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PubMed1992

Rat macrophage activation after treatment with the bleomycin group of antitumour antibiotics in vivo.

We have previously reported that bleomycin and its derivative peplomycin enhance the release of cytokines by rat spleen cells during mitogen-stimulated cell culture in vitro, but liblomycin, another derivative of bleomycin, decreases cytokine release to below untreated control levels. Cytokine release correlated well with the inhibition of subcutaneous tumour growth after treatment with equivalent doses of the three analogues. In contrast, ascites tumour growth is completely inhibited by liblomycin and appears to be at least partly macrophage-mediated because the antitumour effect can be significantly inhibited by carageenan. This study shows that bleomycin and its analogues activate rat peritoneal macrophages and increase interleukin-6 release, O2- production, cell spreading, phagocytosis and random migration of macrophages, but only bleomycin enhances peritoneal macrophage invasion into a monolayer of rat lung endothelial cells in vitro. This study also shows that although liblomycin decreases spleen cell cytokine production and is less effective than bleomycin against subcutaneous tumour, as we have previously reported, the antitumour drug activates peritoneal macrophages and, compared to bleomycin, has a remarkable therapeutic effect on rat ascites tumour.

Animals↗
PubMed1991

Mechanisms of bleomycin-induced lung damage.

Bleomycins are a family of compounds produced by Streptomyces verticillis. They have potent tumour killing properties which have given them an important place in cancer chemotherapy. They cause little marrow suppression, but pulmonary toxicity is a major adverse effect. The mechanisms of cell toxicity are well described based on in vitro experiments on DNA. The bleomycin molecule has two main structural components: a bithiazole component which partially intercalates into the DNA helix, parting the strands, as well as pyrimidine and imidazole structures, which bind iron and oxygen forming an activated complex capable of releasing damaging oxidants in close proximity to the polynucleotide chains of DNA. This may lead to chain scission or structural modifications leading to release of free bases or their propenal derivatives. The mechanisms are well described based on in vitro experiments on DNA, but how they relate to intact cells in whole animals is more tenuous. Bleomycin is able to cause cell damage independent from its effect on DNA by induction lipid peroxidation. This may be particularly important in the lung and in part account for its ability to cause alveolar cell damage and subsequent pulmonary inflammation. The lung injury seen following bleomycin comprises an interstitial oedema with an influx of inflammatory and immune cells. This may lead to the development of pulmonary fibrosis, characterized by enhanced production and deposition of collagen and other matrix components. Several polypeptide mediators capable of stimulating fibroblasts replication or excessive collagen deposition have been implicated in this, but the precise role of these in bleomycin-induced fibrosis is yet to be demonstrated. Current therapy for bleomycin-induced lung damage is inadequate, with corticosteroids most often used. Given the mechanism of action described above, antioxidants and iron chelators might be beneficial. Although, studies to date are equivocal and there is insufficient evidence to promote their use clinically. Novel drugs are currently being developed and it is hoped these may be more useful.

Animals↗
PubMed2005

Pulmonary epithelial permeability in patients treated with bleomycin containing chemotherapy detected by technetium-99m diethylene triamine penta-acetic acid aerosol (99mTc-DTPA) scintigraphy.

PURPOSE: To evaluate pulmonary epithelial permeability using 99mTc-DTPA scintigraphy in patients treated with bleomycin-containing regimens. MATERIAL AND METHODS: Twelve non-smoking chemotherapy-naïve patients with no clinical or radiological evidence of pulmonary disease and treated with bleomycin-containing chemotherapy were tested with 99mTc-DTPA scintigraphy before the first cycle and every 3 weeks until the third month after the end of chemotherapy (total cumulative dose of bleomycin 347.9 mg). RESULTS: Pretreatment values (T1/2 74.93 minutes) of 99mTc-DTPA scintigraphy were significantly higher than those obtained after the total dose of bleomycin (T1/2 51.00 minutes) (p < 0.001). This difference was more important in the later evaluations especially, on the third week and third month measures after discontinuing treatment (p < 0.001). All the tests of Within-Subjects Effects were significant (p < 0.001). Comparing pretreatment and post-treatment scintigraphies the mean T1/2 99mTc-DTPA values decreased as the bleomycin dose increased. CONCLUSION: We conclude that cumulative bleomycin doses are related to increased pulmonary epithelial permeability at a dose of 256.5 mg. However, whether this is related to clinical toxicity is uncertain and large, multi-center prospective studies are needed.

