Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “bleomycin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 865 records · Page 48Linked to original sources
PubMed1984

Characterization of the association of radiolabeled bleomycin A2 with HeLa cells.

The association of [3H]bleomycin A2 and Cu(II):[3H]bleomycin A2 with HeLa cells has been characterized. Under the conditions of our experiments, approximately 0.1% of the total drug in the medium associates with HeLa cells. Both forms of the drug bind to HeLa cells in a specific and saturable manner, with a Km of 20 microM and a Vmax of 2.5 pmol/min/10(6) cells. Scatchard analysis of the specific binding data demonstrates a single set of high-affinity binding sites. Cytotoxic activities of both forms of the drug are similar, with a 50% lethal dose of 0.5 microM at 48 hr. The specific binding in HeLa cells of either the labeled metal-free drug or its copper complex is reversible by a 100-fold excess of either unlabeled drug. Interaction of the drug with cells is temperature sensitive but is unaffected by metabolic poisons, suggesting that this process is not energy dependent. Isolation of DNA from HeLa cells incubated with the drug indicates that 1 mol of either [3H]bleomycin A2 or Cu(II):[3H]bleomycin A2 binds per 10(8) nucleotides. Further studies with the radiolabeled drug are required to define precisely the mechanisms involved in bleomycin uptake and compartmentalization within the cell.

Animals↗
PubMed1984

[Comparison of a continuous infusion with a daily bolus injection of bleomycin in a heterotransplanted human testicular cancer].

Continuous Infusion vs. Bolus Injection of Bleomycin in a Human Testicular Cancer Xenograft System Bleomycin ( Bleomycinum Mack ) ranks among the most effective agents against non-seminomatous testicular cancer. The cytocidal effects of this drug are cell cycle dependent and increase with duration of exposure. Schedule dependency has been demonstrated in conventional murine tumor systems and recently superiority of continuous infusion over bolus injection has been claimed using the "Lewis lung carcinoma". The continuous infusion of bleomycin has found entry into many successful combination chemotherapy regimens without definitive proof of its superiority by a randomized clinical phase II trial. Presently, however, any clinical study comparing single agent activity in untreated patients with testicular cancer would meet ethical restrictions since combination chemotherapy affords cures in 30-80% of all cases. The human tumor xenograft model employing congenitally athymic (nu/nu) mice preserves salient features of the original tumor specimen with remarkable fidelity. Thus structural similarity at the microscopic level ("embryonal carcinoma with choriocarcinoma") and production of beta-HCG both in the donor patient and the subsequent xenograft line "Ma" could be demonstrated. The overall correlation between serum beta-HCG levels and tumor volumes was significantly positive (r = 0.85; p = 0.001), but varied among individual tumor-bearing mice. Covering a total dose range from 10.5-42 mg/kg given over 7 days no difference was found between daily bolus injections and continuous infusion of bleomycin. These data allow for the first time a direct comparison of both schedules of administration in a testicular cancer of human origin. On the basis of these findings the clinical preference for continuous administration of bleomycin is questioned, especially since it may cause considerable discomfort to the cancer patient.

Animals↗
PubMed1984

Modulation of bleomycin-induced pulmonary fibrosis in the BALB/c mouse by cyclophosphamide-sensitive T cells.

Endotracheal bleomycin treatment is an effective inducer of pneumonitis and pulmonary fibrosis. Certain strains of mice, however, develop only minimal or no pulmonary fibrosis after treatment with bleomycin. The mechanism of unresponsiveness or low responsiveness in the BALB/c strain of mice is examined in this article. Pretreatment with cyclophosphamide (100 mg/kg) 2 days prior to bleomycin instillation significantly augmented the fibrotic response in these mice. Treatment by cyclophosphamide alone at the same dosage caused no significant pulmonary disease or fibrosis. Furthermore, suppression of fibrosis in the cyclophosphamide-pretreated animals could be reconstituted with spleen cells from normal untreated donor mice. If the donor spleen cells were depleted of T cells by cytotoxic anti-Thy-1.2 antisera prior to infusion into recipient animals, no such reconstitution was observed, suggesting that a population of splenic T cells was responsible for the effect. Since this dose of cyclophosphamide is known to be cytotoxic for suppressor T cells, these data would signify that the intensity of the lung fibrogenic response to bleomycin in BALB/c mice can be modulated by a population of this T cell subset. Furthermore, the cell reconstitution data would exclude the possibility that cyclophosphamide augments the bleomycin response by non-T-cell-mediated synergistic effects on lung injury. Nevertheless, the results conclusively demonstrate the ability of T cells to modulate pulmonary fibrosis in vivo, at least in the BALB/c mouse.

