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PubMed1995

[Cleavage of a double-stranded DNA target by bleomycin derivatives of oligonucleotides, forming a ternary complex].

Hexadecathymidylate derivatives, containing covalently-bound antitumor antibiotic bleomycin A5, were shown to form a triple-helix complex with double-strand 30-bp DNA-target and to carry out within this complex complementary-addressed DNA modification. Fivefold excess of reagent in relation to target leads to non-specific cleavage mainly of pyrimidine-rich DNA strand. Total degrees of the target-strand cleavage by 5'- and 3'-bleomycin derivatives of hexadecathymidylate were 25 and 35% for purine-rich strand and 47 and 36% for pyrimidine-rich strand. Degrees of non-specific cleavage by 5'-bleomycin derivative of hexadecanucleotide that does not form triple-helix were 6 and 16% for purine- and pyrimidine-rich strands, respectively. Comparison of these data has shown that site-specific cleavage prevailed nonspecific one. Triplex of 5'-bleomycin derivative with DNA melted by 5 degrees C lower (m.p. 40 degrees C) than the similar triplex of hexadecathymidylate. Temperature lowering from 50 to 20 degrees C increases the DNA-cleavage degree according to the increase in the part of target molecules involved in triple-helix formation.

Base Sequence↗
PubMed1994

[Scleroderma of the shoulders after treatment with combined bleomycin and radiotherapy].

INTRODUCTION: There are many causes of scleroderma. We observed a case of scleroderma involving the shoulder and neck area after combined bleomycin and radiotherapy. CASE REPORT: After six cycles of a CHOP-bleo protocol followed by radiotherapy for lymph node lymphoma, a female patient presented scleroderma involving the shoulders and neck area. Total bleomycin dose was 252 mg. DISCUSSION: Among the imputable factors, particularly extrinsic factors, in a series of 33 cases of different chemotherapy protocols published by Peters et al. in 1988, we retained the bleomycin radiotherapy administration sequence as the cause of this complication. Given after bleomycin, radiotherapy could increase the risk of scleroderma.

Adult↗
PubMed1995

Biochemical and functional markers of lung damage after bleomycin treatment.

Lung function tests, including spirometry, and pulmonary transfer factor for carbon monoxide (TLCO), serum angiotensin-converting enzyme (sACE), serum copper (sCU++) and serum procollagen III peptide (sPIIIP) were measured in 20 patients with metastatic testicular carcinoma, before and after treatment with cisplatin, bleomycin, vinblastine or etoposide. A significant decrease of TLCO, total lung capacity and vital capacity was observed at the end of the treatment. No recovery of pulmonary function had taken place 2 yrs after the last dose of bleomycin. This result suggests that bleomycin-induced lung damage is not completely reversible. Serum angiotensin-converting enzyme, remained unmodified, whilst sPIIIP was found to be significantly increased at the end of chemotherapy, but normal 2 yrs after the completion of chemotherapy. Serum Cu++ showed a tendency to decline. No significant correlation was found between sACE, sCu++ and sPIIIP and lung function tests in the follow-up period. These results question the possibility that these markers could be useful indicators of bleomycin-induced lung damage.

Adult↗
PubMed1978

Mitomycin C, vincristine, and bleomycin therapy for advanced cervical cancer.

The Southwest Oncology Group has treated 130 patients with advanced disseminated uterine cervical carcinoma no longer amenable to therapy with further radiation or surgery. Patients received one of three different schedules of mitomycin C, vincristine and bleomycin. A twice weekly schedule of bleomycin and vincristine produced response in 60% of patients. An infusion bleomycin schedule produced response in 39% of patients and a once weekly vincristine bleomycin schedule produced a 25% response rate (45% overall). Responding patients lived significantly longer than nonresponders (30 vs 18 weeks). Toxicities encountered included leukopenia, thrombocytopenia, peripheral neuropathy, gastrointestinal upset, dermatitis, and alopecia. We believe two of the schedules utilized represent an improvement in producing tumor remission induction in this previously recognized refractory carcinoma.

