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PubMed1988

Effect of murine gamma interferon on the cellular responses to bleomycin in mice.

Because in vitro studies have shown inhibition of fibroblast proliferation and collagen synthesis by interferon, we tested the hypothesis that murine gamma interferon inhibits bleomycin-induced pulmonary fibrosis in mice. Mice were divided into the following groups: saline plus vehicle (27), saline plus interferon (29), bleomycin plus vehicle (26), and bleomycin plus interferon (26). Bleomycin or saline were given intratracheally once at the beginning of the experiment and vehicle (phosphate-buffered saline) or interferon was given intramuscularly daily. Mice were killed at 14 or 21 days of the experiment. About half of the mice from each group were used for collagen biochemistry and half for bronchoalveolar lung lavage, transmission electron microscopy (TEM), and morphometry. Hydroxyproline content showed a significant reduction in bleomycin plus interferon compared to bleomycin plus vehicle mice at 21 days. The saline plus vehicle and saline plus interferon mice showed no difference in hydroxyproline content. Similarly, bronchoalveolar lavage showed no differences between saline plus vehicle and saline plus interferon mice; however, all mice treated with bleomycin showed significant increases in total cells as compared to saline treated mice. At 14 and 21 days in bronchoalveolar lavage there were significantly more lymphocytes in bleomycin plus interferon compared to bleomycin plus vehicle mice. In bronchoalveolar lavage, there were usually fewer neutrophils, monocytes and macrophages in bleomycin plus interferon compared to bleomycin plus vehicle mice. Morphometric estimates of the volume of lesion within lung showed no significant differences among the bleomycin treated groups. Stainable collagen fibers were less, but not significantly, in the bleomycin plus interferon compared to bleomycin plus vehicle mice. The number of fibroblasts per volume of lesion was significantly decreased at 14 and 21 days in bleomycin plus interferon compared to bleomycin plus vehicle mice. The total volume of lymphocytes in interstitial lesions was significantly greater at 14 and 21 days in bleomycin plus interferon mice compared to bleomycin plus vehicle mice. These results suggest an inhibitory action of gamma interferon on collagen accumulation and fibroblast proliferation associated with lymphocyte accumulation in the lungs of mice following bleomycin administration.

Animals↗
PubMedDate not supplied

89Strontium-induced bone marrow depression suppresses the early inflammatory response and fibrosis caused by intratracheal bleomycin.

To investigate the effect of bone marrow depression on the development of bleomycin-induced lung injury, F-344/Crl rats were given an intraperitoneal (IP) injection of 89SrCl2 (2 mCi/kg body weight) 7 days prior to the intratracheal (IT) instillation of 7.0 U/kg body weight bleomycin (Sr-bleomycin group). A second group of rats was given an IP injection of saline followed 7 days later by IT bleomycin (bleomycin group). Additional rats were given 89Sr IP and saline IT (Sr group) or saline IP and saline IT (saline group). Rats were sacrificed at 0, 3, 10, 21, and 30 days after the intratracheal instillations. 89Sr administration resulted in significantly lower numbers of circulating blood neutrophils and monocytes in the Sr-bleomycin group compared with the bleomycin group through at least the first 21 days following the IT instillations. Lymphocyte numbers were also depressed in the Sr-bleomycin group at days 3 and 21. Analysis of bronchoalveolar lavage fluid (BALF) revealed significantly reduced protein and lymphocyte numbers in the BALF from the 89Sr-bleomycin group compared with the bleomycin group at day 3, but not at later time points. Neutrophils in BALF were also lower (though not significantly) in the 89Sr-Bleomycin group at day 3. There was no difference in the number of BALF macrophages between the Sr-bleomycin and bleomycin groups at any time point throughout the study. Histology and morphometry showed the same trends as the BALF data with much less severe lesions in the 89SR-Bleomycin group compared with the bleomycin group at day 3, but not at later time points. At day 10, hydroxyproline values were significantly higher in the bleomycin group (47% increase above saline group) than the Sr-bleomycin group (only 18% increase above Sr group), but by day 21, there was no longer a significant difference between these two groups. These results demonstrate that bone marrow depression significantly suppresses the early inflammatory response and collagen deposition caused by a single IT dose of bleomycin, but has little effect on the resolution of bleomycin-induced injury.

Animals↗
PubMed1990

Intracellular DNA strand scission and growth inhibition of Ehrlich ascites tumor cells by bleomycins.

