic fibrotic responses. Lung histamine values determined at 14 and 42 days after bleomycin injury in mi/mi mice were not increased compared to untreated mi/mi animals. However, lung histamine levels in normal mice demonstrated a 300% increase over controls on Day 14 after bleomycin injury, and then returned to baseline by Day 42. The mi/mi BAL cell recovery at 2 weeks after injury and lung hydroxyproline levels at 4 weeks after injury were not altered from baseline. The normal litter mates, in contrast, demonstrated significant increases compared to controls in both of these parameters (p < 0.01, p < 0.04). Although the mi/mi mouse is also deficient in basophils, natural killer cells and functional osteoclasts, there is no evidence of lowered pulmonary defense mechanism and neutrophils and alveolar macrophages are present in normal numbers. This investigation supports the hypothesis that the mast cell contributes to bleomycin-induced lung injury and fibrosis.

Animals↗
PubMed1984

Enhanced antitumor effects of bleomycin and moderate hyperthermia by additional use of ethanol.

The combined effects of moderate local hyperthermia, bleomycin and ethanol were investigated with Lewis lung carcinoma tumors in female C57BL/6 mice. Different combinations of treatments were performed on days 4 and 7 after tumor implantation. Combined treatment of 41 degrees C hyperthermia and bleomycin resulted in mild reductions of tumor growth. Hyperthermia plus bleomycin led to marked reduction in tumor growth under the condition of a 43 degrees C temperature. The antitumor effects of 41 degrees C hyperthermia combined with bleomycin were enhanced by the additional use of ethanol, and these effects were more remarkable than those of 43 degrees C hyperthermia and bleomycin. A possible application of these findings to clinical therapy for advanced esophageal cancer was discussed.

Animals↗
PubMed2004

Expression of nitric oxide synthase, aquaporin 1 and aquaporin 5 in rat after bleomycin inhalation.

OBJECTIVE: Nitric oxide (NO) and aquaporins (AQPs) are believed to play an important role in the pathogenesis of pulmonary inflammation and edema. The aim of this study was to investigate the role of NO synthase (NOS) and AQP in acute lung injury (ALI) lung following bleomycin inhalation in rats. DESIGN AND SETTING: A prospective controlled trial in a university research laboratory. ANIMALS AND INTERVENTIONS: Sprague-Dawley rats were treated by inhalation of 10 U/kg bleomycin hydrochloride in 5 ml of normal saline. Control rats were treated with 5 ml normal saline alone. The animals (6-8 rats per group) were killed on days 4, 7 or 14. MEASUREMENTS AND RESULTS: We analyzed the change in expression of inducible NOS (iNOS), neuronal NOS (nNOS), endothelial NOS (eNOS), aquaporin 1 (AQP1) and aquaporin 5 (AQP5) over time by Western blot. Nitrate and nitrite concentrations were measured in bronchoalveolar lavage fluid (BALF) using a modified Griess reaction. The nitrite and nitrate concentrations in BALF from rats 4 days after bleomycin exposure were greater than those from saline-treated rats. Immunoblotting studies demonstrated increased levels of eNOS in the rat lung at 4, 7 and 14 days and iNOS at 7 and 14 days after bleomycin inhalation. However, nNOS expression was unaltered. Although AQP1 expression was decreased in rats at 4 days, AQP5 expression was increased at 4, 7 and 14 days. CONCLUSIONS: This study demonstrates that NO metabolites increase along with eNOS and iNOS expression during the acute exudative phase in ALI, and that AQP and NOS are regulated independently in bleomycin-induced pulmonary edema.

Animals↗
PubMed1996

Functional mitochondria are essential for Saccharomyces cerevisiae cellular resistance to bleomycin.

The antitumor activity of bleomycin is associated with its ability to produce DNA lesions. The cellular process that repairs bleomycin-induced DNA lesions is not entirely clear. To understand how these DNA lesions are repaired in eukaryotic cells, we used mini Tn3 : : LEU2 :: LacZ transposon mutagenesis to isolate yeast mutants that were hypersensitive to bleomycin. One of the mutants, HCY69, was characterized further and found to be 4- and 3-fold more sensitive, respectively, to bleomycin and hydrogen peroxide, as compared to the parent. The mutant displayed parental resistance to a variety of other DNA-damaging agents. Plasmid rescue and DNA sequence analysis revealed that the transposon interrupted the OXA1 gene, which encodes a protein required to process one of the subunits, cox II, of the cytochrome oxidase complex in mitochondria. A plasmid carrying the native OXA1 gene fully restored drug resistance to strain HCY69. Our data strongly suggest that functional mitochondria are required for cellular protection against the toxic effects of bleomycin.