Adult↗
PubMed1979

Tumour stage of mycosis fungoides treated with bleomycin and methotrexate: report from the Scandinavian mycosis fungoides study group.

The Scandinavian Mycosis Fungoides Study Group have treated 19 patients with mycosis fungoides in tumour stage by systemic chemotherapy. Nine patients were treated with Bleomycin 15 mg i.m. twice weekly for 7 weeks and 10 patients with the same dose of Bleomycin in combination with Methotrexate 15 mg i.m. per m2 body surface each week for 7 weeks. No maintenance treatment was given. The immediate therapeutic effect of Bleomycin alone was considered good in half of the patients. Bleomycin and Methotrexate together produced a better initial effect. In both treatment series the remission was short-lived in the absence of maintenance therapy. The mortality rate was high, especially in combination treatment. Lethal complications occurred in 6 patients during the treatment, 3 of which were thromboembolic, one pancytopenia, one lung fibrosis with pulmonary insufficiency, and one bronchopneumonia. The conclusion is that these two forms of therapy cannot be recommended.

Adult↗
PubMed1996

Lung fibroblast alpha-smooth muscle actin expression and contractile phenotype in bleomycin-induced pulmonary fibrosis.

The emergence of the myofibroblast phenotype (characterized by alpha-smooth muscle actin expression) in wound healing and in tissues undergoing fibrosis is thought to be responsible for the increased contractility of the affected tissues. In bleomycin-induced pulmonary fibrosis, the myofibroblast is also responsible for the observed increase in collagen gene expression. To evaluate further these phenotypic changes in lung fibroblasts, contractile and other phenotypic properties of fibroblasts isolated from lungs of rats with bleomycin-induced fibrosis were compared with those of normal rats using in vitro models. Pulmonary fibrosis was induced in rats by endotracheal injection on day 0, and 7 and 14 days later the animals were sacrificed and lung fibroblasts isolated. Using immunofluorescence, < 10% of fibroblasts from control animals express alpha-smooth muscle actin when cultured as a monolayer. In contrast, 19% and 21% of cells from day 7 and day 14 bleomycin-treated animals, respectively, expressed this actin and with greater intensity than in control lung cells. This increase in actin expression was associated with enhanced contractility when evaluated using a three-dimensional cell culture model consisting of fibroblast-populated collagen gels. This enhanced contractility was abolished by treatment with antibody to transforming growth factor-beta (TGF-beta), whereas exogenous TGF-beta 1 and serum-stimulated contraction of control lung fibroblasts. TGF-beta 1 gene expression was greater in cells from bleomycin-treated animals than those from control lungs. These results show that cells with the myofibroblast phenotype are more abundant in fibrotic lung, and that these cells possess greater contractile capacity in vitro at least partly by virtue of their enhanced endogenous TGF-beta 1 gene expression.

Actins↗
PubMed1996

Inheritance of susceptibility to bleomycin-induced pulmonary fibrosis in the mouse.

Based on the range of patient responses to treatment, and on animal studies, it is hypothesized that individual variation in sensitivity to bleomycin-induced pulmonary fibrosis is controlled genetically. A genetic model has been developed by (a) establishing a distinct difference in bleomycin-induced lung damage in two inbred strains of mice [parental generation: C57BL/6J (fibrosis-prone phenotype) and C3Hf/Kam (fibrosis-resistant phenotype)] and (b) characterizing inheritance of the fibrosing phenotype in the F1 (first filial) and F2 (F1 intercross; second filial) generations derived from the parental strains. Male mice received 100 mg/kg and female mice 125 mg/kg of bleomycin via s.c. osmotic minipump. The animals were sacrificed 8 weeks after treatment or when their breathing rate indicated respiratory distress. The percentage of lung with fibrosis for each mouse was quantified with image analysis of a histological section of the left lung. The mean percentage of fibrosis for the C57BL/6J males was 8.4 +/- 0.8% (SE) and 4.4 +/- 0.8% for females, and the C3Hf/Kam mice of either sex did not present the fibrosing lesion (mean score, 0%). Significant difference (P = 6 x 10(-6)) was measured in percentage of fibrosis between the two strains of F1 males, but not F1 females (P = 0.38), suggesting the presence of an X-linked factor associated with the fibrosing phenotype. From an ANOVA the X-linked factor is estimated to contribute 19% of the fibrosis phenotype. A genetic model of two or three loci controlling the fibrosing phenotype is proposed from the data of the parental, F1, and F2 generations. The mouse model demonstrates that susceptibility to bleomycin-induced pulmonary fibrosis is a heritable trait controlled by a few genetic loci.