A comparison of the intracellular DNA strand scission activities of the antitumor drug bleomycin, three of its metal complexes, demethyl bleomycin A2, and iron-containing, redox-inactivated bleomycin in Ehrlich ascites tumor cells was performed by means of the alkaline elution technique. This comparison was aided by use of CoCl2 to eliminate or minimize post-cell lysis strand scission by bleomycin in aliquots of treated cultures. No strand scission resulted from treatment of cells with the cobalt complex. The levels of intracellular DNA degradation by copper bleomycin and iron bleomycin were equivalent to those produced by metal-free bleomycin. The findings are correlated with previous measurements of growth inhibition by these three bleomycins as well as by cobalt bleomycin and related to the concentrations of radiolabeled bleomycin bound to DNA after treatment of cells with each form of drug. In comparison, both demethyl bleomycin A2 and iron-containing, redox-inactivated bleomycin showed marked, concentration-dependent reductions in random DNA strand scission, as compared with unmodified bleomycin or iron bleomycin prepared from Fe(III) and bleomycin. However, the fraction of DNA from cells treated with these two bleomycins, which eluted through filters prior to alkaline denaturation, was equivalent to that for unmodified bleomycin and Fe(III)bleomycin. The generation of this class of damaged DNA correlates more closely with concentration-dependent growth inhibition by each of the six forms of bleomycin than the degree of random strand scission.

Animals↗
PubMed1993

Histologic, pharmacologic, and immunocytochemical effects of injection of bleomycin into viral warts.

BACKGROUND: The plasma concentration of bleomycin after injection of bleomycin into warts is unknown, as is the long-term stability of bleomycin solution. OBJECTIVE: Our purpose was to measure plasma bleomycin concentration after injection of bleomycin into warts, to relate histologic and immunocytochemical changes in warts to possible mechanisms of action of bleomycin, and to asses the long-term stability of stored frozen bleomycin solution. METHODS: One milligram of bleomycin was injected into warts on the hands of seven men. Blood samples were taken 15 to 120 minutes after injection, and plasma bleomycin was measured by radioimmunoassay. Warts were removed 2 hours and 48 hours after treatment and studied histologically by light microscopy and for the presence of bleomycin by immunocytochemistry. The bleomycin concentration in 8 aliquots of solution stored at -20 degrees C for varying periods was measured by radioimmunoassay. RESULTS: Peak levels of bleomycin of 7 to 113 ng/ml were reached by 45 minutes after injection. Plasma bleomycin exposure ranged from 515 to 5137 ng/ml/min between 15 and 120 minutes after injection. The most pronounced histologic changes at 48 hours were individual keratinocyte apoptosis throughout the epidermis merging into areas of complete epidermal necrosis, diffuse neutrophil accumulation, and microabscess formation at the granular layer. Immunocytochemistry demonstrated tissue-fixed bleomycin in all levels of the epidermis except the basal layer and most prominently in the granular layer. Bleomycin in solution stored for up to 27 months at -20 degrees C in glass showed no significant loss of immunoreactivity. CONCLUSION: The use of bleomycin for the treatment of warts results in significant systemic drug exposure; thus it would be prudent to exclude pregnancy before treating women of child-bearing age. Bleomycin probably has a direct toxic effect on keratinocytes. Dilute bleomycin solution stored at -20 degrees C in glass is stable.

Bleomycin↗
PubMedDate not supplied

Naringin, a grapefruit flavanone, protects V79 cells against the bleomycin-induced genotoxicity and decline in survival.

