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PubMedDate not supplied

The in vitro study of influence of antioxidant enzymes level and repair capacity on cytotoxic bleomycin activity in human and mouse cells.

Bleomycin, an antitumour antibiotic was used to study the possible relationship between DNA single strand breaks repair capacity, antioxidant enzymes level and cytotoxic activity of the drug in mouse cells: AKR and BALB/c and in human cells: CRL 2088 and CRL 1307 (xeroderma pigmentosum). The BALB/c and CRL 1307 cells were used because of having defects in DNA repair capacity. A positive correlation was shown to exist between IC50 values and repair ability which suggested that DNA single strand breaks could be responsible for cytotoxic effects of bleomycin in human and mouse cells. Also antioxidant enzymes level have occurred as, at least partly, participating in bleomycin cytotoxic efficiency. About 10-fold higher resistance of AKR cells to bleomycin in comparison with the other cells, as appeared here, did not exhibit the straight correlation with antioxidant status of the cells. It prompts participation of the other mechanism in bleomycin cytotoxic action than that based on free radical generation. Also drug distribution and metabolism should be considered as a possible factor needed in bleomycin efficacy evaluation.

Animals↗
PubMed2001

[Validity of chromosome analysis and bleomycin sensitivity assay in the prevention of head and neck cancer in Hungary].

Because of unfavourable cancer mortality statistics of Hungary, the search of different biomarkers is one of the most important demands of the national primary cancer prevention programme. The aim of this study was to clarify the usefulness of bleomycin sensitivity assay elaborated in the USA, and to find whether it serves under our environmental conditions as a biomarker of individual sensitivity and risk for head and neck cancer, beside chromosomal aberration analysis. The test reflecting mutagen sensitivity is based on the mean values of chromatid breaks induced by bleomycin in vitro in a single lymphocyte (break/cell = b/c). Since cancer formation is influenced by environmental mutagens, in contrast to others, their 111 head and neck cancer patients were matched not only with 230 healthy controls (106 nonsmokers and 124 smokers), but also with 44 strong alcoholic and smoking patients with liver diseases whose lifestyle did not differ from that of the cancer patients. According to the results of conventional chromosome analysis, the aberrant cell frequency was the highest in the cancer patients (3.34%), while in the alcoholics (2.73%) and healthy smokers (2.88%) the values were similar. Thus, the genetic instability occurring in the form of elevated rate of spontaneous chromosomal aberrations was mostly expressed in head and neck cancer patients. Mutagen sensitivity measured by the b/c values of bleomycin assay was significantly higher in both the cancer (1.16 b/c) and the alcoholic patients (1.34 b/c) compared with the controls (1.0 b/c). The bleomycin sensitivity assay, therefore, seems to be the biomarker not only of cancer, but also the disease of the same etiology such as alcohol-related liver disease. However the method is not suitable for the assessment of individual cancer risk because of the high variability of b/c values in each group, and their considerable overlapping with the controls. It can also be supported with extremely high mutagen sensitivity of Hungarian controls (63 and 67%), which is three-fold of US values (23%). The bleomycin sensitivity assay is not a selective biomarker if comparing to the controls, probably due to the action of more complex exposures under Hungarian environmental conditions. When estimating cancer risk, the results of conventional chromosome analysis offer more information than bleomycin sensitivity assay.

Adult↗
PubMedDate not supplied

[Cleavage of RNA in a hybrid duplex by E. coli ribonuclease H. III. Substrate characteristics of hybrid duplexes of RNA and oligodeoxyribonucleotides containing a bleomycin A5 residue].

The effect of the bleomycin A5 residue linked to four-, eight-, and twelve-mer oligodeoxyribonucleotides on the substrate properties of their tandem and continuous (with or without unmodified octanucleotide effectors) hybrid duplexes was studied using E. coli RNase H. The bleomycin derivatives of oligodeoxyribonucleotides were shown to form hybrid duplexes with practically the same thermostability as those formed by unmodified oligodeoxyribonucleotides. The RNA in the bleomycin-containing hybrid duplexes is cleaved by the E. coli RNase H; however, the initial hydrolysis rate (v0) is 2.6-3.4-fold reduced for the continuous duplexes. In the case of tandem hybrid complexes, the effect of bleomycin on v0 was less pronounced. We hypothesized that steric factors play a key role in the bleomycin inhibition and effectors probably determine the substrate properties of such hybrid complexes. Of all the tandem systems studied, the RNA duplex with the bleomycin-containing tetranucleotide flanked with two effectors displayed the best substrate properties. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 4; see also http://www.maik.ru.