Adult↗
PubMed2003

Protective mechanisms against the antitumor agent bleomycin: lessons from Saccharomyces cerevisiae.

Bleomycin is a small glycopeptide antibiotic used in combination therapy for the treatment of a few types of human cancer. The antitumor effect of bleomycin is most likely caused by its ability to bind to DNA and induce the formation of toxic DNA lesions via a free radical reactive (Fe.bleomycin) complex. However, the chemotherapeutic potential of bleomycin is limited, as it causes pulmonary fibrosis and tumor resistance at high doses. The chemical structure and modes of action of bleomycin have been extensively studied and these provide a foundation towards improving the therapeutic value of the drug. This review provides a first account of the current state of knowledge of the cellular processes that can allow the yeast Saccharomyces cerevisiae to evade the lethal effects of bleomycin. This model organism is likely to provide rapid clues in our understanding of bleomycin resistance in tumor cells.

Antineoplastic Agents↗
PubMed2001

Intracystic chemotherapy with bleomycin in the treatment of craniopharyngiomas.

OBJECT: Since bleomycin has not yet been used very frequently in the treatment of patients with craniopharyngioma, it seemed important to document the course of a series of such patients treated with this preparation. METHODS AND RESULTS: Local chemotherapy with bleomycin was performed in 24 patients (20 children and 4 adults), 16 of whom presented with cystic or mixed (solid/cystic) craniopharyngioma and 8, with recurrent cystic craniopharyngioma. The drug was administered through an Ommaya reservoir, which was placed either by using a direct surgical approach (6 patients) or a stereotactic approach (16 patients), or with endoscopic assistance in patients with hydrocephaly (2 patients). Injection of bleomycin was always preceded by a water-tightness test. Each patient received a 3-mg dose of bleomycin every other day. The total dose of bleomycin injected ranged from 28 mg to 150 mg. Most patients (17, or 70%) were treated only with intracystic chemotherapy. Chemotherapy was followed by surgery in 7 patients. Five were operated on at the beginning of our study, and 2 required surgery because chemotherapy yielded poor results. A toxic dose was injected in 1 patient only: a severe complication, i.e. blindness, was observed. The follow-up period ranged from 2 years to 10 years. CONCLUSION: Our results show that bleomycin can be an alternative in the treatment of cystic craniopharyngiomas or cystic recurrences, as it reduces surgical morbidity and improves clinical results.

Adolescent↗
PubMed2005

Long-term outcome and reconsideration of intracystic chemotherapy with bleomycin for craniopharyngioma in children.

OBJECT: We first reported postoperative intratumoral chemotherapy with bleomycin for craniopharyngiomas in 1985. However, this local bleomycin chemotherapy has not yet been used very frequently. It seems to be necessary for us to report long-term outcome and reconsideration of this treatment. METHODS AND RESULTS: Local bleomycin chemotherapy was performed on 7 children (to 1985) and 11 children (from 1988 to 2004). A total of 11 pediatric patients with recurrent cystic craniopharyngioma was treated by intracystic injection of bleomycin after 1988 and followed up from 3 to 16 years. After 1985, 1 of 7 children whose clinical outcome was fair underwent intracystic injection of bleomycin again. This patient has never had recurrent tumor until now. The children whose clinical outcomes were excellent have no recurrence during follow-up from 21 to 26 years. After 1988, the results showed that cystic recurrences of 7 children have almost disappeared and the children have achieved a good school life, and 3 children are also achieving a good life after additional stereotactic radiosurgery. CONCLUSION: Our results indicate that local bleomycin chemotherapy is effective and that recurrence does not occur after follow-up, which ranged in duration from 3 to 16 years.

Adolescent↗
PubMed2006

Fas- and FasL-deficient mice are resistant to the induction of bleomycin-induced scleroderma.