Animals↗
PubMed1984

Abnormal response of xeroderma pigmentosum cells to bleomycin.

The repair of bleomycin-damaged DNA was examined in human fibroblasts isolated from patients having the disease xeroderma pigmentosum (XP). In normal fibroblasts, the appearance of low-molecular-weight DNA was observed in the presence of increasing amounts of the drug. The studies in XP fibroblasts produced results which differed from those obtained in normal cells in two ways. (a) Prelabeled XP cells from most complementation groups contained more low-molecular-weight DNA than observed in the other human fibroblasts examined. (b) When XP cells were exposed to low doses of bleomycin, the low-molecular-weight DNA disappeared, suggesting induction of a repair process. If the XP cells were exposed to bleomycin in the presence of hydroxyurea and 1-beta-D-arabinofuranosylcytosine, the disappearance of low-molecular-weight DNA was not observed; instead, a normal dose response to the drug was observed. Our results suggest that XP cells show an "induced" repair response following bleomycin treatment and that blocking DNA chain elongation uncovers normal incisions in bleomycin-treated DNA.

Bleomycin↗
PubMed1976

Actions of bleomycin on DNA ligase and polymerases.

Bleomycin inhibited the ligase, which was partially purified from rat ascites hepatoma, AH-130, even at a concentration as low as 0.01-1 mug/ml. The DNA degraded by bleomycin was not repaired by ligase. Therefore, it was suggested that bleomycin at higher concentration produced strand scission of DNA, which could not be repaired by the ligase, and at lower concentration inhibited the ligase reaction presumably by binding to DNA strand or to ligase. Also, the specificity of inhibition by bleomycin on the DNA polymerase of oncogenic RNA virus was tested, comparing with the four kinds of DNA polymerases extracted from the spleen of mice infected with Friend virus. Three kinds of DNA polymerases from spleen were not inhibited by bleomycin, but the fourth enzyme, which was induced in the spleen by virus infection, was inhibited by the antibiotic, when poly-d(AT) and poly-dG with dC were used as template.

Animals↗
PubMed1977

A radioimmunoassay for bleomycin.

A radioimmunoassay for bleomycin, suitable for monitoring serum and urine drug levels, has been developed. Antisera were obtained from rabbits immunized with a conjugate of bleomycin and human serum albumin.Bleomycin labeled with 57Co was used as the tracer. Antibody-bound and free bleomycin were separated by precipitation with polyethylene glycol. The assay could determine bleomycin levels down to 0.025 mug/ml. The assay was precise, with a coefficient of variation of 2.8% Other drugs likely to be administered in combination with bleomycin did not interfere with the radioimmunoassay.

Animals↗
PubMed1978

Quantification of bleomycin pulmonary toxicity in mice by changes in lung hydroxyproline content and morphometric histopathology.

Bleomycin treatment produced dose-dependent changes in lung collagen content and in several measurable histopathological parameters. NIH/Swiss mice were treated twice weekly for 6 weeks with bleomycin, 0, 1, 20, or 40 mg/kg s.c. The two highest doses produced mortalities of 35 and 100%, respectively, as well as loss of body weight and increase in lung wet weight. Lung hydroxyproline content, an index of collagen, increased to 40 to 50% above control levels at 6 and 8 weeks after initiation of treatment with bleomycin 20 mg/kg. Morphometric analysis was applied to the following parameters at light microscopy: number of intraalveolar macrophages and leukocytes, total pulmonary cell count, alveolar wall thickness, and percentage of consolidation of lung parenchyma. The two highest doses produced increases in all of these parameters as compared to controls. The most marked changes occurred in the number of intraalveolar cells, which in the group given 20 mg/kg rose to 150, 190, and 210% of controls at 4, 6, and 8 weeks. The lowest dose of bleomycin, 1 mg/kg twice weekly for 6 weeks, evoked no pulmonary or other toxicity by the parameters examined. This model of chronic pulmonary toxicity may be useful in analog development, in testing potential antidotes, and in examining the effects of other factors that might modify the pulmonary toxicity of bleomycin.

Animals↗
PubMed1994

Production and function of murine macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury.

