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PubMed2003

Bleomycin-induced pulmonary toxicity in chemotherapy for testicular cancer.

Bleomycin is an antibiotic agent with antitumour activity, discovered in 1966 by Umezawa et al. Today, bleomycin is commonly used in chemotherapy for various tumour types. In testicular cancer especially, bleomycin is one of the key drugs in induction chemotherapy. It has the advantage of less myelotoxicity; however, its severe and potentially fatal pulmonary toxicity has limited its dose intensity. Several clinical trials have focused on eliminating bleomycin from the regimen or reducing the bleomycin dose for testicular cancer patients with good prognosis. However, the results indicate that bleomycin is still an essential component of induction chemotherapy when only three courses are administered. This review will focus on bleomycin-induced pulmonary toxicity in chemotherapy for testicular cancer, followed by a brief review of recent basic understanding of the pathogenesis of lung fibrosis.

Animals↗
PubMed1984

The effect of bleomycin and oxygen on rat lung.

The interaction of bleomycin and oxygen on rat lung was studied by giving endotracheal injections of bleomycin or saline to rats which subsequently breathed air or oxygen for 24 or 48 h. In the first protocol bleomycin or saline treated rats were exposed to 24 h of air or 100% oxygen and then breathed air for a further 6 d after which they were killed. In the second protocol bleomycin or saline treated rats were exposed to 48 h of air or up to 48 h of 100% oxygen. All animals in this protocol either died or were killed at the 48 h time point. The lungs were fixed in full inflation and 6 histological sections prepared from each. The volume densities of alveolar air, duct air, alveolar walls, intra-alveolar cells and non-parenchyma were quantitated using standard point counting techniques. In addition, the percent of alveoli containing fibrin was determined. The results demonstrated a synergistic effect of oxygen and bleomycin toxicity after both 24 and 48 h oxygen exposure. This was most marked for alveolar fibrin deposition which was significantly greater (p less than 0.001) in the bleomycin and oxygen groups than the saline/air, saline/oxygen or bleomycin/air groups. In the 48 h study the volume density of intra-alveolar cells was also significantly greater in the bleomycin/oxygen group than all other groups (p less than 0.05). It is concluded that bleomycin and oxygen exhibit synergistic toxic effects and that their concurrent administration should be avoided.

Animals↗
PubMed1997

Pirfenidone attenuates bleomycin-induced changes in pulmonary functions in hamsters.

The antifibrotic potential of pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) was examined in a single intratracheal bleomycin dose hamster model of pulmonary fibrosis. Bleomycin-induced fibrosis and the effectiveness of pirfenidone treatment were assessed by measuring pulmonary functions (Cqst, TLC, VC, IC, FRC, RV) and the level of hydroxyproline in whole lung homogenates. Thirty-five male golden Syrian hamsters were randomized into four experimental groups: saline instilled and fed a control diet of rat chow (SCD, n = 8); saline instilled and fed the control diet containing 0.5% (w/w) pirfenidone (SPD, n = 8); bleomycin instilled and fed the control diet (BCD, n = 7); and bleomycin instilled and fed the control diet containing 0.5% pirfenidone (BPD, n = 10). Twenty-one days following bleomycin instillation Cqst/TLC, TLC, VC, and IC were significantly reduced and total lung hydroxyproline levels were significantly increased in the BCD and BPD groups as compared with the SCD and SPD groups, respectively. Pirfenidone ingestion significantly attenuated these bleomycin-induced pertubations in pulmonary functions and lung hydroxyproline levels (BCD versus BPD). The data obtained in this study provide evidence of the benefical effects of pirfenidone in the hamster model of bleomycin-induced pulmonary fibrosis both at the functional and biochemical level.

Animals↗
PubMedDate not supplied

Nitrite production in mouse 3T3 fibroblasts by bleomycin-stimulated peripheral blood mononuclear cell factors.