We have recently shown that apoptosis is induced in the lesional skin in a murine scleroderma model by local bleomycin injections, and the apoptotic pathway was mainly mediated by Fas/Fas ligand (FasL) signaling. To further investigate the involvement of apoptosis in scleroderma, we examined whether the induction of dermal sclerosis is suppressed in Fas-deficient (lpr) and FasL-deficient (gld) mice. Results of histological examination showed that the induction of dermal sclerosis by bleomycin treatment was significantly suppressed in both lpr and gld mice, in comparison with wild-type mice. The ratio of collagen contents in the bleomycin-treated skin as compared with PBS-treated skin was significantly lower in both lpr and gld mice than that in wild-type mice. The number of TUNEL-positive infiltrating cells was markedly increased following bleomycin exposure (60 +/- 11.4/HPF) in comparison with PBS treatment (9.5 +/- 6.0/HPF) in wild-type mice, which was significantly decreased in both lpr (22 +/- 4.5/HPF, P < 0.05) and gld (26 +/- 6.1/HPF, P < 0.05) mice. Our findings that lpr and gld mice were resistant to the induction of dermal sclerosis by bleomycin further suggest that Fas/FasL pathway is an important contributor involved in the pathophysiology of bleomycin-induced dermal sclerosis.

Animals↗
PubMed2006

Lack of evidence for caveolin-1 and CD147 interaction before and after bleomycin-induced lung injury.

Immunohistochemical and in vitro studies indicate that caveolin-1, which occurs abundantly in alveolar epithelial type I cells and microvascular endothelial cells of the lung, is selectively downregulated in the alveolar epithelium following exposure to bleomycin. Bleomycin is also known to enhance the expression levels of metalloproteinases and of the metalloproteinase inducer CD147/EMMPRIN in lung cells. Experimental in vitro data has showed that MMP-inducing activity of CD147 is under the control of caveolin-1. We studied the effects of bleomycin on the expression of caveolin-1, CD147 and metalloproteinases using an alveolar epithelial rat cell line R3/1 with properties of both alveolar type I and type II cells and explanted rat lung slices. In parallel, retrospective samples of bleomycin-induced fibrosis in rats and mice as well as samples of wild type and caveolin-1 knockout animals were included for immunohistochemical comparison with in vitro data. Here we report that treatment with bleomycin downregulates caveolin-1 and increases CD147 and MMP-2 and -9 expression/activity in R3/1 cells using RT-PCR, Western blot analysis, MMP-2 activity assay and immunocytochemistry. Immunofluorescence double labeling revealed that caveolin-1 and CD147 were not colocalized in vitro. The in vitro findings were confirmed through immunohistochemical studies of the proteins in paraffin embedded precision-cut rat lung slices and in fibrotic rat lung tissues. The caveolin-1-negative hyperplastic ATII cells exhibited enhanced immunoreactivity for CD147 and MMP-2. Caveolin-1-negative ATI cells of fibrotic samples were mostly CD147 negative. There were no differences in the pulmonary expression of CD147 between the normal and caveolin-1 deficient animals. The results demonstrate that bleomycin-induced lung injury is associated with an increase in CD147 expression and MMP activity, particularly in alveolar epithelial cells. In addition, our data exclude any functional interaction between CD147 and alveolar epithelial caveolin-1.

Animals↗
PubMed2001

Molecular modeling of the three-dimensional structure of Fe(II)-bleomycin: are the Co(II) and Fe(II) adducts isostructural?

The molecular modeling of Co(II)-bleomycin previously performed by us through NMR and molecular dynamics indicates that the most favorable structure for this complex is six-coordinate, with the secondary amine in beta-aminoalanine, the N5 and N1 nitrogens in the pyrimidine and imidazole rings, respectively, and the amide nitrogen in beta-hydroxyhistidine as equatorial ligands. The primary amine and either the carbamoyl group or a solvent molecule are proposed to occupy the axial sites. In this report, the results of the molecular modeling of Fe(II)-bleomycin are presented. The NMR data for the ferrous derivative of the drug have already been reported by us, and were used here to generate the necessary restraints for this modeling work. For Co(II)-bleomycin, two new models exhibiting N-carbamoyl ligation to the metal centers were also assayed and compared with the ones previously examined. The results of this investigation on Fe(II)- and Co(II)-bleomycin are most consistent with a six-coordinate structure with five endogenous N-donors and a solvent molecule or the carbamoyl group as the sixth ligand. Comparisons of the best Co(II)- and Fe(II)-bleomycin models with the NMR-generated structures for some relevant metallo-BLMs favor the model with only endogenous ligands and N-carbamoyl ligation as the structure probably held in solution by both Co(II)- and Fe(II)-bleomycin.