The effect of naringin, a grapefruit flavonone was studied on bleomycin-induced genomic damage and alteration in the survival of cultured V79 cells. Exposure of V79 cells to bleomycin induced a concentration dependent elevation in the frequency of binucleate cells bearing micronuclei (MNBNC) and a maximum number of MNBNCs were observed in the cells treated with 50 microg ml(-1) bleomycin, the highest concentration evaluated. This genotoxic effect of bleomycin was reflected in the cell survival, where a concentration dependent decline was observed in the cells treated with different concentrations of bleomycin. Treatment of cells with 1 mm naringin before exposure to different concentrations of bleomycin arrested the bleomycin-induced decline in the cell survival accompanied by a significant reduction in the frequency of micronuclei when compared with bleomycin treatment alone. The cell survival and micronuclei induction were found to be inversely correlated. The repair kinetics of DNA damage induced by bleomycin was evaluated by exposing the cells to 10 microg ml(-1) bleomycin using single cell gel electrophoresis. Treatment of V79 cells with bleomycin resulted in a continuous increase in DNA damage up to 6 h post-bleomycin treatment as evident by migration of more DNA into the tails (% tail DNA) of the comets and a subsequent increase in olive tail moment (OTM), an index of DNA damage. Treatment of V79 cells with 1 mm naringin reduced bleomycin-induced DNA damage and accelerated DNA repair as indicated by a reduction in % tail DNA and OTM with increasing assessment time. A maximum reduction in the DNA damage was observed at 6 h post-bleomycin treatment, where it was 5 times lower than bleomycin alone. Our study, which was conducted on the basis of antioxidant, free radical scavenging and metal chelating properties of naringin demonstrates that naringin reduced the genotoxic effects of bleomycin and consequently increased the cell survival and therefore may act as a chemoprotective agent in clinical situations.

Animals↗
PubMed1990

Effects of three cysteine pro-drugs on bleomycin-induced lung fibrosis in hamsters.

The cysteine pro-drug Z2196 ((2RS, 4R)-2-methylthiazolidine carboxylic acid) and two drugs with methyl esters attached to Z2196 (Z2197 and Z2199) were evaluated for antifibrotic effects in the hamster bleomycin model of lung fibrosis. Each drug or phosphate-buffered saline (PBS) was given daily (300 mg/kg intraperitoneally) for 2 days before intratracheal instillation of bleomycin (7.5 units/kg) or saline for an additional 13 days. Lung collagen measured as hydroxyproline was significantly increased to 138% of the control groups in the PBS + Bleomycin treated group, but the Z2196 + Bleomycin group was increased to 108% and was not statistically different from controls. Protein content of bronchoalveolar lavage supernatant in PBS + Bleomycin treated hamsters was significantly increased to 326% of controls. The protein content of bronchoalveolar lavage supernatant for all cysteine pro-drug + Bleomycin treated hamsters was increased to 160% of PBS + Bleomycin treated hamsters. All the Bleomycin treated hamsters had significantly more cells and more neutrophils recovered in bronchoalveolar lavage than controls. The PBS + Bleomycin treated hamsters had significantly more lymphocytes in bronchoalveolar lavage than all the other treatment groups. The Z2196 + Bleomycin and Z2197 + Bleomycin hamsters had significantly less monocytes in BALF than PBS + Bleomycin hamsters. The lung total sulfhydryl and nonprotein sulfhydryl in PBS + Bleomycin treated hamsters were increased to 210% and 253% of controls, respectively, whereas in Z2196 + Bleomycin hamsters they were increased to 152% and 153%, respectively. Histopathology of PBS + Bleomycin hamsters showed a diffuse mixed mononuclear alveolitis, multifocal fibrosis and peribronchiolar fibrosis, whereas Z2196 + Bleomycin hamsters showed notably less alveolitis and fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Combined modality therapy with bleomycin, hyperthermia, and radiation.

In an attempt to develop better combination therapies for use with local radiation, the interaction between bleomycin and hyperthermia +/- radiation was studied in the FSaIIC tumor system. In cells exposed in vitro to bleomycin at 37 degrees C and at pH 7.40, the drug was substantially more toxic toward normally oxygenated than hypoxic cells. At hyperthermic temperatures (42 degrees or 43 degrees C), however, the differential killing between the normally oxygenated and hypoxic cells disappeared and bleomycin became significantly more toxic. Exposure to bleomycin at pH 6.45 did not substantially alter the cytotoxicity of the drug at 42 degrees or 43 degrees C. In tumor growth delay experiments, combining bleomycin, hyperthermia, and radiation induced long delays, and the more successful sequences were bleomycin----radiation----hyperthermia or bleomycin----hyperthermia----radiation. If radiation was given prior to drug and hyperthermia, however, the sequence was significantly less effective. In tumor excision experiments performed 24 h after treatment, increasing doses of bleomycin produced a shallow, log-linear increase in tumor cell kill at 37 degrees C, but bleomycin followed by hyperthermia (43 degrees C, 30 min) led to about 1 log more cell killing. Administration of bleomycin just prior to treatment with a single dose of radiation was cytotoxically additive. In this assay the most effective trimodality treatment sequence was bleomycin----hyperthermia----radiation. In tumor subpopulations defined by Hoechst 33342 dye staining, bleomycin at 37 degrees C was about two-fold more toxic toward the bright (presumably well-oxygenated) cells than toward the dim (presumably hypoxic) cell subpopulation. The addition of hyperthermia following bleomycin produced nearly a log more tumor cell killing in both the bright and dim tumor cells. The combination of bleomycin followed by hyperthermia and then radiation was at least additive in the bright cells and caused a large cell kill, but in comparison, there was marked sparing of the dim cells. These results indicate that treatment with bleomycin and hyperthermia in conjunction with radiation can add substantially to tumor cell killing. This combination is significantly less effective in the hypoxic than oxic tumor regions, however, in spite of in vitro data which demonstrate that the cytotoxicity of bleomycin at hyperthermic temperatures is not oxygen-dependent.