Animals↗
PubMed1996

Cytotoxicity of bleomycin and external radiation in squamous cell cancer cell lines of head and neck.

Bleomycin, a natural antibiotic toxic to dividing cells, has been successfully used in combinations for treatment of recurrent head and neck cancer. In this study, we investigated five recently established head and neck squamous cell cancer lines (UT-SCC-2, UT-SCC-8, UT-SCC-9, UT-SCC-12A, UT-SCC-19A) in terms of response to bleomycin and radiation treatment. Experiments were carried out using the 96-well plate clonogenic assay for concentration determinations causing 20% (IC20), 50% (IC50), and 90% (IC90) inhibition of clonogenic survival and dose-response calculations for bleomycin. Survival fraction after a radiation dose of 2 Gy (SF2) was used as a measure for radiation sensitivity. The sensitivity for bleomycin was in good accordance with radiation sensitivity except for cell line UT-SCC-9. This was the cell line most sensitive to radiation (SF2 = 0.25 +/- 0.03) but was fairly resistant to chemotherapy (IC50 = 11.5M). Sensitivity patterns may suggest partly different mechanisms of action.

Antibiotics, Antineoplastic↗
PubMed1979

Bleomycin-induced injury and metaplasia of alveolar type 2 cells. Relationship of cellular responses to drug presence in the lung.

Metaplastic epithelial cells are often observed lining alveoli in bleomycin-induced pulmonary fibrosis. The hypothesis that these cellular changes are induced by the direct action of the drug on differentiating Type 2 cells is now examined in a sequential study to correlate the presence of 3H bleomycin in the lung with the pattern of injury and repair of the alveolar epithelium. A single intravenous dose or multiple small intraperitoneal doses induce focal necrosis of Type 1 epithelial cells followed by Type 2 cell regeneration. At the time of maximal deoxyribonucleic acid (DNA) synthesis in these cells, significant amounts of 3H bleomycin are demonstrable in the lung by scintillation counting; and in autoradiographs, the drug appears to concentrate in epithelial cells. Subsequently many abnormal Type 2 cells are seen. Some are binucleate, and others show nuclear disruption. The usual process of differentiation to Type 1 cells does not occur; instead, a variety of epithelial forms are found, including fetal-like tubular structures and ciliated and squamous metaplastic cells. The correlation of epithelial injury and repair with the direct demonstration of bleomycin in the lung indicates that Type 2 cells are susceptible to injury in the division and differentiation phases of the cell cycle and may then produce a variety of inappropriate alveolar lining cells.

Animals↗
PubMed1997

Comparison of intratumoral administration of cisplatin versus bleomycin for treatment of periocular squamous cell carcinomas in horses.

