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PubMed1984

Enhancement of bleomycin-mediated DNA damage by epidermal microsomal enzymes.

The role of epidermal microsomal enzymes in catalyzing bleomycin-mediated chain breakage in calf-thymus DNA and in DNA isolated from neonatal rat epidermis was studied. Aerobic incubation of bleomycin with epidermal microsomes, epidermal or calf-thymus DNA and NADPH caused substantial chain breakage of the DNA which was dependent upon concentrations of drug, microsomal protein and NADPH. The reactive oxygen scavenger superoxide dismutase, the metal chelator EDTA, and cytochrome c each inhibited the enzyme-mediated chain breakage reaction. Scavengers of hydrogen peroxide and hydroxyl radicals, including catalase and benzoate and inhibitors of microsomal cytochrome P-450-dependent monooxygenases such as 1-benzylimidazole, metyrapone and alpha-naphthoflavone, had no inhibitory effects on bleomycin-mediated DNA chain breakage. In contrast, ascorbic acid significantly enhanced DNA damage by bleomycin. These studies indicate that mammalian epidermis possesses membrane-bound enzyme activity capable of enhancing bleomycin-mediated chain breakage of DNA and that oxidation/reduction of adventitious iron and generation of reactive oxygen participate in the reaction. These responses in the epidermis could directly relate to the mechanism of action of intralesional injections of bleomycin which are used quite effectively in the management of recalcitrant human warts. Either epidermal or wart virus DNA or both could be targets for this pharmacologic effect of the drug which is augmented by epidermal microsomal enzymes.

Animals↗
PubMed1987

Bleomycin-induced aggregation of presolubilized and nuclear chromatin from L1210 cells.

These studies have identified a new activity of bleomycin (in addition to the well-known DNA cleavage): drug-induced chromatin aggregation. Bleomycin treatment of presolubilized chromatin from L1210 nuclei resulted in two types of effect as shown by sedimentation analysis of intact nucleoprotein. The first effect was a dose-dependent fragmentation of chromatin to mononucleosomes (12 S) and subnucleosomal fragments (under 5 S). The second effect was aggregation manifested by the generation of large chromatin particles (over 120 S) that sedimented faster than the original material (20-40 S). Bleomycin treatment of nuclei from L1210 cells resulted in a similar, almost bimodal, size distribution of drug-released chromatin fragments. Increasing levels of bleomycin produced a gradual enhancement of the amount of small fragments (under 5 S) accompanied by generation of large, aggregated particles. Aggregation caused by high drug concentrations significantly reduced the overall extent of chromatin solubilization and allowed only the release of the most degraded fragments from nuclei. The aggregation required intact nucleoprotein, since it was not detected after high-salt deproteinization of bleomycin-treated presolubilized or nuclear chromatin. The aggregation phenomenon reflects a novel activity of bleomycin which may contribute to the drug's antiproliferative properties.

Animals↗
PubMed1993

Potentiation of bleomycin antitumor effectiveness by electrotherapy.

Electrotherapy was investigated for its ability to increase the responsiveness of murine tumors to bleomycin treatment. Mice bearing fibrosarcoma were treated with 250 micrograms bleomycin and then with 0.6 mA direct current (DC) for 60 min. Antitumor effects of single treatments were moderate with bleomycin, but significant with electrotherapy. Combined treatment with bleomycin followed by electrotherapy was more effective than either treatment alone. Tumor growth delay of the animals after combined treatment was greater than the summation of tumor growth delays after single treatments. The results of our study indicate that bleomycin and electrotherapy treatments interact, with electrotherapy potentiating the effectiveness of bleomycin treatment.

Animals↗
PubMed1976

Stimulatory effect of bleomycin on the synthesis of acidic glycosaminoglycans in cultured fibroblasts derived from rat carrageenin granuloma.