OBJECTIVE: It is well known that bleomycin induces tissue fibrosis, including pulmonary fibrosis or scleroderma-like conditions. However, the pathogenesis has not been completely elucidated. We recently observed that peripheral blood mononuclear cells (PBMCs) stimulated by bleomycin show growth stimulatory activity for fibroblasts. Nitric oxide (NO) is an important mediator of immune and inflammatory responses, and has recently been suggested to play a role in the pathogenesis of autoimmune disorders. In this study, we have examined whether bleomycin-stimulated PBMCs induce nitrite production in mouse 3T3 fibroblasts in vitro. METHODS: PBMCs were obtained from 6 patients with systemic sclerosis (SSc) and 6 normal volunteers, and stimulated by bleomycin; the culture supernatants were collected as conditioned medium (CM). The release of nitrite from 3T3 fibroblasts after incubation with CM was determined by Griess reagents. Induction of inducible NO synthase (iNOS) mRNA expression in 3T3 fibroblasts after incubation with CM was examined by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. RESULTS: Bleomycin induced significant nitrite release from PBMCs in a time-dependent manner. Stimulation with CM increased nitrite production in 3T3 fibroblasts, which was significantly inhibited by antibodies against interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and iNOS inhibitor, L-NMMA. CM from SSc patients induced higher amounts of nitrite from 3T3 fibroblasts, compared with that from normal subjects, although the difference was not significant. CM induced iNOS mRNA expression in 3T3 fibroblasts in a time-dependent manner. CONCLUSION: These results suggest that bleomycin, as well as IL-1 beta and TNF-alpha, induce NO release from mononuclear cells, and that these cytokines furthermore stimulate fibroblasts to produce NO, which raises the possibility of the involvement of NO in the development of tissue fibrosis induced by bleomycin.

3T3 Cells↗
PubMed1999

Animal model of sclerotic skin. II. Bleomycin induced scleroderma in genetically mast cell deficient WBB6F1-W/W(V) mice.

OBJECTIVE: Previously, we established a mouse model of scleroderma induced by repeated subcutaneous bleomycin injections. In this model, increased numbers of mast cells were observed in the lesional skin of dermal sclerosis, and degranulation of mast cells was prominent prior to the increase of mast cell numbers. Mast cells have been suggested to play an important role in tissue fibrosis. In this study, we investigated whether dermal sclerosis is also induced by bleomycin administration in genetically mast cell deficient WBB6F1-W/W(V) mice. METHODS: Bleomycin was subcutaneously injected every day in WBB6F1-W/W(V) and their normal littermate WBB6F1-+/+ mice for 4 weeks, and mice were analyzed for histological sclerosis, mast cell number, plasma histamine level, and hydroxyproline content. RESULTS: Four weeks' injections of bleomycin effected histological dermal sclerosis in both mast cell deficient and control strains; however, at 1 week, dermal sclerosis was induced only in WBB6F1-+/+ mice. Mast cells gradually increased in number around or on the edge of sclerotic lesions in WBB6F1-+/+ mice, as the dermal sclerosis developed. Hydroxyproline content of the skin of WBB6F1-+/+ mice was higher than that of WBB6F1-W/Wv mice at 1 week, but was not statistically significant. After 2 weeks' treatment with bleomycin, the hydroxyproline content of the skin was similar in both strains. The number of infiltrating macrophages and CD4+ T cells also gradually increased in both strains; however, the difference did not reach significance during the course of bleomycin treatment. CONCLUSION: These results show that mast cell is not necessary for inducing dermal sclerosis by bleomycin, and other types of inflammatory cells such as infiltrating macrophages or T lymphocytes may play a role in triggering induction of dermal sclerosis via fibrogenic cytokines. However, mast cell releasing mediators or cytokines may play a role in accelerating formation of dermal sclerosis, in particular, at an early phase of the sclerotic process, and not merely as a result of sclerosis.

Animals↗
PubMed2005

[Therapeutic effect and pathology changing of eyelid xanthelasma by Bleomycin A5].