Bleomycin↗
PubMed2004

Increased expression of TGF-beta1 in the sclerotic skin in bleomycin-'susceptible' mouse strains.

We previously reported a mouse model for scleroderma by repeated local injections of bleomycin. In this study, we investigated the level of transforming growth factor-beta1 (TGF-beta1) in various mice strains, in order to determine whether the expression of TGF-beta1 correlates with the susceptibility to bleomycin-induced scleroderma. Histological examination revealed prominent dermal sclerosis with increased collagen deposition in the bleomycin-treated skin in B10.A and C3H/HeJ strains as compared with BALB/c, C57BL/6J and DBA/2 strains. Collagen contents in the skin were also increased in B10.A and C3H/HeJ strains. Analysis of skin lesions from B10.A and C3H/HeJ exhibited the increased mRNA expression and protein synthesis of TGF-beta1. TGF-beta1 concentrations in culture supernatants of skin fibroblasts and spleen macrophages were significantly increased by bleomycin stimulation in B10.A and C3H/HeJ strains, and TGF-beta1 gene expression in fibroblasts derived from B10.A and C3H/HeJ strains was significantly increased by bleomycin stimulation. Thus we conclude that C3H/HeJ and B10.A mice are susceptible to bleomycin-induced scleroderma, which may be, in part, due to increased TGF-beta1 gene expression and protein production.

Animals↗
PubMed1990

[Inhibitory effect of bleomycin A6 on human colon cancer xenografts in nude mice].

As evaluated by clonogenic assay, bleomycin A6 was found to be highly active against established human cancer cell lines derived from colon cancer (HT-29) and cecum cancer (Hce-8693). These human cancer cells have been serially transplanted in nude mice. At a tolerable dosage level, bleomycin A6 exerted remarkable growth inhibition on human colon cancer HT-29 and cecum cancer Hce-8693 xenografts (approximately 90% inhibition). No histopathological changes were found in the organs of treated animals. Compared on the basis of equitoxic doses (1/9 LD50), bleomycin A6 exerted much stronger growth inhibition against colon cancer HT-29 xenografts in nude mice than 5-fluorouracil and mitomycin C, with inhibition rates of 82%, 12% and 53%, respectively. More extensive necrosis was found in tumors treated with bleomycin A6 than in those treated with mitomycin C or 5-fluorouracil. The ratio values of non-necrotic tumor tissue to whole tumor tissue for bleomycin A6, mitomycin C and 5-fluorouracil were 0.33, 0.65 and 0.57, respectively. These observations indicate that bleomycin A6 is a potent antitumor agent against colon cancer xenografts and may be useful in human colon cancer chemotherapy.

Animals↗
PubMed1991

Oral N-acetylcysteine reduces bleomycin-induced collagen deposition in the lungs of mice.

N-acetylcysteine (NAC) has been employed in the treatment of acute lung injury but its therapeutic value is as yet unproven. In the present study we examined the effect of both L- and D-forms of NAC as inhibitors of bleomycin-induced fibrosis in mice. We hypothesized that, because of the D-form is not metabolized, it may be more effective than the L-form in ameliorating lung injury and fibrosis. Both drugs were given daily in the drinking water at a dose of approximately 400 mg.kg-1 body weight commencing one week prior to a single intratracheal instillation of bleomycin at a dose of 6 mg.kg-1 body weight. Lung injury was assessed 35 days later by measuring total lung collagen content, lung wet weight and examination of tissues by light and electron microscopy. Total collagen content and lung wet weight of animals receiving bleomycin together with L-NAC were 2.90 +/- 0.03 mg and 0.23 +/- 0.01 g, respectively. The values for collagen content, but not wet weight, were significantly less (p less than 0.05) than those given for bleomycin alone (3.90 +/- 0.02 mg and 0.260 +/- 0.005 g, respectively), but greater than (p less than 0.05) controls (2.10 +/- 0.01 mg and 0.160 +/- 0.002 g, respectively). Values for collagen content and wet weight of animals given bleomycin together with D-NAC (3.10 +/- 0.02 mg and 0.21 +/- 0.01 mg, respectively) were both significantly greater than values for control animals but lower than animals given bleomycin alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcysteine↗
PubMed1985

Influence of ethidium bromide on hyperthermic modification of bleomycin-DNA interaction.