Animals↗
PubMed1980

[Animal experiments for intratumoral chemotherapy with bleomycin (author's transl)].

The intense clinical interest in bleomycin as an anti-tumour agent has led to different methods of administration in an attempt to administer sufficiently high concentrations of the drug to the tumor. Therefore, a study was designed to determine the distribution and the therapeutic effect of a bleomycin emulsion and aqueous bleomycin after different routes of application. The tissue distribution of radioactively labelled bleomycin emulsion and aqueous bleomycin was determined in tumor-free CF 1 and tumor-bearing (EL 4, L 1210) C 57 Bl 6 and DBA 2 mice after local (s.c., i.t.) and systemic (i.v.) injection. The distribution studies for aqueous 57Co-bleomycin showed increased activity in the injection sites and the lymph nodes draining the injection sites after s.c. and i.t. injection compared to i.v. administration of the drug. In comparison to the aqueous local administration, the application of 57Co-bleomycin emulsion resulted in a disproportional increase of the 57Co-bleomycin concentration at the injection sites and in the draining lymph nodes. To prove the therapeutic relevance of the bleomycin tissue distribution tumor-bearing (line 10) strain 2 guinea pigs were treated with different modes of bleomycin. Animals with already lymphogenously metastasized tumors have been cured by means of low i.t. doses of the bleomycin emulsion. Guinea pigs treated with i.t. administration of aqueous bleomycin need, compared to the bleomycin emulsion, five times higher doses for tumor-free survival. Intravenously treated animals died either because of progressive tumor growth or because of toxic bleomycin effects. These findings made by animal experiments favor the i.t. treatment of head and neck carcinomas with a bleomycin emulsion.

Animals↗
PubMed2005

Attenuation of bleomycin-induced lung fibrosis in rats by mesna.

Lung fibrosis is a common side effect of the chemotherapeutic agent, bleomycin. Current evidence suggests that reactive oxygen species may play a key role in the development of lung fibrosis. The present study examined the effect of mesna on bleomycin-induced lung fibrosis in rats. Animals were divided into three groups: (1) saline control group; (2) Bleomycin group in which rats were injected with bleomycin (15 mg/kg, i.p.) three times a week for four weeks; (3) Bleomycin and mesna group, in which mesna was given to rats (180 mg/kg/day, i.p.) a week prior to bleomycin and daily during bleomycin injections for 4 weeks until the end of the treatment. Bleomycin treatment resulted in a pronounced fall in the average body weight of animals. Bleomycin-induced pulmonary injury and lung fibrosis was indicated by increased lung hydroxyproline content, and elevated nitric oxide synthase, myeoloperoxidase, platelet activating factor, and tumor necrosis factor-alpha in lung tissues. On the other hand, bleomycin induced a reduction in reduced glutathione concentration and angiotensin converting enzyme activity in lung tissues. Moreover, bleomycin-induced severe histological changes in lung tissues revealed as lymphocytes and neutrophils infiltration, increased collagen deposition and fibrosis. Co-administration of bleomycin and mesna reduced bleomycin-induced weight loss and attenuated lung injury as evaluated by the significant reduction in hydroxyproline content, nitric oxide synthase activity, and concentrations of myeoloperoxidase, platelet activating factor, and tumor necrosis factor-alpha in lung tissues. Furthermore, mesna ameliorated bleomycin-induced reduction in reduced glutathione concentration and angiotensin activity in lung tissues. Finally, histological evidence supported the ability of mesna to attenuate bleomycin-induced lung fibrosis and consolidation. Thus, the findings of the present study provide evidence that mesna may serve as a novel target for potential therapeutic treatment of lung fibrosis.