Bleomycin↗
PubMed1985

Effective DNA cleavage by bleomycin-vanadium(IV) complex plus hydrogen peroxide.

It has been firstly found that the bleomycin-vanadyl(IV) complex is effectively capable of cleaving DNA in the presence of hydrogen peroxide. The 1:1 bleomycin-VO(IV) complex has been characterized by ESR and electronic absorption spectra, and its ESR parameters (go = 1.982 and Ao = 93.5 G) are indicative of VO(N5) coordination type for the metal-binding environment. The mode of nucleotide sequence cleavage induced by the present bleomycin-VO(IV)-H2O2 complex system was appreciably different from the corresponding Fe(III) complex system. Of special interest is the fact that the bleomycin-vanadium complex system more preferentially attacked G-A(5'----3') sequences than the bleomycin-iron complex system.

Base Sequence↗
PubMed1983

Influence of bleomycin on the metabolism of dermal collagen in albino rats.

The metabolism of collagen in male rats by treatment with bleomycin was studied following the injection of [3H]proline and the determination of specific and total activity of [3H]hydroxyproline in skin collagen fractions and urine. In the case of the bleomycin-treated animals, there was found to be an increase in the neutral salt soluble collagen content with no change in insoluble collagen content as compared to the control group. The specific and total radioactivity of [3H]hydroxyproline in soluble and insoluble collagen fractions was also increased. Examination of [3H]hydroxyproline activity in soluble and insoluble collagen showed that the conversion of soluble to insoluble collagen was improved by the bleomycin-treated group. It was found that this was accompanied by a decrease in urinary excretion of total hydroxyproline and [3H]hydroxyproline during the first 12 hr after the administration of [3H]proline. Therefore, the results of the present investigation clearly indicate that the maturation of soluble to insoluble collagen is promoted and accompanied by a decrease in the catabolism of soluble collagen in the bleomycin-treated animals. In addition, administration of bleomycin increased the synthesis of collagen.

Animals↗
PubMed1985

Poly(ADP-ribose) synthetase activity during bleomycin-induced lung fibrosis in hamsters.

Bleomycin damages cellular DNA and is a potent inducer of pulmonary fibrosis. It has been shown to act through a superoxide-mediated mechanism. We are interested in determining the biochemical mechanisms involved in fibrosis and in this preliminary study we have examined the temporal relationship between early biochemical events associated with DNA damage and fibrosis, in lungs of hamsters after administration of 0.75 unit of bleomycin. The activities of poly(ADP-ribose) synthetase, an enzyme associated with DNA repair, inducible superoxide dismutase (SOD) and prolyl hydroxylase as well as the tissue levels of NAD+ and hydroxyproline in the lung were determined. All three enzyme activities expressed as per milligram DNA or per lung, increased upon bleomycin treatment over the saline-administered controls. Lung poly(ADP-ribose) synthetase activity which is sensitive to DNA breaks, increased first (24% over control in 1 day, P less than 0.0001), attained the maximum value on the 5th day (952% over control, P less than 0.0001), and started to decline thereafter and approached near the control value on 14th day. Bleomycin treatment induced a rapid change in the level of lung NAD+. After 1 day the level of NAD+ was reduced by 42% compared to the control (P less than 0.001), further declined to 65% (P less than 0.001) on the 3rd day, and stayed at that level until the 7th day. On the 14th day, however, the NAD+ level was still lower (29%, P less than 0.05) but approaching the value in the control animals. The activity of prolyl hydroxylase showed significant increase on the 3rd day (50% over control, P less than 0.0001) after bleomycin administration. The enzyme activity continued to increase until the end of the experiment (490% of control, P less than 0.0001, on Day 14). The content of undialyzable hydroxyproline, a marker for collagen, was also increased significantly in the lung tissue on the 3rd day (30% over control, P less than 0.05), continued to increase and reached the highest level on the 14th day (71% over control, P less than 0.001). A significant increase in the activity of SOD (19% over control, P less than 0.001) was seen on the 5th day which continued to increase and attained the highest value on Day 14 (115% over control, P less than 0.0001).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