OBJECTIVE: To investigate the effects of Bleomycin A5 on the pathology and ultrastructure of eyelid xanthelasmas. METHODS: Twenty-five randomly selected outpatients from our hospital received 0.2 ml of a 0.4% Bleomycin A5 solution. The drug was directly injected into the tumor every 10 days. In other 5 cases (double up-eyelids xanthelasma), one eye received 0.2 ml of 0.4% Bleomycin A5 injection once and another eye was used as controlling. After one month, operations were performed to remove double up-eyelids xanthelasma tissues, one half of the tissues were investigated by histochemistry; the other half was cut into 1.0 mm x 1.0 mm x 1.5 mm pieces and investigated by electron microscopy. RESULTS: The clinical investigation demonstrated that 25 cases of the Bleomycin treated tumors disappeared completely and the skin color recovered. The eyelids kept their normal morphology and function. Histopathologic investigation of the Bleomycin treated groups showed fibroblasts hyperplasia and sparse foam cells in shallow derma. In the control group, there are large foam cells in shallow layer of derma. The ultrastructure of the treated specimens showed fat droplets decrease in foam cells in contrary to the control group. CONCLUSIONS: Bleomycin A5 can rapidly inhibit the proliferation of foam cells and induce xanthelasma disappearance. Bleomycin A5 is an easy and safe method to treat eyelid xanthelasma and can be widely used in clinical work.

Adult↗
PubMed1991

The hypersensitivity of the Chinese hamster ovary variant BL-10 to bleomycin killing is due to a lack of glutathione S-transferase-alpha activity.

As a means to understand the fundamental mechanisms of bleomycin cell killing, we previously isolated 19 bleomycin-sensitive mutants which represent at least six genetically distinct complementation groups (T.D. Stamato, B. Peters, P. Patil, N. Denko, R. Weinstein, and A. Giaccia. Cancer Res., 47: 1588-1592, 1987). One class of mutants represented by the cell line BL-10 displays only hypersensitivity to killing by bleomycin in both acute (16 h) and chronic treatments but no sensitivity to killing by other DNA-damaging agents. Complementation studies between this mutant and human fibroblasts suggested that the human gene which corrects the defect of BL-10 rested on human chromosome 6. It has been reported that the gene for human glutathione S-transferase (GST) alpha also resides on chromosome 6. Measurements of selenium-independent peroxidase (alpha-GST + glutathione peroxidase) activity in wild-type Chinese hamster ovary (CHO) cells, using cumene hydrogen peroxide as a substrate, gave a value of 112 nmol of glutathione oxidized/min/mg protein compared with 88.1 nmol of glutathione oxidized/min/mg protein for BL-10. Measurement of the selenium-dependent peroxidase activity, using H2O2 as a substrate, resulted in 65.9 nmol of reduced glutathione oxidized/min/mg protein in CHO and 81.5 nmol of reduced glutathione oxidized/min/mg protein for BL-10. In other words, BL-10 cells did not exhibit a difference in their ability to metabolize both substrates in contrast to CHO cells. This indicates that BL-10 possesses little alpha-GST activity. Transfection of BL-10 cells with a mammalian expression vector containing the alpha-GST gene increases the survival of BL-10 to bleomycin and does not increase the bleomycin resistance of two other bleomycin mutants which lie in different genetic complementation groups. These data strongly implicate a role for alpha-GST in the resistance of cells to bleomycin.

Animals↗
PubMed1985

The redox state of activated bleomycin.

Activated bleomycin appears to have two more oxidizing equivalents than the Fe(III).bleomycin to which it spontaneously decays. Activated bleomycin reacts with NADH and thio-NADH, two-electron reductants, and with KI, a one-electron reductant, to yield Fe(III).bleomycin. The observed stoichiometries were 0.85 +/- 0.07 eq of thio-NADH oxidized or 1.5 +/- 0.25 eq of KI oxidized per mole of activated bleomycin. None of these reactions requires the presence of a redox mediator, as does the reduction of Fe(III).bleomycin by NADH or thio-NADH. The oxidations of both pyridine nucleotide coenzymes and of KI are inhibited by DNA, the usual bleomycin target.

Bleomycin↗
PubMed1987

Microsome-stimulated activation of ferrous bleomycin in the presence of DNA.

The inhibition of Fe(II)-bleomycin activation, by a large excess of DNA, is overcome by rat liver microsomes in the presence of NADPH. This release of inhibition, as indicated by increased yields of base propenal from DNA scission, is enhanced by menadione, is inhibited by superoxide dismutase, and is therefore dependent on superoxide anion. Microsomal activation of Fe(II)-bleomycin doubles the stoichiometry of base propenal yield compared to that obtained upon self-activation of the drug; 0.5 mol of base propenal is formed and 0.5 mol of NADPH is oxidized per mol of Fe(II)-bleomycin. In the presence of a large excess of DNA, Cu(II)-bleomycin is not reduced and Fe(III)-bleomycin is neither reduced nor activated by microsomes in cases where activation of Fe(II)-bleomycin is maximal. We suggest that in vivo, electron transport enzymes at or near the nucleus can stimulate the activation of Fe(II)-bleomycin under conditions where self-activation does not readily occur.