We investigated the role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in bleomycin-induced lung injury, a model of interstitial lung disease. Bleomycin stimulates a T cell-dependent pulmonary inflammatory response characterized by an increase in leukocyte infiltration, fibroblast proliferation, and collagen synthesis. Intratracheal challenge of CBA/J mice with bleomycin resulted in a significant time-dependent increase in MIP-1 alpha protein levels both in whole-lung homogenates and bronchoalveolar lavage fluid. The kinetics of MIP-1 alpha expression were biphasic, with the first peak occurring at 2 days postinstillation and the second peak at 16 days. These levels of Ag expression temporally correlated with the accumulation of granulocytes, lymphocytes, and mononuclear phagocytes in the lung. In addition, immunohistochemical staining identified alveolar macrophages and bronchial epithelial cells as the primary cellular sources of MIP-1 alpha production. Interestingly, passive immunization of bleomycin-challenged mice with anti-MIP-1 alpha Abs significantly reduced pulmonary mononuclear phagocyte accumulation and fibrosis. These experiments establish that MIP-1 alpha protein is expressed in the lungs of bleomycin-treated mice and provide evidence that MIP-1 alpha promotes leukocyte accumulation and activation. Furthermore, these findings support the notion that leukocyte accumulation and activation are linked to fibrosis.

Animals↗
PubMed1993

Cells enriched for catalase are sensitized to the toxicities of bleomycin, adriamycin, and paraquat.

L cells were enriched about 100-fold for catalase by the transcription of the transfected cDNA for human catalase. In spite of substantial enrichment for catalase, the transfected cells (LFN7C/B3) were not resistant to the cytotoxicity of a variety of agents which reduce dioxygen, including paraquat, menadione, adriamycin, phenazine methosulfate, and bleomycin. Instead, they were more sensitive to paraquat, bleomycin, and adriamycin than the untransfected cells from which they derived. Desferrioxamine afforded the cells enriched for catalase modest protection from the toxicities of bleomycin, paraquat, or adriamycin, suggesting that enrichment for iron as a consequence of the increased cellular content of catalase accounted for some of the increased sensitivities. The increased sensitivity of the LFN7C/B3 cells to bleomycin and paraquat was also attributed to the ability of catalase in cells to prevent the drug-induced consumption of O2; by capturing H2O2 before it can escape the cell and converting it to O2, catalase can maintain the concentration of O2 either for repeated rounds of chemical reduction or for direct interaction with the toxin. As predicted by this formulation, the toxicities of paraquat and of bleomycin were increased in an atmosphere of 40% dioxygen in comparison with an atmosphere of 20% dioxygen.

Animals↗
PubMed1995

Bleomycin-induced DNA damage and repair in wild-type and thymidine kinase-deficient Friend mouse erythroleukaemia cells.

In this paper the DNA damage and repair induced by the radiomimetic agent bleomycin are compared in murine Friend erythroleukaemia wild-type 707 cells and a thymidine kinase-deficient sub-clone BUF. Comparisons are made using results obtained from the alkaline comet assay and unscheduled DNA synthesis experiments. Further analysis to determine the fidelity of bleomycin-induced repair as indicated by mutagenesis to hypoxanthine-phosphoribosyltransferase deficiency was also conducted. Similar sensitivities to bleomycin treatments were observed in the two cell types with the comet assay, while similar levels of dose-dependent excision repair following bleomycin treatments were also detected in unscheduled DNA synthesis experiments. Comet assay and unscheduled DNA synthesis experimental results are in agreement. Survival and induced hypoxanthine-phosphoribosyltransferase mutant frequencies were observed to be unaffected by a thymidine kinase-deficiency in Friend erythroleukaemia cells. The results of this investigation suggest no overall difference in the repair capacities or the repair fidelity of Friend 707 relative to BUF cells following bleomycin treatments.

Animals↗
PubMed1996

Differential expression of elastin and alpha 1(I) collagen mRNA in mice with bleomycin-induced pulmonary fibrosis.