The effect of hyperthermic treatment on the binding of 59Fe-labeled bleomycin to DNA has been studied. Enhanced binding was observed at elevated temperatures. The influence of the DNA-intercalating agent, ethidium bromide, on bleomycin-DNA interaction was also studied and revealed a considerable decrease in this interaction at ethidium bromide levels below 1 microgram/ml. Ethidium bromide was observed to remove the enhanced bleomycin-DNA interaction recorded previously following incubation at hyperthermic temperatures. Synergistic action of bleomycin and hyperthermia on loss of clonogenic ability of HT29R cells is reported. Incubation of cells under hyperthermic conditions with bleomycin in the presence of ethidium bromide removes this synergism, producing a less than additive effect for the action of bleomycin and heat after ethidium bromide effects are taken into account.

Adenocarcinoma↗
PubMedDate not supplied

Peplomycin and bleomycin effects on human colon cancer cells.

The lethal effects of peplomycin and bleomycin on cultured human colon cancer cells (LoVo) were compared by using the technique of inhibition of colony formation. The survival of LoVo cells after treatment for 1 h with either peplomycin or bleomycin was characterized by a biphasic exponential curve. When the exposure time was extended to 24 h, both drugs produced much greater cytotoxic effects, with survival decreased to less than 0.10% for bleomycin and less than 0.02% for peplomycin. Both peplomycin and bleomycin, in a dose-dependent manner, inhibited the incorporation of thymidine into cells. On an equal-weight basis, the cytotoxicity of peplomycin (24-h exposure) was similar to that of bleomycin. Both agent also inhibited the incorporation of leucine and uridine after 24 h of drug exposure, but to a lesser extent than inhibition of thymidine incorporation. However, after 1 h of exposure, such inhibitory effects were minimal. These results demonstrate that prolonged peplomycin or bleomycin exposure produces greater cell-kill than shorter drug exposure. Schedules with continuous drug administration should be explored clinically.

Bleomycin↗
PubMed1986

Inhibition of bleomycin-induced pulmonary fibrosis by nordihydroguaiaretic acid. The role of alveolar macrophage activation and mediator production.

The role of alveolar macrophage activation and release of mediators remains unclear. In this study, this role is examined with respect to the effects of relatively selective inhibitors of arachidonate metabolism on the pathogenesis of pulmonary fibrosis. CBA/J mice were administered bleomycin (0.037 units) endotracheally to induce pulmonary fibrosis. Daily intraperitoneal injections of a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) inhibited pulmonary fibrosis in a dose-dependent manner (15-25 mg/kg body weight), as assessed by both lung collagen synthesis and total lung hydroxyproline content. The less specific inhibitor BW755c was also effective at a dose of 25 mg/kg. In contrast, the cyclooxygenase inhibitor, ibuprofen (15 mg/kg), was completely ineffective. Correlated with this antifibrogenic activity of NDGA was the inhibition of several other parameters of bleomycin-induced pulmonary fibrosis. Bleomycin treatment caused a greater than threefold increase in the percentage of alveolar macrophages expressing Ia antigen (from 7.7% +/- 1.07% to 29.9% +/- 4.16% of total recoverable alveolar macrophages). NDGA, but not ibuprofen, inhibited this increase in a dose-dependent manner. Associated with this indication of macrophage stimulation was an increase in spontaneous macrophage production of fibroblast growth factor (MDGF) activity as a result of bleomycin instillation. This increase was also inhibited by NDGA treatment. In contrast, bleomycin treatment caused a reduction in alveolar macrophage interleukin-1 (IL-1) production, and NDGA treatment did not alter this reduction, which suggests that MDGF is separate from IL-1 in this case, and that MDGF played a more dominant role, at least in this model of pulmonary fibrosis. This antifibrogenic activity of NDGA was accomplished without any reduction in spontaneous macrophage prostaglandin (PG)E2 production, which suggests the selectivity (versus cyclooxygenase pathway) of NDGA inhibition and the relative lack of importance of macrophage-derived PGE2 in modulating fibrogenesis in this model. The results of this study have thus demonstrated the importance of alveolar macrophage stimulation and increased production of MDGF in the pathogenesis of bleomycin-induced pulmonary fibrosis. The data also suggest that both macrophage parameters are subject to regulation by arachidonate metabolites.

Animals↗
PubMed1989

A comparative study of the interactions of bleomycin with nuclei and purified DNA.