Animals↗
PubMed2003

Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis.

OBJECTIVE: Potentially fatal pulmonary toxicity is a dreaded complication of bleomycin. Increased use of granulocyte colony-stimulating factor in patients receiving chemotherapy has been paralleled by an increased incidence of bleomycin-induced pulmonary toxicity. We investigated whether granulocyte colony-stimulating factor (25 microg x kg(-1) x day(-1), 4 days) enhanced endotracheal bleomycin-induced (5 mg/kg) acute lung injury and fibrosis in rats. SETTING: University laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: We compared the effects of alveolar instillation of bleomycin in rats treated with either granulocyte colony-stimulating factor or saline. MEASUREMENTS AND MAIN RESULTS: Mortality was 25% with bleomycin only and 50% with bleomycin + granulocyte colony-stimulating factor. Granulocyte colony-stimulating factor increased alveolar neutrophil recruitment, pulmonary edema, and lung myeloperoxidase activity on day 4. Lung static compliance on day 15 was severely decreased with bleomycin alone and showed a further significant decrease when granulocyte colony-stimulating factor was added (controls, 3.85 +/- 0.14 mL/kPa; bleomycin, 1.44 +/- 0.06 mL/kPa; and bleomycin + granulocyte colony-stimulating factor, 0.65 +/- 0.09 mL/kPa; control vs. bleomycin, p <.0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor, p =.0003). Lung morphology with bleomycin + granulocyte colony-stimulating factor showed, in addition to the changes observed with bleomycin alone, four patterns indicating more severe disease: honeycomb foci, pleural thickening with hyaline fibrosis, interstitial granuloma with increased number of macrophages but not neutrophils, and established interstitial fibrosis. Lidocaine, which prevents neutrophil adhesion to endothelial cells, inhibited granulocyte colony-stimulating factor-related exacerbation of acute lung injury (bronchoalveolar lavage fluid cells and pulmonary edema) and pulmonary fibrosis (lung static compliance and morphologic changes). CONCLUSIONS: Granulocyte colony-stimulating factor enhances bleomycin-induced lung toxicity by a mechanism that probably involves neutrophils.

Animals↗
PubMed1981

Chemical synthesis of radiolabeled bleomycin A2 and its binding to DNA.

A method for the preparation of biologically active [3H]- and [13C]bleomycin A2 is described. Demethyl Cu(II):bleomycin A2, isolated after pyrolysis of Cu(II):bleomycin A2, was methylated with either [3H]-or [13C]methyl iodide, which resulted in Cu(II):bleomycin A2 labeled in the dimethylsulfonium moiety. Copper was removed by treatment with dithizone in chloroform, and structures were verified by thin-layer chromatography and 1H and 13C nuclear magnetic resonance spectroscopy. Copper-free [3H]-and [13C]bleomycin A2 are active in the degradation of DNA in vitro. Gel exclusion chromatograhy and equilibrium dialysis were used to determine the apparent equilibrium constants for binding of [3H]bleomycin A2 and Cu(II):[3H]bleomycin A2 to calf thymus DNA, noncovalently associated polydeoxyguanylate:polydeoxycytidylate, and noncovalently associated polydeoxyadenylate:polydeoxythymidylate. In 2.5 mM sodium phosphate buffer, pH 7.0, binding data obtained by gel filtration with calf thymus DNA reveal an apparent equilibrium constant for [3H]bleomycin A2 of 5.7 X 10(5)/mol and for Cu(II):[3H]bleomycin A2 of 3.9 X 10(5)/mol. One molecule of [3H]bleomycin A2 binds for every 3.7 base pairs in DNA, and one molecule of Cu(II):[3H]bleomycin A2 binds for every 2.8 base pairs in DNA. Analysis of binding data with calf thymus DNA, noncovalently associated polydeoxyguanylate:polydeoxycytidylate, and noncovalently associated polydeoxyadenylate:polydeoxythymidylate obtained by equilibrium dialysis reveals, in each instance, 2 types of binding sites for both the copper and metal-free form of the antibiotic. For those sites in calf thymus DNA with tighter binding affinity, the apparent equilibrium constant for [3H]bleomycin A2 was 6.8 X 10(5)/mol and for the Cu(II):[3H]bleomycin A2 complex, 4.4 X 10(5)/mol. As seen with calf thymus DNA, the affinity of [3H]bleomycin A2 is slightly greater than that of Cu(II):[3H]bleomycin A2 for the synthetic DNAs, although more of the copper form of the drug binds to these polymers.