Interstitial pulmonary fibrosis is characterized by increased production of connective tissue components, including collagen and elastin. The role of elastin turnover in pulmonary fibrosis is not clear, and it is not known whether elastin and collagen are regulated separately or together during the inflammatory process. Mice with bleomycin-induced pulmonary fibrosis were investigated to determine the temporal and spatial changes in localization of elastin mRNA expression, as well as to compare elastin mRNA expression with that of alpha 1(I) collagen mRNA expression. In control (saline-treated) lungs, elastin mRNA was detected by in situ hybridization in arterial walls. No signal was found in alveolar or airway walls or in pleura; alpha 1(I) collagen mRNA was detected in the tissue underlying the airway epithelium. An increase in elastin mRNA expression in muscular arteries was observed 3 days after bleomycin instillation. Expression was also seen in the adventitia of terminal airways and adjacent small blood vessels. Expression of alpha 1(I) collagen mRNA increased in the tissue underlying the airway epithelium. In the pleura, alpha 1(I) collagen mRNA expression was found, although no pleural thickening was evident. The alpha 1(I) collagen mRNA expression was particularly increased in the adventitia of terminal airways and in associated small blood vessels. Obvious in areas of fibrosis, elastin mRNA expression was occasionally increased in the pleura and airway wall 7 days after bleomycin treatment; alpha 1(I) collagen mRNA expression was generally stronger than elastin mRNA expression in areas of fibrosis and was frequently intense in the adventitia of airways and associated blood vessels. The fibrotic areas showed increased elastin mRNA expression 14 and 30 days after bleomycin treatment. The arteries in fibrotic areas showed normal elastin mRNA levels. In the areas of fibrosis and in the adventitia of airways and adjacent blood vessels, alpha 1(I) collagen mRNA expression was very high. In conclusion, lung elastin biosynthesis is markedly altered by bleomycin treatment. The localization and intensity of elastin mRNA expression is different from the expression of alpha 1(I) collagen mRNA.

Animals↗
PubMed1996

[DNA strand breaks in epithelial cells from mice with bleomycin induced pulmonary fibrosis].

Bleomycin-induced cytotoxicity is believed to be caused by single- and double-strand DNA breaks. To examine the effect of bleomycin on DNA strand breaks and the role of these breaks in bleomycin induced pulmonary fibrosis in mice, we analyzed DNA strand breaks in situ by TdT-mediated dUTP-biotin nick end labeling (TUNEL), previously described by Gavrieli et al. The nuclei of bronchiolar epithelial cells were strongly stained 1 hr to 12 hr after bleomycin administration, and after that period DNA damage was repaired. Nuclei of alveolar epithelial cells showed positive signals correlated with progression of fibrosis. Although corticosteroids did not block the early DNA damage in bronchiolar epithelial cells, they did inhibit later damage to alveolar epithelial cells and fibrosis. We speculate that the DNA damage in alveolar epithelial cells and the progression of fibrosis in later stages are associated with inflammatory cytokines. These findings show the location and the time course of the DNA damage in bleomycin-induced pneumonitis in mice, and they indicate that the prolongation of DNA damage in alveolar epithelial cells is closely related to fibrinogenesis.

Animals↗
PubMed1978

Improved therapeutic index of bleomycin when administered by continuous infusion in mice.

The effects of three different dosage schedules on both therapeutic effect and pulmonary toxicity of bleomycin were studied in mice. Therapy was assessed by both survival and decreased tumor size in mice bearing Lewis lung carcinoma. Lung toxicity was estimated in nontumored mice as increases in lung collagen content by measuring lung hydroxyproline concentrations. In the first set of experiments, bleomycin injections twice daily (low-dose, high-frequency) produced a significant (34%) increase in lifespan over controls, whereas the same total dose given twice weekly did not result in increased survival. Both schedules produced pulmonary toxicity. Continuous sc infusion of bleomycin via an osmotic minipump was compared to these two schedules of intermittent injection. Identical total doses of drug were administered in all three schedules. Continuous infusion for 7 days produced marked inhibition of tumor growth (T/C = 16%), which was significantly better than twice weekly or ten-times weekly injection of the same total dose. Furthermore, at a total dose of 40 mg/kg of bleomycin, continuous infusion did not result in measurable pulmonary toxicity, whereas both schedules of bolus injection produced significant increases in lung collagen content. Thus, continuous infusion of bleomycin improved its therapeutic effect against Lewis lung carcinoma and also reduced its pulmonary toxicity.

Animals↗
PubMed1996

Toxicity and antitumor activity of niosomal bleomycin in tumor bearing mice.

Niosomal encapsulation of bleomycin enhanced the antitumor activity against Ehrilich ascites and sarcoma-180 models. The niosomal/free drug mean survival time values of 1.28 was achieved in Ehrlich ascites infected animals. Niosomal bleomycin considerably increased the 40 days survival rate in mice. Tumor volume doubling time of S-180 tumor was also increased significantly in niosomal treated animals. Histopathological studies of lung and jejunum of Niosomal bleomycin treated mice, confirmed the less toxic potential of encapsulated bleomycin. The suppression of peripheral and bone marrow WBC counts upon niosomal bleomycin treatment was not substantial.

Animals↗
PubMed1997

[Molecular design of apoptosis inducing agents derived from bleomycin].