OBJECTIVE: To compare therapeutic benefits of intratumoral administration of cisplatin and bleomycin for squamous cell carcinoma of the eyelids in horses. ANIMALS: 25 horses with 27 T2-stage periocular squamous cell carcinomas. PROCEDURE: Horses were treated 4 times at 2-week intervals with a slow-release formulation of cisplatin (1 mg/cm3 of tissue) or bleomycin (1 IU/cm3 of tissue). A two-stage design was used to minimize the sample size in each treatment arm. RESULTS: The local control rate at 1 year for lesions treated with cisplatin was 93 +/- 6%, and with bleomycin was 78 +/- 10%. Difference in local control duration between the 2 treatment groups was not significantly different. A high tumor proliferative fraction index value was associated with a higher local (infield) control rate, but also with a higher risk of marginal and regional recurrences. Tumors with a low proliferative fraction index value (< 28%) had 9.5-times higher (P = 0.0411) risk of recurrence than those with a high index value. Local acute reactions were similar in the 2 treatment groups, and chronic reactions were not observed. CONCLUSIONS: Cisplatin and bleomycin were effective anticancer agents for carcinoma of the eyelid in horses. Based on therapeutic benefit and treatment cost, cisplatin was found to be a better choice for intratumoral chemotherapy of eyelid carcinomas. CLINICAL RELEVANCE: Results of this study confirm the value of intratumoral chemotherapy, using cisplatin, for treatment of cutaneous squamous cell carcinomas in horses.

Animals↗
PubMed1979

Effect of hyperthermia on DNA single-strand breaks induced by bleomycin in Hela cells.

The effect of hyperthermia (43 approximately 45 degrees) on DNA single-strand breaks induced by bleomycin was examined in HeLa cells by the alkaline sucrose gradient sedimentation analysis. When HeLa cells were exposed to a temperature of 43 degrees approximately 45 degrees for 1 hr, only a small number of DNA single-strand breaks than bleomycin treatment at 37 degrees. The DNA strand breaks induced by bleomycin were almost completely repaired by post-treatment incubation of the cells in the control medium at 37 degrees. On the contrary, the repairing capacity of the cells was markedly inhibited by post-treatment incubation at 43 degrees, and this inhibition of cell repair seemed irreversible because no repair was found after an additional incubation of the cells at 37 degrees for 1 hr. These results support the possibility that the mechanism of synergism between the effect of bleomycin and hyperthermia may be related to the inhibition of DNA repair.

Bleomycin↗
PubMedDate not supplied

Elevation of the erythrocyte sedimentation rate precedes exacerbation of bleomycin-induced pulmonary toxicity: report of two cases and review of literature.

Bleomycin is included in a number of potentially curative chemotherapy regimens. It is associated with distinct forms of pulmonary toxicity, with interstitial pneumonitis the most common. Early detection of pulmonary toxicity is not always predictable by monitoring serial chest radiographs and pulmonary function tests. Even newer serum markers are not useful indicators of bleomycin-induced pulmonary damage. Two patients developed bleomycin pulmonary toxicity, in both of whom increases in erythrocyte sedimentation rate (ESR) preceded clinical deterioration and radiographic changes. The ESR may have potential significance as a monitoring test in patients receiving bleomycin.

Adult↗
PubMed1998

Early detection of bleomycin-induced lung injury in rat using indium-111-labeled antibody directed against intercellular adhesion molecule-1.

UNLABELLED: We have investigated whether an (111)In-labeled mouse monoclonal antibody to rat intercellular adhesion molecule-1 ((111)In*aICAM-1) could detect lung injury early in rats treated with bleomycin. METHODS: Rats received an intravenous injection of either (111)In*aICAM-1 or (111)In-labeled normal mouse IgG ((111)In*nmIgG) and were imaged and killed 24 hr later. Lung injury was induced by an intratracheal injection of bleomycin 4 or 24 hr before the rats were killed. After death, tissue was removed and activity was measured, lungs were cryostat-sectioned to detect the presence of ICAM-1 by immunofluorescence, and the up-regulation of LFA-1alpha was examined on blood polymorphonuclear leukocytes (PMNs) using fluorescence-activated cell-sorter (FACS) analysis. RESULTS: In rats injected with (111)In*aICAM-1, the percent injected dose/organ in lungs both at 4 and 24 hr postbleomycin increased significantly compared to the values in either uninjured rats or rats that received (111)In*nmIgG. At 4 and 24 hr postinjury, the target-to-blood (T/B) ratio was 8/1 and 6/1, respectively. For (111)In*nmIgG, the T/B ratio at 4 hr was 0.5/1 and 0.4/1 at 24 hr. In (111)In*aICAM-1 rats injured at 4 or 24 hr, images could easily be distinguished from uninjured rats. All images of (111)In*nmIgG rats showed only cardiac blood-pool and liver activity with little lung activity. Lung ICAM-1 immunofluorescence intensity increased in the bleomycin-treated samples compared to uninjured lungs. Expression of LFA-1alpha on PMNs increased 19% and 210% at 4 hr and 24 hr postinjury, respectively, compared to control values. CONCLUSION: Biodistribution and imaging data demonstrate that (111)In*aICAM-1 can detect early acute bleomycin-induced lung injury. Immunofluorescence and FACS data suggest that (111)In*ICAM-1 uptake is a specific process. This antibody has potential as an early radionuclide detector of acute inflammations.