Animals↗
PubMed1988

Alterations in pulmonary protective enzymes following systemic bleomycin treatment in mice.

Repeated bleomycin administration in animals and humans produces significant lung fibrosis. The pathogenesis of this toxicity may be multifactorial, but it appears to be initiated through the production of radical oxygen species by an activated bleomycin-iron-oxygen ternary complex. Protection of lung tissue from bleomycin-induced toxicity may occur through both specific metabolic inactivation of bleomycin by the enzyme bleomycin hydrolase, as well as by such non-specific antioxidants as catalase and the glutathione system. The effect of chronic, systemic administration of bleomycin on the activities and levels of these enzymes and proteins in pulmonary tissue is unknown. C57BL/6 mice were injected subcutaneously with saline, non-fibrogenic (2 mg/kg) and fibrogenic (10 mg/kg) doses of bleomycin twice-weekly for 6 weeks. Animals were killed at 0, 1.5, 3, and 6 weeks after initiation of bleomycin treatment. Catalase activity was increased more than 50% at 3 weeks in the low-dose animals, and was decreased over 40% at 6 weeks in the high-dose animals. Total lung glutathione levels were unaffected in both groups, although glutathione reductase activity was increased significantly (over 2-fold) at 1.5 and 3 weeks in the high-dose animals. At 6 weeks glutathione reductase was increased 7- and 12-fold in low and high-dose animals respectively. Glutathione peroxidase activity also was elevated more than 2-fold above control values at 6 weeks in both sets of animals. There was no evidence of induction of bleomycin hydrolase activity at any time point. Rather, bleomycin hydrolase activity was decreased significantly to 30 and 40% of control values at 3 and 6 weeks, respectively, in mice receiving the fibrogenic doses of bleomycin. These results demonstrate that chronic, systemic administration of non-fibrogenic and fibrogenic doses of bleomycin produces changes in activity of lung antioxidant defense mechanisms. The early loss of lung bleomycin hydrolase activity may contribute to the pathogenesis of bleomycin-induced pulmonary toxicity following repeated drug exposure.

Animals↗
PubMed1989

Bleomycin and cyclophosphamide toxicity in mice with damaged lung tissue.

The clinical use of several anticancer drugs, including bleomycin and cyclophosphamide (CP), is often associated with lung damage which progresses to fibrosis. The effect of existing lung damage on the toxicity of these agents has not been investigated. Male BALB/c mice were treated intraperitoneally with 400 mg/kg butylated hydroxytoluene (BHT), 100 mg/kg CP or 100 mg/kg bleomycin, alone or in combination. Based on analyses of pulmonary DNA synthesis, each agent alone elicited significant lung damage with cell proliferation, peaking on Day 4 for BHT, Day 7 for CP and Day 14 for bleomycin. Quantitatively, the BHT lesion was greater than CP which was much greater than bleomycin. Mice given 100, 75, 50, 40 or 25 mg/kg bleomycin 1 day after BHT exhibited 100, 90, 22, 20 and 21% mortality, respectively. Treatment with 100, 50, 40 or 25 mg/kg CP 1 day after BHT resulted in 100, 54, 33 and 0% mortality, respectively. No mice treated with BHT, bleomycin or CP alone died. Total lung hydroxyproline content, an index of fibrosis, was significantly increased 14 days after the initial treatment in mice given BHT and 50 mg/kg bleomycin compared to mice treated with BHT, bleomycin or vehicle alone. Mice treated with 50 mg/kg CP 1 day after BHT did not develop fibrosis in excess of that attributable to the BHT alone. Treatment of mice with 100 mg/kg CP followed 1 or 2 days later by 100 mg/kg bleomycin resulted in 20-40% mortality, but no increase in lung hydroxyproline content compared to CP alone. Bleomycin delayed the onset of lung cell proliferation normally seen after treatment with BHT while CP attenuated this cell division only after it had begun. Treatments involving BHT and bleomycin did not alter lung sulfhydryl content. These data indicate that overall toxicity is increased in mice pretreated with BHT and then given bleomycin or CP while lung injury is enhanced only after bleomycin. The mechanism of the interaction with bleomycin is not known but may be related to a rapid inhibition of lung repair and not to oxidative stress.

Animals↗
PubMed2005

Bleomycin lung toxicity: who are the patients with increased risk?