Reactive oxygen species (ROS) are often involved in the mechanism of apoptosis. Bleomycin consists of an oxygen activating domain and a DNA binding domain, and is an antitumour agent that induces double-strand scission in DNA by oxygen activation. However, bleomycin only weakly induces apoptosis in limited conditions. Previously we have reported efficient oxygen activation by iron complexes of synthetic models of bleomycin namely PYML designed by the direct analogy to the BLM metal core. Recently, novel ligands having symmetrized coordination environment consisting of two histidine units and a pyridine (HPH) were prepared. Oxygen activating efficiency of the iron complexes of the synthetic ligands increased by introducing electron donating substituent into the pyridine ring. HPH compounds have no DNA binding region which is present in bleomycin. HPH compounds but not bleomycin induced apoptosis in mouse leukemia L1210 cells.

Animals↗
PubMed1979

Control of permeation of bleomycin A2 by polyene antibiotics in cultured Chinese hamster cells.

Control of permeation of bleomycin A2, a well-known antitumor antibiotic, in combination with various polyene macrolide antibiotics was analyzed in cultured Chinese hamster cells in vitro. Three polyene antibiotics, filipin, pentamycin, and pimaricin, were found to enhance the action of bleomycin A2 remarkably, while amphotericin B or nystatin could not. Although DNA synthesis and colony-forming activity of polyene-sensitive Chinese hamster V79 cells were synergistically inhibited by the combination of filipin and bleomycin A2, in a polyene-resistant subline (AMBR-1) derived from V79, they were only slightly affected in the presence of both drugs. The cellular uptake of [14C]bleomycin A2 by V79 was enhanced 2- to 4-fold in the presence of increasing doses of filipin or pentamycin, but not in the presence of amphotericin B. The treatment of V79 cells with filipin for 20 to 30 min was enought to block DNA synthesis almost completely when combined with 20 microgram belomycin A2 per ml. The pretreatment of the hamster cells with 6 microgram filipin per ml for 60 min continued to enhance the inhibitory action by bleomycin A2 of DNA synthesis up to 5 hr after the removal of filipin from the cultured medium.

Amphotericin B↗
PubMed1997

Interactive lethal and mutagenic effects of ultraviolet light and bleomycin in yeast: synergism or antagonism?

The mutagenic interactions of ultraviolet light and bleomycin in haploid populations of Saccharomyces cerevisiae were analyzed. Survival and mutation frequency as a function of different bleomycin concentrations after one conditioning dose of UV radiation were determined. Furthermore, corresponding interaction functions and sensitization factors were calculated. A synergistic interaction between UV light and bleomycin was shown for both lethal and mutagenic events when the cells were in nutrient broth during the treatments. Conversely, the interaction between UV light and bleomycin was antagonistic when the cells were in deionized water during the treatment. The magnitude of lethal and mutagenic interactions depends on dose, and thus presumably on the number of lesions. The observed interactions between UV light and bleomycin suggest that the mechanism that is most likely involved is the induction of repair systems with different error probabilities during the delay of cell division.

Bleomycin↗
PubMed1998

Differential expression of extracellular matrix remodeling genes in a murine model of bleomycin-induced pulmonary fibrosis.

Exposure to the chemotherapeutic drug bleomycin leads to pulmonary fibrosis in humans and has been widely used in animal models of the disease. Using C57BL/6 bleomycin-sensitive mice, pulmonary fibrosis was induced by multiple intraperitoneal injections of the drug. An increase in the relative amounts of steady-state alpha1(I) procollagen, alpha1(III) procollagen, and fibronectin mRNA as well as histopathological evidence of fibrosis was observed. The effect of bleomycin on the expression of the enzymes responsible for extracellular matrix degradation, the matrix metalloproteinases (MMPs), and their inhibitors (TIMPs), was selective and showed temporal differences during the development of fibrosis. Of the MMPs tested, bleomycin treatment resulted in the up-regulation of gelatinase A and macrophage metalloelastase gene expression in whole-lung homogenates, whereas gelatinase B, stromelysin-1, and interstitial collagenase gene expression was not significantly changed. Timp2 and Timp3, the murine homologues of the respective TIMP genes, were constitutively expressed, whereas Timp1 was markedly up-regulated during fibrosis. The strong correlation between enhanced extracellular matrix gene expression, differential MMP and TIMP gene expression, and histopathological evidence of fibrosis suggest that dysregulated matrix remodeling is likely to contribute to the pathology of bleomycin-induced pulmonary fibrosis.

Animals↗