Animals↗
PubMed1998

A parallel study of in vitro sensitivity to benzo[a]pyrene diol epoxide and bleomycin in lung carcinoma cases and controls.

BACKGROUND: Because only a fraction of smokers develop neoplastic lesions, host factors may affect their susceptibility to the carcinogenic effects of tobacco smoke. Benzo[a]pyrene diol epoxide (BPDE) is the metabolic product of benzo[a]pyrene (B[a]P), a constituent of tobacco smoke. Therefore, BPDE sensitivity may shed some light on smoking-related carcinogenesis. METHODS: First, differential BPDE sensitivity was tested in five lymphoblastoid cell lines. Then sensitivity to BPDE and bleomycin (an excellent lung carcinoma risk predictor) was tested in parallel in the lymphocytes of 57 lung carcinoma cases and 82 controls. RESULTS: The optimal BPDE treatment duration was 24 hours. The xeroderma pigmentosum cell line was the most sensitive, followed by head and neck cancer, ataxia telangiectasia, and normal cells. The mean breaks per cell for cases and controls were 0.78 and 0.46, respectively (P < 0.0001). BPDE sensitivity was significantly associated with lung carcinoma, with an odds ratio (OR) of 7.26, compared with an OR of 4.56 for bleomycin sensitivity. There was also a dose-response correlation between the quartiles of BPDE-induced breaks and lung carcinoma risk, with ORs of 2.39, 3.12, and 15.03. It is noteworthy that individuals who were sensitive to both BPDE and bleomycin had a significantly increased OR of 38.36. CONCLUSIONS: BPDE sensitivity may be a biologic marker to identify individuals who are susceptible to the carcinogenic effects of tobacco smoke. BPDE and bleomycin sensitivity might represent different repair or sensitivity pathways; however, when these assays are used in parallel, they might refine our ability to identify high risk individuals.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1998

Early granulocyte-macrophage colony-stimulating factor expression by alveolar inflammatory cells during bleomycin-induced rat lung fibrosis.

Topical administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) into the subcutaneous tissue or in the pulmonary alveoli of the rat induces a fibrotic reaction characterized by the presence of alpha-smooth muscle actin-rich myofibroblasts, suggesting that GM-CSF plays a role in the development of fibrotic changes. A high level of expression of GM-CSF also has been demonstrated in epidermal cells during human atopic dermatitis. It is accepted that transforming growth factor beta1 (TGF-beta1) plays a key role in the modulation from fibroblast into myofibroblast, although it is not known how TGF-beta1 activity is stimulated. Up until now, no evidence of early GM-CSF expression during development of fibrosis has been reported. Herein we have studied, using RT-competitive PCR, the expression of GM-CSF mRNA during the early steps of pulmonary fibrosis development after intra-alveolar instillation of bleomycin, a well-established experimental model of this lesion. GM-CSF mRNA was already increased in the total lung at 6 hours and maximal at 12 hours after bleomycin instillation and returned to basal levels at 24 hours. This was followed by an increase of TGF-beta1 and TGF-beta receptor type II (but not of types I and III) mRNAs. Analyses of macrophages and polymorphonuclear neutrophils isolated by bronchoalveolar lavage 12 hours after bleomycin instillation indicated that they were responsible, at least in part, for the accumulation of GM-CSF mRNA. Our results show for the first time that GM-CSF is expressed, very early and temporarily, by inflammatory cells accumulating in the alveolus after bleomycin administration and before the appearance of TGF-beta1. Moreover, we have shown that GM-CSF induces the expression of TGF-beta1 mRNA by alveolar macrophages. Our data support the possibility that GM-CSF participates in the initial steps of the chain of events leading to fibrosis, perhaps through a stimulation of TGF-beta1 production.