Fe(III)-bleomycin associates strongly with rat liver nuclei and binds to nuclear DNA. Metal-free and Cu(II)-bleomycin, however, do not bind to nuclei. The treatment of nuclei with activated iron-bleomycin results in nucleic base and base propenal release from the DNA, and also gives membrane peroxidation. Isolation and quantitation of the base propenals and free bases released subsequent to activated bleomycin treatment reveal an alteration in the stoichiometry of these products compared to those released from purified DNA. With nuclei, significantly less propenal is formed, although the yield of free base is equivalent to that from purified DNA. The membrane peroxidation products from nuclei are the same as those obtained from microsomal membranes treated with activated bleomycin. Superoxide dismutase inhibits the membrane peroxidation but has no effect on the DNA breakage reactions. The results implicate a role for iron in mediating the in vivo action of bleomycin and also reveal a potentially toxic effect, membrane peroxidation, separate from DNA damage.

Animals↗
PubMed1989

Response of plateau-phase C3H 10T1/2 cells to radiation and concurrent administration of bleomycin.

The mode and extent of interaction between bleomycin and radiation were assessed in contact-inhibited cultures of C3H 10T1/2 cells, which in confluent monolayers display a low turnover rate and behave more like late-responding normal tissues in vivo with respect to response to fractionated radiotherapy (i.e., having a low alpha/beta value). Plateau-phase C3H 10T1/2 cultures were exposed to gamma rays delivered in 1, 2, 5, or 10 fractions. The radiation doses administered ranged from 2 Gy in one exposure to 26 Gy in 10 fractions. Half of the cultures were also treated with 1 micrograms/ml of bleomycin for 5 days during which radiation was also given. It was found that 1 micrograms/ml of bleomycin sterilized approximately 40% of the C3H 10T1/2 cells in the cultures. The radiation dose-survival curves of various fractionation schedules (1, 2, 5, and 10 fractions) plus bleomycin were displaced downward (i.e., to lower survival levels) but not modified in shape. The alpha/beta ratios, parameters of the linear-quadratic model of cell survival, were 2.6 (2.2-3.1) and 2.4 (1.8-3.1) Gy for radiation only and radiation plus bleomycin, respectively. This observation indicates that the effect of combining irradiation and bleomycin on C3H 10T1/2 cells in monolayers was additive.

Animals↗
PubMed1976

Synthesis and the lethality of bleomycin in bacteria.

The bleomycins are antitumor agents composed of various cationic amides of a common inactive bleomycinic acid. At 1 mug/ml at 37 degrees, the naturally occurring spermidine derivative of bleomycin (A5) was far more lethal to Escherichia coli than were several other bleomycins tested. An exponential loss of viability was produced for 2 hr in various strains of E. coli growing in a synthetic medium. In the stringent E. coli, strain 15 TAU (thymine-arginine-uracil) rel A+ (arginine), withholding thymine did not affect the rate of killing. However, uracil starvation completely blocked killing by the antibiotic. Arginine deprival partially inhibited bleomycin killing in the stringent cell but had little effect on the lethality of the antibiotic in a relaxed isogenic strain actively synthesizing RNA. Similar results were obtained with another isogenic pair, stringent CP78 and relaxed CP79. Thus, the lethality of the antitumor agent, bleomycin, which is reported to produce breaks in bacterial and animal cell DNA in vivo and in vitro appeared totally dependent on RNA synthesis in E. coli. Nevertheless, chloramphenicol, which blocks protein synthesis and relaxes RNA synthesis in the stringent strains, also significantly inhibited the lethal action of the antibiotic, reducing the exponential rate of killing.

Arginine↗
PubMed1976

[Investigations on the accumulation of radio-bleomycin in gynaecological tumors (author's transl)].

The indication for treatment with Bleomycin in gynaecological tumors is as yet not well defined. At present Bleomycin is primarily used for advanced gynaecological malignancies. Results of our investigations show that the individual affinity of gynaecological tumors to Bleomycin is very variable. In subsequent investigations it should therefore be determined whether the accumulation of radio-Bleomycin and the sensitivity of a gynaecological malignant tumor to Bleomycin therapy show a positive correlation. The probable chances of success of a course of chemotherapy with Bleomycin could then be predicted.

Adenocarcinoma, Mucinous↗
PubMed1976

Combined use of bleomycin in radiotherapy of a mouse mammary carcinoma.

Experiments were carried out to determine TCD50 (50% tumor control dose) of 3rd generation isotransplants of a C3H mouse mammary carcinoma treated or not treated with Bleomycin. If the antibiotic was injected 30 min before a single X-ray dose, TCD50 was reduced. This reduction in TCD50 was independent of Bleomycin dose of more than 15 mg/kg, because of the upward-concave nature of Bleomycin dose-cell survival curve. The combined effect, when tested by TCD50 assays, appeared less than additive. This effect was further examined by a series of TD50 assays which revealed that these tumor cells were capable of repairing the potentially lethal damage induced by X-rays and that induced by Bleomycin. It was also found that the potentially lethal damage after combined X-ray and Bleomycin treatments was repaired. These findings indicated that the combined X-ray and Bleomycin treatment resulted in additive effect if the repair of potentially lethal damage in tumor cells were taken into account.