Cultured fibroblasts derived from rat carrageenin granuloma were treated with bleomycin and the synthesis of hexosamine-containing substances was compared with that in control cells. Four day treatment with o.1 mug bleomycin/ml resulted in a significant increase of the production of these macromolecules by the cells, though DNA synthesis was remarkably inhibited at this dose of bleomycin. The stimulatory effect could be seen as early as the second day of bleomycin treatment, and was enhanced with increasing treatment time. Further fractionation of the hexosamine-containing substances revealed that synthesis of acidic glycosaminoglycans was more sensitive to bleomycin than that of glycoproteins, i.e., acidic glycosaminoglycans increased by 80% and glycoproteins by 53% after four day treatment with 0.1 mug bleomycin/ml. The increased components of acidic glycosaminoglycans included not only hyaluronic acid but also sulphated glycosaminoglycans. Collagen synthesis was increased by 23% by the same dose of bleomycin. N-Acetyl-beta-glucosaminidase, one of the degradation enzymes for acidic glycosaminoglycans released into the cultured medium, was decreased significantly by bleomycin.

Acetylglucosaminidase↗
PubMed1982

Spectroscopic studies on bleomycin-iron complexes with carbon monoxide, nitric oxide, isocyanide, azide, and cyanide and comparison with iron-porphyrin complexes.

The bleomycin-iron complexes with CO, NO, C2H5NC, OH-, N-3, CN-, and CH3NH2 were characterized by electronic, ESR, 1H-NMR, and Mössbauer spectroscopies and the findings were compared with the corresponding hemoprotein complexes. The 1H-NMR and Mössbauer features for the CO and C2H5NC adducts of the bleomycin-Fe(II) complex are consistent with an S = 0 ferrous assignment. The OH-, CH3NH2, and N-3 adducts of the bleomycin-Fe(III) complex show the ESR, 1H-NMR, and Mössbauer spectra typical of a low-spin Fe(III). The unique Mössbauer parameters of the bleomycin-Fe(II)-NO complex demonstrate mixing between the NO pi- and the Fe 3d-orbitals. The magnitude of the proton chemical shifts over +/- 50 ppm indicates a high-spin ferric type for the bleomycin-Fe(III)-CN complex. The Mössbauer parameters (delta EQ = 0.89 and delta = 0.48 mm/s) of the CN- adduct differ substantially from those of typical low-spin hemoprotein-cyanide complexes. Except for the CN- adduct, the Mössbauer and crystal field parameters of these bleomycin-iron complexes are similar to those of the corresponding hemoprotein complexes.

Azides↗
PubMed1991

Effects and levels of coenzyme Q10 in lung and liver in bleomycin-hamster model of lung fibrosis.

As part of an ongoing study to search for potential antifibrotic agents which may reduce bleomycin-induced fibrosis of lung, hamsters were treated with 25 mg/kg coenzyme Q10 (CoQ10) for 2 days prior to and daily for 14 days after intratracheal instillation of bleomycin (5 U/kg body wt.). CoQ10 was found not to attenuate bleomycin-induced lung fibrosis. Treatment with CoQ10 did not raise the lung and liver content of CoQ10. On the other hand, bleomycin treatment alone tended to increase the lung and liver content of CoQ10. At the higher dose (7.5 U/kg), bleomycin almost doubled the hepatic CoQ10 content. Treatment with the lower dose (5 U/kg) of bleomycin and CoQ10 was always associated with higher levels of CoQ10 in both liver and lungs than treatment with either of them alone.

Animals↗
PubMed1991

Spin-trapping studies of the oxidation-reduction reactions of iron bleomycin in the presence of thiols and buffer.

The reaction of ferrous bleomycin with dioxygen is reexamined to clarify whether radical species derived from molecular oxygen are generated. Detection of low levels of spin-trapped oxyradicals confirm the production of OH during this reaction when bleomycin is present in excess, but not when iron and drug concentrations are equal. In phosphate buffer, hydroxyl radicals continue to be spin trapped for at least 15 min after Fe(II)bleomycin has been oxidized to Fe(III)bleomycin. In HEPES buffer, detection of a HEPES radical in the absence of spin trap over the same period independently supports the conclusion that reactive radicals are present after the initial oxidation of Fe(II)bleomycin is complete. When glutathione is included in the aerobic reaction mixture, thiyl radical species are spin trapped. The reaction of Fe(III)bleomycin with cysteine produces thiyl radical without spin-trapped hydroxyl radical.