Animals↗
PubMed1988

Synergistic cytotoxicity and DNA strand break formation by bromodeoxyuridine and bleomycin in human tumor cells.

5-Bromo-2'-deoxyuridine (BrdUrd) is a thymidine analogue whose cellular effects are related to its incorporation into DNA. BrdUrd is a known radiosensitizing agent that could potentially enhance the activity of chemotherapeutic agents that interact directly with DNA. Therefore we studied the interaction of BrdUrd and bleomycin in a human head and neck squamous carcinoma cell line, SQ20B. Using a colony-forming assay and analyzing results by the median-effect method, we have shown that there is synergistic cytotoxicity between BrdUrd and bleomycin. Synergism is evident when BrdUrd is administered prior to bleomycin or when the two drugs are applied simultaneously and is evident at a variety of BrdUrd:bleomycin concentration ratios. Alkaline elution of DNA from cells exposed to BrdUrd and bleomycin demonstrated greater single strand break formation than expected from the individual single strand break frequencies induced by each drug alone. BrdUrd did not affect the rate of repair of bleomycin-induced single strand breaks or the formation of double strand breaks. Although the mechanism of this interaction at the molecular level is unclear, our studies suggest that a direct interaction of bleomycin with BrdUrd-substituted DNA may be the cause of the synergism of these two agents.

Algorithms↗
PubMed1989

In vitro activity of bleomycin, tallysomycin S10b, and liblomycin against fresh human tumor cells.

The objective of this study was to compare the relative in vitro cytotoxicity of bleomycin to that of two newer-generation analogues, tallysomycin S10b and liblomycin. The latter compound is of particular interest as it has recently been shown in preclinical studies to be free of a potential to cause pulmonary injury and yet to possess only a minor potential to produce myelotoxicity. Using the adhesive tumor cell culture system, we evaluated the activity of these three drugs against a panel of 13 human tumors of various types. The range of concentrations chosen was determined and normalized using a nonleukemic permanent mouse hematopoietic progenitor cell line. Those drug concentrations achieving 90% inhibition of growth (IC90) against the murine cell line were: 6.11 microM bleomycin; 7.53 microM tallysomycin S10b; and 0.6 microM liblomycin. When tested against fresh human tumors at equally myelotoxic IC90 concentrations, bleomycin and tallysomycin S10b (nonmyelotoxic compounds) both achieved 90% growth inhibition of all tumors, while liblomycin (a myelotoxic compound) produced an IC90 inhibition in 69% of all tumors. A comparison of drug IC90 values against individual fresh tumors indicated a correlation between bleomycin and its structurally related analogue tallysomycin S10b. No such correlation, however, was seen with liblomycin in comparison to either bleomycin or tallysomycin S10b. The relative activity of liblomycin versus that of bleomycin and tallysomycin S10b varied with individual tumors tested. The response rate of liblomycin, a myelotoxic compound within this normalized range, appears promising. These data represent the first comparison of liblomycin to bleomycin against a spectrum of fresh human tumors using a stem cell assay technique.

Bleomycin↗
PubMed1989

Release of nucleosomes from nuclei by bleomycin-induced DNA strand scission.