Bleomycin↗
PubMed1985

Photo-induced nicking of deoxyribonucleic acid by ruthenium(II)-bleomycin in the presence of air.

A new metallobleomycin, ruthenium(II)-bleomycin A2 was prepared. When irradiated at 366 nm the ruthenium complex (1-10 microM) was found to break a 121-base pair DNA restriction fragment at specific sites (usually the pyrimidine residues located at the 3'-side of guanine). Care was taken to rule out complications due to the presence of trace amounts of iron. Photo-induced damage by cobalt-bleomycin in the presence of light, and redox-mediated damage by bleomycin and iron produced DNA cleavage at sites similar to ruthenium-bleomycin. In contrast to cobalt-bleomycin, ruthenium-bleomycin required oxygen as well as light to cause significant damage to DNA.

Air↗
PubMed1983

Responses of Huntington's disease and ataxia telangiectasia lymphoblastoid cells to bleomycin.

Ionizing radiation sensitive, mutant human lymphoblastoid cell lines derived from patients with Huntington's disease (HD), or ataxia telangiectasia (AT) both showed cross sensitivity to bleomycin, as assayed by reduced cell viability and increased frequency of chromosome aberrations compared to normal controls. In contrast to AT cells which failed to show inhibition of DNA synthesis after exposure to ionizing radiation, or bleomycin treatment, the sensitive cells from HD patients had depressed rates of DNA synthesis after damage with these agents, similar to that seen in normal cells. In terms of progression through the cell cycle bleomycin damaged AT cells moved from G1 into S and from S to G2 + M at almost the same rate as untreated cells. Bleomycin treated HD cells showed a large proportion of cells blocked in G1, cells were slowed down in S, the rate of entry to G2 + M was reduced and only 5% of cycling cells reached G2. Progress through the cell cycle in normal cells exposed to bleomycin showed a partial block in G1 and the rate of entry to G2 + M was reduced. These differences in response of normal, AT and HD cells to ionizing radiation and bleomycin treatment indicates that the defect underlying the sensitivity is different in HD cells from that in AT cells.

Ataxia Telangiectasia↗
PubMed1979

The repair of bleomycin-induced DNA damage and its relationship to chromosome aberration repair.

Previous studies using the technique of premature chromosome condensation indicated that nearly one-half of the bleomycin-induced chromatid breaks and gaps in CHO cells could be repaired within 1 h (repair starting at 30 min) after treatment. Cycloheximide and streptovitacin A (but not hydroxyurea or hycanthone) inhibited chromosome repair. The purpose of this study was to measure the kinetics of DNA repair after bleomycin treatment using the alkaline elution technique and to determine whether various inhibitors could block this repair. After bleomycin treatment, the major proportion of the repair of DNA damage occurred within 15 min, with significant repair evident by 2 min. This fast repair component was inhibited by 0.2% EDTA. A slower repair component was observed to occur up to 60 min after bleomycin treatment. None of the inhibitors tested were found to have a significant effect on the repair of bleomycin damage at the DNA level. Since chromosome breaks were observed not to begin repair until after 30 min while over 50% of the DNA was repaired by 15 min, these results suggest that the DNA lesions that are repaired quickly are not important in the formation of chromosome aberrations. Further, since cycloheximide and streptovitacin A blocked chromosome repair but had little measurable effect on DNA repair, these results suggest that the DNA lesions responsible for chromosome damage represent only a small proportion of the total DNA lesions produced by bleomycin.

Animals↗
PubMed1990

A unique human mutant B-lymphoblastoid cell line (ataxia telangiectasia) which exhibits increased sister-chromatid exchange retaining hypersensitivity to neocarzinostatin and bleomycin.