Bleomycin is an antibiotic drug with anticancer properties produced by Streptomyces verticillus [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459]. It was isolated in 1966 by Umezawa et al. and its mechanism of action is breaking the DNA double helix by the production of free radicals, which is oxygen and iron dependent [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Bleomycin may be inactivated by bleomycin hidrolase presents in normal and tumoral cells [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94; Jules-Elysee K, White DA. Bleomycin-induced pulmonary toxicity. Clinics Chest Med 1990;11:1-20]. The complex bleomycin-Fe has been the most studied because bleomycin joins the DNA and Fe at the same time, and release of free radicals happens in the presence of molecular oxygen [Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Bleomycin has a renal metabolism with 50% of dose eliminated in 4h after its administration and 70% in the next 24h. Its half-life (T 1/2) is not altered, although the creatinine clearance drops to 25-35 ml/min [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. This drug has been used as cytostatic treatment of many malignant tumors, such as germ cell tumors, lymphomas, head and neck, and Kaposi's sarcomas [Chen XL, Li WB, Zhou AM et al. Role of endogenous peroxynitrite in pulmonary injury and fibrosis induced by bleomycin A5 in rats. Acta Pharmacol Sin 2003;24:697-702]. Minor important adverse effects are myelossupression, nauseas, vomiting, allergic reactions, mucositis, alopecia, erythema, hyperkeratosis, hypopigmentation, skin ulceration, and acute arthritis [Cheson BD. Pharmacology of cancer chemotherapy: miscellaneous chemotherapeutic agents. In De Vita Jr. VT, Hellmann S, Rosenberg AS, editors. Cancer principles and practice of oncology. Lippincott Willians & Wilkins; 2001. p. 452-459; Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94]. Fever is reported in 20-50% of patients and some of them present hyperthermia [Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch Toxicol 1991;65:81-94].

Antibiotics, Antineoplastic↗
PubMed1987

Copper-dependent cleavage of DNA by bleomycin.

DNA strand scission by bleomycin in the presence of Cu and Fe was further characterized. It was found that DNA degradation occurred readily upon admixture of Cu(I) or Cu(II) + dithiothreitol + bleomycin, but only where the order of addition precluded initial formation of Cu(II)--bleomycin or where sufficient time was permitted for reduction of the formed Cu(II)--bleomycin to Cu(I)--bleomycin. DNA strand scission mediated by Cu + dithiothreitol + bleomycin was inhibited by the copper-selective agent bathocuproine when the experiment was carried out under conditions consistent with Cu chelation by bathocuproine on the time scale of the experiment. Remarkably, it was found that the extent of DNA degradation obtained with bleomycin in the presence of Fe and Cu was greater than that obtained with either metal ion alone. A comparison of the sequence selectivity of bleomycin in the presence of Cu and Fe using 32P-end-labeled DNA duplexes as substrates revealed significant differences in sites of DNA cleavage and in the extent of cleavage at sites shared in common. For deglycoblemycin and decarbamoylbleomycin, whose metal ligation is believed to differ from that of bleomycin itself, it was found that the relative extents of DNA cleavage in the presence of Cu were not in the same order as those obtained in the presence of Fe. The bleomycin-mediated oxygenation products derived from cis-stilbene were found to differ in type and amount in the presence of added Cu vs. added Fe. Interestingly, while product formation from cis-stilbene was decreased when excess Fe was added to a reaction mixture containing 1:1 Fe(III) and bleomycin, the extent of product formation was enhanced almost 4-fold in reactions that contained 5:1, as compared to 1:1, Cu and bleomycin. The results of these experiments are entirely consistent with the work of Sugiura [Sugiura, Y. (1979) Biochem. Biophys. Res. Commun. 90, 375-383], who first demonstrated the generation of reactive oxygen species upon admixture of O2 and Cu(I)--bleomycin.

Bleomycin↗
PubMed1988

Degradation of structurally modified DNAs by bleomycin group antibiotics.