Mononucleosomes were released from both isolated mammalian (hog thyroid) and protozoan (Tetrahymena) nuclei by the bleomycin-induced DNA-strand breaking reaction. Trout sperm nuclei, on the other hand, were protected from the bleomycin-mediated DNA degradation. The mononucleosomes released from the bleomycin-treated nuclei contained the core histones H2A, H2B, H3, and H4; while HMG1 and HMG2 proteins, in addition to the core histones, were detected in the mononucleosomes obtained by micrococcal nuclease digestion of nuclei. HMGs, but not H1 histone, were dissociated into the supernatant by cleavage of chromatin DNA with bleomycin, whereas both HMGs and H1 were found in that fraction by digestion of nuclei with micrococcal nuclease. HMG1 and HMG2 were exclusively dissociated from chromatin with 1 mM bleomycin under the solvent condition where the DNA strand-breaking activity of the drug is repressed. These observations suggest the possibility that bleomycin preferentially binds to linker DNA regions not occupied by H1 histone in chromatin and exclusively dissociates HMG proteins and breaks the DNA strand. The results of the effects on bleomycin-induced DNA cleavage of nuclei of various drugs including polyamines, chelating agents, intercalating antibiotics such as mitomycin C or adriamycin, and radical scavengers are also presented.

Animals↗
PubMed1975

The effects of bleomycin on immunocompetence in man.

Bleomycin was administered to six patients with advanced cancer. Multiple parameters of both antibody- and cell-mediated immunity were followed serially to characterize the effects of bleomycin on immunocompetence in humans. Antibody-mediated immunity, including primary vaccination with keyhole limpet hemocyanin, was not depressed. While there was no significant suppression of cell-mediated immunity, phytohemagglutinin-stimulated lymphocyte blastogenesis was reduced after treatment with bleomycin. The in vitro effects of bleomycin on lymphocyte stimulation were studied, and while thymidine incorporation was significantly inhibited by bleomycin, leucine incorporation was not reduced even at high concentrations of bleomycin. We have concluded that bleomycin does not suppress immunocompetence in man.

Antibody Formation↗
PubMed1984

Kinetics of DNA repair synthesis induced by bleomycin and N-methyl-N-nitrosourea in isolated rat liver nuclei.

Purified rat liver nuclei were incubated in the presence of a labeled deoxyribonucleoside triphosphate and bleomycin (an antitumor agent) or N-methyl-N-nitrosourea (MNU, a direct-acting carcinogen) to compare their abilities to induce DNA repair synthesis. It was found that bleomycin induced the incorporation of [3H]dTMP and, to a lesser extent, [3H]dCMP and [3H]dAMP, whereas MNU induced incorporation of [3H]dAMP exclusively. The bleomycin-induced DNA repair was linear with time, whereas the MNU-induced repair was more complex, requiring an induction period and lasting only 90 minutes. The extent of incorporation measured after a 15- or 30-minute preexposure to bleomycin was proportional to the time of preexposure and the repair reaction was completed within 30 minutes. The extent of incorporation measured after preexposure to MNU increased less than proportionally with the time of preexposure and the repair reaction lasted a total of approximately 90 minutes. The interactions between bleomycin and MNU damage and repair were also examined. It was found that, following preexposure to MNU and subsequent repair in the presence of bleomycin, the repair activities induced by the two compounds were not additive. Our data are in agreement with previous studies on the base excision induced by bleomycin and MNU and suggest that the in vitro nuclear system reflects the physiological changes induced by the interaction of a compound with DNA.

Animals↗
PubMed1981

Potentiation of bleomycin cytotoxicity toward cultured mouse cells by hyperthermia and ethanol.

The effects of hyperthermia and ethanol on bleomycin cytotoxicity toward mouse mammary carcinoma FM3A cells in culture were followed in terms of clonal growth in a soft agar medium. Heating the cells at 43 degrees during or before bleomycin treatment sensitized them to bleomycin. Heat treatment after drug treatment was less effective. Bleomycin cytotoxicity was also greatly potentiated by exposing the cells to ethanol at a concentration of more than 4% (v/v) at 37 degrees before or after drug treatment. However, when the cells were exposed to ethanol during bleomycin treatment, the potentiation of cytotoxicity was reduced, and a higher concentration of ethanol was required for inducing equivalent sensitization. The cytoxicity of pepleomycin, a potent antitumor agent derived from bleomycin, was also greatly potentiated by hyperthermia and ethanol. The cellular uptake of 3H-pepleomycin was not increased by either treatment, and thus the increased cytotoxicity was not correlated with a change in membrane permeability to the drug. The sensitizing effect of hyperthermia or ethanol was maximum when the drug treatment was carried out immediately after the cells were exposed to heat or ethanol. Sensitization decreased linearly as the time interval between the two treatments was increased, and after a 6 hr interval the sensitizing effect of either agent disappeared. This recovery from the sensitized state was not inhibited by cycloheximide or by incubation in phosphate-buffered saline instead of complete growth medium, but it was reversibly inhibited at 0 degrees. It is suggested that the modes of action of hyperthermia and ethanol in inducing cell sensitization of bleomycin are similar.