Chromosome aberrations and sister-chromatid exchanges (SCEs) were examined in 4 ataxia telangiectasia (AT)-derived B-lymphoblastoid cell lines (B-LCLs) (AT-S, AT-SHI, AT-SHI B13A and AsHa) following treatments with neocarzinostatin (NCS) and bleomycin. All of these cell lines exhibited extremely high frequencies of chromosome aberrations with the NCS and bleomycin treatments. Among them, AsHa, a mutant B-LCL originating from an AT patient, showed high frequencies of SCEs under high bromodeoxyuridine (BrdU) concentrations retaining hypersensitivity to NCS and bleomycin with regard to chromosome aberrations. A clear BrdU dose-dependent increase in SCEs (9.85 SCEs/cell at 40 micrograms/ml, 36.65 SCEs/cell at 100 micrograms/ml on average) in this mutant was observed. When AsHa mutant cells were treated with NCS (0.02 microgram/ml) and/or bleomycin (5.0 micrograms/ml) under 40 micrograms/ml BrdU (minimum BrdU concentration for sister-chromatid differential staining), SCE levels increased from 9.85 (baseline level) to 21.1 with NCS and 20.5 with bleomycin, in a dose-dependent manner. These observations indicate that AsHa is a unique AT-derived mutant cell clone with a high SCE character retaining the original hypersensitivity to bleomycin and NCS.

Antibiotics, Antineoplastic↗
PubMed1987

Acute respiratory failure induced by bleomycin and hyperoxia: pulmonary edema, cell kinetics, and morphology.

The acute manifestations of experimental bleomycin- and hyperoxia-induced lung damage were examined. Hamsters were treated with 5 U/kg bleomycin intratracheally followed by exposure to 80% oxygen (O2). As little as 12 hr of O2 exposure potentiated the bleomycin injury; however, the onset of mortality was 72 hr after treatment. The onset of pulmonary edema, measured by radiolabeled tracers, also occurred 72 hr after treatment. Cell kinetics studies showed that 24 hr exposure to 80% O2 did not alter early alveolar cell proliferation. Treatment with bleomycin alone did result in an early increase in alveolar macrophage and type II pneumocyte labeling. Animals treated with both bleomycin and hyperoxia had an increase in macrophage labeling, but not in type II pneumocyte labeling. We conclude that increased macrophage numbers associated with suppressed type II pneumocyte proliferation may play key roles in the potentiation and development of lung damage caused by bleomycin and hyperoxia treatment.

Animals↗
PubMed1990

Enhancement of cytotoxicity of bleomycin by dithiocarbamates: formation of bis(dithiocarbamato) cu(II).

Properties of the reactions of dithiocarbamates and their Cu(II) or Fe(III) complexes with Ehrlich cells were determined and related to their effects on the inhibition of cell proliferation caused by bleomycin and Cu bleomycin. In complete culture medium containing Eagle's minimal essential medium plus Earles salts and 2.5% fetal calf serum, dimethyl- and diethyldithiocarbamates and their copper complexes inhibit cell proliferation and cause cell death. The copper complexes are more effective agents. Ferric tris-diethyldithiocarbamate is also a cytotoxic species. In contrast, when cells are exposed to dimethyldithiocarbamate or its copper complex in Ringer's buffer under metal-restricted condition, washed, and then placed in complete medium, the copper complex is much more active in inhibiting cell growth. The difference is magnified when dihydroxyethyldithiocarbamate and N-methylglucamine dithiocarbamate and their copper complexes are compared in complete media. Incubation of bleomycin or copper bleomycin with Ehrlich cells in Ringer's buffer with or without dimethyldithiocarbamate or bis-dimethyldithiocarbamato Cu(II) leads to no enhancement of cytotoxicity from combinations of agents, except when the two copper complexes are present. Diethyl- or dimethyldithiocarbamate readily extracts copper from Cu(II)bleomycin and iron from Fe(III)bleomycin when ethylacetate is present to remove the tris-dithiocarbamato Fe(III) complex from aqueous solution. When bis-dimethyldithiocarbamato Cu(II) is incubated with Ehrlich cells, copper is released from the complex and bound to high molecular weight and metallothionein fractions. A reductive mode of dissociation of the copper complexes in cells is supported by ESR experiments. Reactions of diethyl- and dimethyldithiocarbamato Cu(II) with thiol compounds demonstrates one possible mechanism of reduction of these complexes.