Bleomycin↗
PubMed1996

Measurement of hydroxyl radicals catalyzed in the immediate vicinity of DNA by metal-bleomycin complexes.

A recently developed sensitive fluorimetric assay has been used to examine whether free hydroxyl radicals (HO.) are generated in the immediate vicinity of DNA by Fe(II)-bleomycin. When aqueous solutions of SECCA (the succinimidyl ester of coumarin-3-carboxylic acid) are irradiated with gamma rays or incubated with Fe(II)-bleomycin or Fe (II)-EDTA in the presence of ascorbate and H2O2, 7-hydroxy-SECCA, a fluorescent product of the interaction of HO. with SECCA, is generated. Studies with catalase and several HO. scavengers indicate that the fluorescence induction is mediated by HO. On the contrary, Cu(II)-bleomycin complexes under similar conditions fail to induce 7-hydroxy-SECCA fluorescence. When SECCA is conjugated to DNA via SECCA-polylysine-DNA complexes and incubated in the same iron-containing systems, the relative ability of the scavengers to reduce the fluorescence again demonstrates the generation of 7-hydroxy-SECCA by HO. However, while the fluorescence is practically eliminated by high concentrations of DMSO (100 mumols dm-3) in the systems with Fe(II) or Fe(II)-EDTA, it is not possible to reduce it similarly in the case of Fe(II)- bleomycin. These data demonstrate the generation of HO. by Fe(II)-bleomycin in the immediate vicinity of DNA. Because the experiments simulate the lifetime of HO. expected in cells, these data suggest that, if such DNA-associated HO. radicals are also produced in vivo by bleomycin, these would not be scavengable by intracellular scavengers and they could interact with chromatin.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Damage to lymphocytes by X-ray and bleomycin measured with the cytokinesis-block micronucleus technique.

Chromosome damage induced by X-irradiation or bleomycin was measured using the cytokinesis-block micronucleus assay in the peripheral blood lymphocytes of 6 newborn, 8 young and 10 elderly individuals. An increase in the frequency of spontaneous micronuclei with age was observed. There was no difference in the X-irradiation-induced micronucleus frequency between the 3 groups. There was a significant increase with age in the number of micronuclei induced by bleomycin. Kinetochore-labelling studies revealed that the percentage of kinetochore-positive induced micronuclei was higher for bleomycin (36.2-43.3%) than for X-irradiation (17.1-19.7%). The age-related increase in frequency of spontaneous or bleomycin-induced micronuclei was due to increases in both kinetochore-positive and kinetochore-negative micronuclei. The frequency of kinetochore-positive or -negative micronuclei induced by X-irradiation was not different between the 3 age groups. These results suggest that bleomycin is more potent in inducing whole-chromosome loss than X-rays, and that lymphocytes from aged individuals are more sensitive to bleomycin in terms of both chromosome breakage and whole chromosome loss.

Adult↗
PubMed1989

Defective repair of DNA single- and double-strand breaks in the bleomycin- and X-ray-sensitive Chinese hamster ovary cell mutant, BLM-2.

Using filter elution techniques, we have measured the level of induced single- and double-strand DNA breaks and the rate of strand break rejoining following exposure of two Chinese hamster ovary (CHO) cell mutants to bleomycin or neocarzinostatin. These mutants, designated BLM-1 and BLM-2, were isolated on the basis of hypersensitivity to bleomycin and are cross-sensitive to a range of other free radical-generating agents, but exhibit enhanced resistance to neocarzinostatin. A 1-h exposure to equimolar doses of bleomycin induces a similar level of DNA strand breaks in parental CHO-K1 and mutant BLM-1 cells, but a consistently higher level is accumulated by BLM-2 cells. The rate of rejoining of bleomycin-induced single- and double-strand DNA breaks is slower in BLM-2 cells than in CHO-K1 cells. BLM-1 cells show normal strand break repair kinetics. The level of single- and double-strand breaks induced by neocarzinostatin is lower in both BLM-1 and BLM-2 cells than in CHO-K1 cells. The rate of repair of neocarzinostatin-induced strand breaks is normal in BLM-1 cells but retarded somewhat in BLM-2 cells. Thus, there is a correlation between the level of drug-induced DNA damage in BLM-2 cells and the bleomycin-sensitive, neocarzinostatin resistant phenotype of this mutant. Strand breaks induced by both of these agents are also repaired with reduced efficiency by BLM-2 cells. The neocarzinostatin resistance of BLM-1 cells appears to be a consequence of a reduced accumulation of DNA damage. However, the bleomycin-sensitive phenotype of BLM-1 cells does not apparently correlate with any alteration in DNA strand break induction or repair, as analysed by filter elution techniques, suggesting an alternative mechanism of cell killing.