Actins↗
PubMed1989

Bleomycin hydrolase is a unique thiol aminopeptidase.

Bleomycin hydrolase, which hydrolyzes the carboxamide bond in the pyrimidoblamic acid moiety of the bleomycin molecule, also cleaved several p-nitroanilide substrates with a neutral or basic amino acid residue and dipeptide substrates such as L-leucyl-glycine. The activity of bleomycin hydrolase was inhibited by two thiol protease inhibitors, E-64 and leupeptin, as well as by N-ethylmaleimide. These results suggest that bleomycin hydrolase is a thiol aminopeptidase. Magnesium ion, sodium chloride, ethylenediaminetetraacetic acid and 1,2-dihydroxybenzene-3,5-disulfonic acid specifically activated the enzymatic hydrolysis of L-arginine-p-nitroanilide, but did not that of L-leucine-p-nitroanilide. Lineweaver-Burk plots showed that Km values of the enzymatic activity for L-arginine-p-nitroanilide were altered by these reagents, although Vmax values were almost unaltered.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1998

Catalytic properties of the cysteine aminopeptidase PepC, a bacterial bleomycin hydrolase.

PepC is a cytoplasmic thiol aminopeptidase widely conserved among lactic acid bacteria. PepC from Lactococcus lactis shares 35-38% identity with aminopeptidases of eukaryotic origins: the yeast and mammalian bleomycin hydrolases (BLMase). In this work we investigated the hydrolytic activity of PepC towards various substrates: bleomycin A2, aminoacyl-p-nitroanilides (pNA) and peptides. First, we found the bleomycin hydrolase activity of lactococcal PepC and measured similar kinetics parameters to those reported for the mammalian BLMase. Second, the results obtained on aminoacyl-pNA confirmed the capacity of the enzyme to release a broad range of amino acids and the pH activity profile suggests the presence of an ionic interaction between the enzyme and the free alpha-amino group of the substrate. Third, the aminopeptidase activity measured on peptide substrates revealed that PepC possesses an extended binding site which interacts with the peptidic backbone of the substrate. The hydrolytic efficiency is highly dependent on the length of the peptide, optimal for tetrapeptides and further enhanced by the presence of hydrophobic residues in the P' positions of the substrate. These enzymatic properties are of importance for the design of specific inhibitors and the biological function of the bleomycin hydrolases.

Bacterial Proteins↗
PubMed1999

Human bleomycin hydrolase binds ribosomal proteins.

Bleomycin hydrolase (BH) is a cysteine proteinase that inactivates the anticancer drug bleomycin. Yeast BH forms a homohexameric structure that resembles a 20S proteasome and binds to single-stranded RNA and DNA. We now demonstrate that human BH (hBH) interacts and colocalizes with ribosomal proteins. Using a yeast two-hybrid system, we found hBH bound to human homologues of rat ribosomal proteins L11 and L29. The N-terminus of hBH (amino acids 14-175), which contains a catalytic Cys93, was critical for the binding to L11 in the two-hybrid environment. hBH precipitated 35S-labeled L11 and L29 in vitro, and hBH colocalized with L11 and L29 as determined by immunofluorescence. In addition to cytosolic bleomycin hydrolase, we found abundant bleomycin hydrolase activity associated with the ribosomal subcellular fraction by differential centrifugation. hBH was also detected by Western immunoblotting in a high-speed particulate fraction, where the majority of L11 and L29 were found. In vitro experiments showed recombinant hBH binds to Chinese hamster ovary cell microsomes. Thus, our data strongly suggest that hBH exists as both a free cytosolic and ribosome-associated protein.

Animals↗