Animals↗
PubMedDate not supplied

Relative pulmonary toxicity and antitumor effects of two new bleomycin analogs, pepleomycin and tallysomycin A.

The relative therapeutic and toxic effects of two new analogs were compared with bleomycin over a range of doses. Therapeutic effects were determined in mice bearing Lewis lung carcinoma and B16 melanoma. On a milligram-per-kilogram basis, tallysomycin A was two to three times as potent as bleomycin in inhibiting the growth of these two experimental solid tumors in vivo. However, tallysomycin A was also two to three times as potent as bleomycin in producing pulmonary toxic effects. Lethality and skin toxicity were similarly increased. Pepleomycin, on the other hand, was approximately equivalent to bleomycin in antitumor potency but exhibited significantly less pulmonary toxicity. Despite this decreased lung toxicity, pepleomycin was more lethal, with 50% and 100% mortality at doses which produced 0 and 19% mortality, respectively, in mice treated with bleomycin. Pepleomycin also had a peculiar central nervous system toxicity characterized by hyperirritability and persistent gyrating movements of the animals. Thus, there are distinct quantitative as well as qualitative differences in the therapeutic and toxic properties of these two analogs compared to bleomycin.

Animals↗
PubMed1981

The development of bleomycin-induced pulmonary fibrosis in neutrophil-depleted and complement-depleted rats.

The development of bleomycin-induced pulmonary fibrosis was studied in rats depleted of neutrophils for 1 week and in rats depleted of complement for 1 week. Lung injury was assessed by histologic evaluation and by the biochemical measurement of total lung collagen. Qualitatively, histologic evidence of damage induced by bleomycin showed that damage progressed in a similar manner in neutropenic and complement-depleted animals when compared with normal animals. However, analysis of total lung collagen at 1 week after bleomycin administration revealed that collagen deposition was increased in neutropenic animals and decreased in animals depleted of complement when compared with untreated animals that received bleomycin. There were no significant differences in lung collagen levels at 1 month after bleomycin treatment in neutrophil-depleted or complement-depleted animals when compared with animals that received bleomycin alone.

Animals↗
PubMed1982

Inhibition of collagen accumulation by glucocorticoids in rat lung after intratracheal bleomycin instillation.

Male Fischer 344 rats were given a single lung instillation of bleomycin sulfate (0.6 units/100 g). some animals were treated 24 hr after bleomycin administration with triamcinolone diacetate. Steroid treatment was continued on alternate days for 4 weeks. At the end of 4 weeks, the lungs of rats receiving bleomycin alone had two-fold increases of both prolyl hydroxylase activity and proteinaceous hydroxyproline as compared to control values. The lungs of bleomycin-treated rats which received 4 mg of triamcinolone diacetate per kg on alternate days had a 33% increase of prolyl hydroxylase activity and proteinaceous hydroxyproline content of bleomycin-treated animals receiving glucocorticoid (8 mg/kg) on alternate days were the same as control values. The results indicate that alternate day administration of the synthetic glucocorticoid triamcinolone diacetate blocks lung collagen accumulation following a single intratracheal dose of bleomycin to rats.

Animals↗
PubMed1982

The role of soluble factors in bleomycin-induced pulmonary fibrosis.

Endotracheal administration of bleomycin causes pulmonary fibrosis characterized by increased collagen synthesis and deposition. Incubation of normal lung mince with neutral salt soluble extracts of lungs from normal and bleomycin-treated rats caused a dose-dependent inhibition of collagen and noncollagenous protein synthesis. Bleomycin-treated lung extracts, however, were significantly less effective in such inhibition when compared with normal lung extracts. This inhibitory activity was not diminished by dialysis in tubing with nominal molecular weight cutoff of 10,000 but was destroyed by heat (70 C) and trypsin digestion. This inhibitory activity could not be ascribed to residual serum or bleomycin in the lung extracts. Fractionation on Sephacryl S-200 (Pharmacia, Piscataway, NJ) showed inhibitory activity to be heterogeneous with Mr (apparent molecular weight) greater than 100,000. Extracts from spleen showed similar inhibitory activity but showed no difference in intensity between normal and bleomycin-treated spleen. These data suggest that loss or decrease in production of lung inhibitory regulatory factors is partly responsible for the noted increase in collagen production and deposition in bleomycin-induced pulmonary fibrosis.

Animals↗