Animals↗
PubMed2006

Radiological findings following postsurgical intratumoral bleomycin injection for cystic craniopharyngioma.

OBJECTIVES: The purpose of this study was to compare the radiological findings before and after intratumoral bleomycin injection in patients with cystic craniopharyngioma so as to define the role of adjuvant intracavitary bleomycin chemotherapy for cystic craniopharyngiomas. PATIENTS AND METHODS: Eleven patients whose craniopharyngioma was confirmed cytologically and/or histologically were retrospectively reviewed. The follow-up duration ranged from 9 to 79 months (mean, 31.6 months). Only the solid portion of the cystic craniopharyngiomas was excised before repeated injections of bleomycin (15-180 mg in total) into the cystic portion through an Ommaya reservoir were given. The patients were evaluated neuroradiologically before and after bleomycin administration. RESULTS: After the completion of all treatment cycles, the disappearance or shrinkage of the tumor was initially noted in all cases on follow-up CT and/or MR imaging studies. However, tumor recurrence was seen in four cases with a mixed tumor type. CONCLUSION: Postoperative bleomycin injection in cystic craniopharyngioma does not appear to totally eradicate the tumor and does not stop tumor recurrence unless the cyst is the only portion of the craniopharyngioma that is left. Nevertheless, postoperative bleomycin injection decreases and stabilizes tumor size, and thus may be considered as an option of treatment modalities in patients with predominantly cystic craniopharyngiomas.

Adolescent↗
PubMed2004

Changes in pulmonary surfactant function and composition in bleomycin-induced pneumonitis and fibrosis.

Bleomycin is a widely accepted cancer drug but may induce life-threatening interstitial lung disease in a subset of patients. We evaluated the effect of bleomycin administration on pulmonary surfactant function and composition in rabbit lungs. In order to obtain a uniform response to bleomycin, aerosol technology was employed for bronchoalveolar delivery of 1.8 U/kg b.w. bleomycin. On days 4, 8, 16, 24, 32, and 64 after challenge, bronchoalveolar lavages were performed. Sham-aerosolized rabbits served as controls. In the early acute respiratory distress syndrome (ARDS)-like post-bleomycin period (4-16 days), marked loss of surface activity of the large surfactant aggregate (LA) fraction of surfactant was noted. In parallel, reduced percentages of LA, but only minor changes in surfactant apoproteins (SP)-A, SP-B, and SP-C, were encountered. Analysis of the surfactant lipid profile showed impressively enhanced cholesterol and significantly decreased phosphatidylglycerol (PG) levels. The relative content of dipalmitoyl-PC (DPPC) was slightly increased, and a several-fold increase within the 1-O-alkyl-2-acyl subclass of PC was observed. During the prolonged fibroproliferative period, a highly significant downregulation of SP-B and SP-C levels was observed. This was paralleled by an upregulation of the total extracellular phospholipid pool, with a far-reaching normalization of the (phospho)-lipid profile. The biophysical surfactant function never fully normalized within the 64-day observation period. In conclusion, bleomycin caused marked abnormalities of pulmonary surfactant, with the profile of changes being different between the early ARDS and the late fibrotic phase.

Administration, Inhalation↗
PubMed2000

Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin.