Animals↗
PubMed1983

Bleomycin--mode of action with particular reference to the cell cycle.

Over the last four years, investigations into the mechanism of interaction between bleomycin and DNA have been pursued at a rapid pace. This is, no doubt, because of the potential of bleomycin as a tool for molecular biology. It seems likely that the precise nature of the interaction between Fe(II), oxygen and bleomycin will be elucidated in the near future together with the nature of the binding between the complex and DNA. More information on the mechanism of strand scission including the involvement of free radical mechanisms and sequence specificity may also be expected. In contrast to this picture of rapid progress at the molecular level, interest in studies of bleomycin action at the cellular level appears to have waned. This is despite the fact that most of the important questions which have been raised regarding effects of the drug on cell cycle progression, the possibility of a selective action on on-cycling cells and the nature of 'recovery from potentially-lethal damage' remain unresolved. There is no doubt that, for most cell types, bleomycin produces a block at the early G2 stage of the cell cycle. There is considerable doubt, however, as to how many of the cells blocked for a significant period remain clonogenically viable. This question is amenable to being answered using a vital DNA stain, such as Hoechst 33342, and cell sorting but this does not appear to have been done. The relationship between G2 blockage and repair of DNA damage has also not been resolved. Neither has the question of whether or not DNA breaks which remain unrepaired are different in nature from the majority of repairable lesions. The data on the relative sensitivity of exponential and plateau phase cells are conflicting and their in vivo significance unclear. Well designed experiments to examine the bleomycin sensitivity of those cells in solid tumors which survive radiation treatment could help to answer this question. Evidence that the phenomenon of 'recovery from potentially lethal damage' is therapeutically-exploitable is mainly lacking. It would be of great relevance to known whether or not the effect can be observed in normal tissues. However, the evidence that the effect is not simply an artefact of clonogenic assay procedures is scanty and this possibility must be borne in mind.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Effect of in vitro cleavage of apurinic/apyrimidinic sites on bleomycin-induced mutagenesis of repackaged lambda phage.

Previous studies have revealed bleomycin to be a potent base-substitution mutagen in repackaged phage lambda. In order to assess the role of apurinic/apyrimidinic (AP) sites in bleomycin-induced mutagenesis, bleomycin-damaged lambda DNA was treated with putrescine or endonuclease IV to effect cleavage of bleomycin-induced AP sites. The DNA was then packaged, the phage grown in SOS-induced E. coli, and the frequency of clear-plaque mutants in the progeny was determined. Bleomycin-induced mutagenesis was decreased approx. 2-fold by treating the DNA with putrescine, but was unaffected by endonuclease IV. The results are consistent with the production of bleomycin-induced mutation at certain AP sites having a closely opposed single-strand break, since such sites are cleaved by putrescine but not by endonuclease IV.

Bacteriophage lambda↗
PubMed1991

Biochemical evidence for two different mechanisms for bleomycin-induced cell killing.

Using pulsed-field gel electrophoresis, we have measured the ability of two bleomycin-sensitive mutants, XR-1 and BL-10, to repair DNA double-strands breaks (DSB). XR-1 was originally isolated by its hypersensitivity to killing with ionizing radiation, but we have also shown that it is sensitive to killing with bleomycin. In contrast, BL-10 was isolated by its extreme sensitivity to killing with bleomycin, and it is not cross-sensitive to other DNA breaking agents. A 1-h treatment of bleomycin induces a similar number of DNA double-strand breaks in XR-1, BL-10 and CHO cells. However, XR-1 is unable to repair bleomycin-induced DNA double-strand breaks, whereas BL-10 possesses the same kinetics of repair as parental CHO. These data lead us to conclude that at least two mechanisms of killing exist for bleomycin; one of them is DNA DSB-dependent, and the other seems to be DNA DSB-independent.

Animals↗