Animals↗
PubMed1984

A comparison of lymphocyte populations in lung tissue and in bronchoalveolar lavage fluid of rats at various times during the development of bleomycin-induced pulmonary fibrosis.

The purpose of this study was to compare lymphocyte populations in lung lavage fluid and in lung tissue during the development of bleomycin-induced pulmonary fibrosis. At various times after bleomycin treatment, animals were killed and lavaged, and lung tissue cells were extracted. Lymphocyte populations were identified by immunofluorescent techniques, using monoclonal antibodies, and quantitated on the fluorescence-activated cell sorter. Normal control rat lung tissue was comprised of 91% T-cells (helper-to-suppressor cell ratio of approximately 1:1) and 9% B-cells. After bleomycin administration, a significant increase in the percentage of B-cells in lung tissue was observed within 3 days, with peak levels (approximately 28%) occurring at 7 days. Changes in the T-cell subset populations were also observed in lung tissue; at 14 days after the administration of bleomycin, the helper-to-suppressor T-cell ratio was 2:1, at 30 and at 120 days, the ratio was reversed to 1:2. These represent significant changes from the 1:1 ratio found in control animals. No lymphocytes were observed in the lavage fluid of control animals or in animals at 30 and 120 days after bleomycin treatment. Significant populations of lymphocytes were found in the lavage fluid at 3, 7, and 14 days after bleomycin treatment. These lymphocytes consisted of approximately 90% T-cells (helper-to-suppressor cell ratio of 1:1) and 10% B-cells. There were no significant changes in the lymphocyte populations found in the lavage fluid after the administration of bleomycin. The results demonstrate that specific lymphocyte populations are changing in lung tissue during the development of the fibrotic process, whereas this shift in populations does not occur in the lymphocyte populations found in lavage fluid.

Animals↗
PubMed1984

Differences in effects of immediate and delayed hyperoxia exposure on bleomycin-induced pulmonary injury.

Several reports have suggested that patients treated with bleomycin may be at greater risk of developing respiratory failure when exposed to elevated concentrations of oxygen. We studied the interactions of bleomycin and hyperoxia in Syrian golden hamsters. Animals were instilled intratracheally with bleomycin at a dose of 0.5 unit/100 g of body weight, followed immediately by exposure to 70% oxygen for 72 hours. Mortality was 90% in these hamsters, compared to 15% in an age-matched control group treated with bleomycin alone. Postmortem studies revealed that pathologic changes were confined to the lungs which showed severe, hemorrhagic, diffuse alveolar damage. To determine the effect of delaying exposure to hyperoxia, bleomycin at a dose of 0.5 unit/100 g of body weight was instilled and animals were kept in room air for 1 and 2 months before exposure to 70% or 100% oxygen for 72 hours. No significant increase in mortality or interstitial pneumonitis and fibrosis was seen in these groups during or after the hyperoxic exposures. Mortality in controls treated with saline and hyperoxia was zero. We conclude that simultaneous treatment with bleomycin and hyperoxia results in a synergistic effect on mortality and on the development of pulmonary fibrosis. However, there is no synergism if the hyperoxic exposure is delayed for at least 1 month following bleomycin treatment.

Animals↗
PubMed1976

Determination of the bleomycin-inactivating enzyme in biopsies.

A method for the determination of the Bleomycin-inactivating enzyme is described. The amount of conversion of active Bleomycin to inactive Bleomycin is used as a measure for the determination of the Bleomycin-inactivating enzyme activity. The active Bleomycin is determined in a DNA-dependent DNA polymerase assay; in a certain Bleomycin concentration range the resulting reduction of the activity of the DNA-dependent DNA polymerase is correlated linearly when plotted semilogarithmically. By application of this method it has been found that the activity of the Bleomycin-inactivating enzyme is highest in liver and present in lower concentrations in testis, spleen, lung, brain, and skin.

Bleomycin↗