Increased expression of matrix metalloproteinases, particularly gelatinase B (MMP-9), has been described in the lungs in pulmonary fibrosis. Intratracheal bleomycin is often used experimentally to produce lesions resembling human fibrosing alveolitis. To assess the role of gelatinase B in bleomycin-induced fibrosing alveolitis, we instilled bleomycin intratracheally into gelatinase B-deficient mice and gelatinase B+/+ littermates. Twenty-one days after bleomycin the two groups of mice were indistinguishable in terms of pulmonary histology and total lung collagen and elastin. However, the lungs of gelatinase B-deficient mice showed minimal alveolar bronchiolization, whereas bronchiolization was prominent in the lungs of gelatinase B+/+ mice. Gelatinase B was identified immunohistochemically in terminal bronchiolar cells and bronchiolized cells 7 and 14 days after bleomycin in gelatinase B+/+ mice, and whole lung gelatinase B mRNA was increased at the same times. Many bronchiolized cells displayed Clara cell features by electron microscopy. Some bronchiolized cells stained with antibody to helix transcription factor 4, a factor associated with the ciliated cell phenotype. Thus, fibrosing alveolitis develops after intratracheal bleomycin irrespective of gelatinase B. However, gelatinase B is required for alveolar bronchiolization, perhaps by facilitating migration of Clara cells and other bronchiolar cells into the regions of alveolar injury.

Animals↗
PubMed1998

Induction of leukotriene production by bleomycin and asparaginase in mast cells in vitro and in patients in vivo.

Bleomycin and asparaginase are widely used antineoplastic agents which may induce allergic or inflammatory side-effects. Mast cells are implicated as effector cells in allergic and inflammatory responses. The aim of this study was to establish whether bleomycin or asparaginase modulate leukotriene production in vitro and in vivo. Leukotriene C4 (LTC4) production by murine bone marrow-derived mast cells (BMMC) was determined by radioimmunoassay (RIA). Leukotriene production in patients was assessed by determining leukotriene E4 and N-acetyl-leukotriene E4 in urine by means of combined HPLC and RIA. Bleomycin induced an up to 2.1-fold increase in LTC4 production both in unstimulated and in calcium ionophore-stimulated mast cells. In 3 of 7 patients treated with bleomycin, a greater than 2-fold increase in endogenous leukotriene production was observed. This effect was associated with febrile responses and was most pronounced in a patient who developed an Adult Respiratory Distress Syndrome (ARDS). Asparaginase increased leukotriene production up to 10-fold in stimulated but not in unstimulated BMMC. In a patient who developed an anaphylactic reaction after treatment with asparaginase, a pronounced increase in urinary leukotriene concentration was observed. In contrast to bleomycin or asparaginase, a number of other cytostatic agents did not significantly change leukotriene production by BMMC. Our data indicate that some of the inflammatory and allergic side-effects of bleomycin and asparaginase could be mediated by leukotrienes, a possible source of which may be mast cells.

Adult↗
PubMed1973

Characterization of bleomycin-resistant DNA.

After reaction of DNA with high concentrations of bleomycin, approximately 80% of the DNA becomes trichloroacetic acid (TCA) soluble. The remaining 20% of the DNA remains TCA insoluble. Upon further treatment of this TCA-insoluble material with high concentrations of the drug, no further drug action can be detected. Drug action is defined as fragmentation of DNA to smaller molecular size, release of free bases, and TCA solubilization. This material which is not attacked by bleomycin has been termed bleomycin-resistant DNA. This bleomycin-resistant DNA does not compete with native DNA in the bleomycin reaction indicating that there is no binding or inactivation of the drug by the resistant DNA. The resistant DNA shows very little hyperchromicity when heated through the melting temperature for the corresponding native DNA, indicating a single-stranded structure. Results of sedimentation and equilibrium analyses yield a molecular weight of about 4,000 daltons. This value is the same regardless of the source of the native DNA. Finally, the bleomycin-resistant DNA exhibits a base composition similar to that of the native DNA from which it was derived.

Animals↗
PubMed1998

Changes in c-Jun but not Bcl-2 family proteins in p53-dependent apoptosis of mouse cerebellar granule neurons induced by DNA damaging agent bleomycin.