Bleomycin-mediated DNA strand scission has been shown to be diminished at certain sequences in proximity to 5-methylcytidines. We have investigated the molecular basis of this observed diminution using selective bleomycin (BLM) modifications at the C-terminus. Of the four different bleomycin congeners investigated, only bleomycin A2 and bleomycin BAPP were substantially affected by cytidine methylation. We have also examined the effect of other DNA modifications on bleomycin-mediated strand scission. Methylation at the N6 position of adenosine resulted in diminution of DNA cleavage by all four bleomycin congeners. The presence of bulky 5-(glucosyloxy)methyl groups in the major groove of T4 DNA had little effect on the efficiency of DNA strand scission mediated by bleomycin A2 or B2, suggesting the absence of important steric interactions between Fe(II).BLM and DNA in the major groove. In contrast, DNA cleavage mediated by bleomycin congeners was very sensitive to a major DNA conformational change, the B----Z transition. Salt and MgCl2 titrations of the DNA copolymers poly(dG-dC).poly(dG-dC) and poly(dG-MedC).poly(dG-MedC) demonstrated that bleomycin A2 and B2 did not cleave Z-DNA efficiently. In addition, circular dichroism titrations of these copolymers revealed that both bleomycin congeners increased the cation concentration necessary to induce the B----Z transition, implying that bleomycin preferentially binds to and stabilizes B-form DNA. These results are consistent with a model in which cytidine methylation at appropriate sequences of DNA is sufficient to induce subtle conformational changes that render the helix unreceptive to cleavage by some bleomycin congeners.

Bleomycin↗
PubMed1977

Inhibition of bleomycin-induced [3H] thymidine 5'-triphosphate incorporation into liver and hepatoma nuclei by N-ethyl maleimide and daunomycin.

The addition of bleomycin to a nuclear incorporating system results in an increased incorporation of 3H-thymidine 5'-triphosphate (3H-TTP) into the DNA of liver and hepatoma nuclei. Bleomycin added to the nuclear incorporating system also produces scissions of DNA as determined by sucrose density gradient centrifugation of the extracted DNA. The action of bleomycin is dependent on the presence of sulfhydryl agents in the incubation mixture. Two compounds, N-ethyl maleimide and daunomycin, inhibit the bleomycin-induced incorporation of 3H-TTP preferentially. N-Ethyl maleimide inhibits bleomycin-induced activity in liver and hepatoma 7777 nuclei equally. Lower levels of daunomycin inhibit the bleomycin-induced activity in the hepatoma 7777 nuclei than are required to inhibit the activity in liver nuclei. The two compounds inhibit the bleomycin effect by different mechanisms. The addition of N-ethyl maleimide to bleomycin in the incubation system prevents bleomycin from causing breaks in the DNA. The addition of daunomycin, despite inhibition of bleomycin-induced 3H-TTP incorporation, does not affect the bleomycin-produced breaks in the DNA. N-Ethyl maleimide acts by binding to the DNA and by competing with a sulfhydryl agent for bleomycin-sensitive sites on the DNA. Daunomycin apparently inhibits a repair enzyme that is responsible for the increased incorporation following bleomycin treatment.

Animals↗
PubMed1989

The effects of bleomycin on alveolar macrophage growth factor secretion.

Previous work in this laboratory has demonstrated increased secretion of fibroblast growth factor (MDGF) activity by alveolar macrophages obtained from mice with bleomycin-induced pulmonary fibrosis. The mechanism by which bleomycin promotes this increase in MDGF secretion is not clear, however. The purpose of this study was to determine the direct effects of bleomycin on alveolar macrophages. Normal rat alveolar macrophages obtained by lavage were cultured in the presence or absence of bleomycin; conditioned media from these cultures were dialyzed to remove bleomycin and then assayed in vitro for MDGF activity. Alveolar macrophages incubated with 0.01 microgram to 1 microgram/ml bleomycin for 18 hours secreted significantly more MDGF than macrophages incubated without bleomycin. Viability of macrophages as determined by exclusion of trypan blue and release of LDH was unaffected by any dose tested. Maximal MDGF production was seen with bleomycin doses of greater than or equal to 0.1 microgram/ml. When alveolar macrophages were incubated with 0.1 microgram/ml bleomycin for 0.5-18 hours, MDGF activity was detected as early as 1 hour, with peak responses found at 4-8 hours. Macrophages stimulated with bleomycin continued to produce significant amounts of MDGF even after bleomycin was removed and replaced with fresh (bleomycin-free) media. MDGF secretion by bleomycin-stimulated alveolar macrophages was inhibited by cycloheximide, and the 5-lipoxygenase inhibitors NDGA (nordihydroguairetic acid) and BW755c, indicating not only a requirement for protein synthesis but also for metabolites of the 5-lipoxygenase pathway of arachidonic acid metabolism for full expression of activity(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