Tumor suppressor gene p53 is a critical regulator of the cellular response to DNA damage. To examine the function of p53 in postmitotic CNS neurons, we cultured cerebellar granule cells from 15-day-old wild type and p53-deficient mice, and analyzed changes of protein expression in apoptosis elicited by DNA damage. When cerebellar granule cells from wild type mice were treated with bleomycin, a DNA strand-break inducing agent, neuronal death occurred. In contrast, cells from p53-deficient mice were resistant to bleomycin-induced neuronal death. Furthermore, cells from p53 heterozygous mice showed an intermediate resistance between wild type and p53-deficient mice. These results show that p53 is required for the bleomycin-induced cerebellar granule cell death. To examine which proteins are involved in this apoptosis, we examined changes in protein levels of the Bcl-2 family, including Bcl-2, Bcl-X and Bax. The relative amounts of these proteins did not change after bleomycin treatment, suggesting that the changes in the levels of these Bcl-2 family proteins are not necessary for apoptosis in this system. In contrast, the levels of c-Jun protein significantly increased 6 h after treatment with bleomycin in wild type but not in p53-deficient cerebellar granule cells. These results raise the possibility that c-Jun is required for p53-dependent neuronal apoptosis induced by bleomycin.

Animals↗
PubMed1982

Adjuvant vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum chemotherapy regimen with and without maintenance in patients with resected stage IIB testis cancer.

A total of 42 patients with stage IIB nonseminomatous germ cell tumors of the testis after orchiectomy and retroperitoneal lymph node dissection received adjuvant chemotherapy with the modified vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum regimen. Of the patients 29 had N2B and 13 had N3 nodal categories. Adjuvant vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum chemotherapy was given with maintenance in the first 24 patients and without maintenance (2 months of chemotherapy) in the subsequent 18. Chemotherapy with maintenance was given for 1 year and began with 2 inductions 3 to 4 weeks apart: 600 mg./m.2 intravenous cyclophosphamide, 30 mg. intravenous bleomycin, 1 mg./m.2 intravenous actinomycin D and 4 mg./m.2 intravenous vinblastine on day 1, 20 mg./m.2 bleomycin daily by continuous 24-hour induction on days 1 to 3 and 120 mg./m.2 intravenous cis-platinum with mannitol-induced diuresis on day 4. Maintenance with 6 mg./m.2 intravenous vinblastine and 1 mg./m.2 intravenous actinomycin D every 3 weeks was initiated 3 weeks after the second induction for the remainder of the year. Adjuvant vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum chemotherapy without maintenance was given for 2 months and used 3 inductions identical to those described previously. Complete remission has been maintained in 41 of 42 patients: all 24 who received maintenance chemotherapy and 17 of 18 who did not. One patient had a relapse with sarcoma and 6 required broad-spectrum antibiotics for fever during myelosuppression. A temporary increase in the serum creatinine of more than 2 mg. per cent occurred in 1 patient. Chronic renal failure or pulmonary fibrosis was not seen. Our results show that vinblastine, actinomycin D, bleomycin, cyclophosphamide and cis-platinum chemotherapy is effective in the prevention of recurrences in patients with resected stage IIB disease, and suggest that adjuvant chemotherapy is equally effective with or without maintenance.

Adolescent↗
PubMed2001

Lung vagal afferent activity in rats with bleomycin-induced lung fibrosis.

Bleomycin treatment in rats results in pulmonary fibrosis that is characterized by a rapid shallow breathing pattern, a decrease in quasi-static lung compliance and a blunting of the Hering-Breuer Inflation Reflex. We examined the impulse activity of pulmonary vagal afferents in anesthetized, mechanically ventilated rats with bleomycin-induced lung fibrosis during the ventilator cycle and static lung inflations/deflations and following the injection of capsaicin into the right atrium. Bleomycin enhanced volume sensitivity of slowly adapting stretch receptors (SARs), while it blunted the sensitivity of these receptors to increasing transpulmonary pressure. Bleomycin treatment increased the inspiratory activity, while it decreased the expiratory activity of rapidly adapting stretch receptors (RARs). Pulmonary C-fiber impulse activity did not appear to be affected by bleomycin treatment. We conclude that the fibrosis-related shift in discharge profile and enhanced volume sensitivity of SARs combined with the increased inspiratory activity of RARs contributes to the observed rapid shallow breathing of bleomycin-induced lung fibrosis.

Adaptation, Physiological↗