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PubMed1992

Scleroderma in association with the use of bleomycin: a report of 3 cases.

Although an association between exposure to bleomycin and the development of scleroderma has been suspected, few cases are reported. We describe the development of cutaneous scleroderma in 3 patients coincident with the use of bleomycin in low cumulative doses of less than 100 U. Dramatic clinical improvement occurred in 2 patients treated with high dose steroids. Our series of 3 patients supports a causal connection between bleomycin and scleroderma. In light of the widespread use of bleomycin, this complication may be under-appreciated.

Adult↗
PubMed2004

Induction of apoptosis by bleomycin in p53-null HL-60 leukemia cells.

The role of p53 in apoptosis and the contrasting p53 status in tumors prompted us to investigate the bleomycin-induced apoptosis in p53-null human leukemia HL-60 cells (bleomycin at 160 microM for 7.5 h). Cells with apoptotic phenotype increased from 0.87% in controls to 9.40% in bleomycin-treated cells. Both the enzymes, caspase-3 and -8, were activated. Furthermore, the apoptotic phenotypes totally disappeared with zVAD-fmk, a caspase inhibitor. Besides, cytochrome c release from mitochondria happened simultaneously to apoptotic phenotypes, shrinkage of mitochondria but being independent of the mitochondrial permeability transition, since cyclosporine A and bongkrekic acid were inefficient on induced apoptosis. On the other hand, incubations with bleomycin (BLM) did not result in detectable changes in the expression of Bcl-2- and Bax-mRNA neither Bcl-2- or Bax-proteins. In conclusion, we suggest that BLM can produce apoptosis independently of p53 through three mechanisms: i) at the nuclear level by its endonuclease activities; ii) at the cell membrane, by activating caspases; and iii) at the mitochondria by releasing cytochrome c. These results indicate that BLM-induced apoptosis in HL-60 cells results from the activation of a mitochondria-dependent caspase cascade which includes also the activation of the initiator caspase-8.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Solid-phase synthesis of deglycobleomycin and bleomycin.

The bleomycins are a group of structurally related glycopeptide antibiotics originally isolated from Streptomyces verticillus in the 1960s. They are used for the treatment of cancers including Hodgkin's lymphomas, carcinomas of the skin, head and neck, and testicular tumors. Whereas analogs of bleomycin have been synthesized to facilitate an understanding of its biochemical properties, the complexity of the molecule has severely limited the total number of analogs synthesized. The solid-phase synthesis of fully functional and active deglycobleomycin and bleomycin analogs is described. This approach has resulted in the synthesis of over 160 unique deglycobleomycin and bleomycin analogs in the past two years, an accomplishment that would not have been possible without the solid-phase methodology.

Anti-Bacterial Agents↗
PubMed2004

DNA damage in human colonic mucosa cells induced by bleomycin and the protective action of vitamin E.

Using the alkaline comet assay, we showed that bleomycin at 0.1-5 microg/ml induced DNA strand breaks and/or alkali-labile sites, measurable as the comet tail moment, in human colonic mucosa cells. This DNA damage was completely repaired during a 120-minute post-treatment incubation of the cells. Post-treatment of the bleomycin-damaged DNA with 3-methyladenine-DNA glycosylase II (AlkA), an enzyme recognizing alkylated bases, gave rise to a significant increase in the extent of DNA damage, indicating that the drug could induce alkylative bases in DNA. We did not observe any change in the comet tail moment in the presence of catalase. Vitamin E ((+)-alpha -tocopherol) decreased DNA damage induced by bleomycin. The results obtained suggest that hydrogen peroxide might not be involved in the formation of DNA lesions induced by bleomycin in the colonic mucosa cells.

Bleomycin↗
PubMed2004

[Relationship between bleomycin-induced pulmonary fibrosis and vascular endothelial cell injury].

OBJECTIVE: To explore the relationship between the injury of vascular endothelial cells and formation of lung fibrosis by bleomycin (BLM) in rats. METHODS: The rats of experimental groups were treated with bleomycin intratracheally to induce pulmonary fibrosis. The expression of vascular endothelial growth factor (VEGF) in pulmonary tissues were analyzed qualitatively and quantitatively by immunohistochemistry and image analysis system. RESULTS: (1) HISTOLOGY: Edema in rat alveoli and alveolar septum, inflammatory cells exudation, degeneration and necrosis of type I and type II alveolar epithelial cells (AETI and AETII), ruptured alveolar basement membrane, as well as swollen vascular endothelial cells and karyopyknosis were observed in 3 d and 7 d after treatment with BLM. AETII proliferation, with more fibroblasts in alveolar septum, and new capillary vessel formation in 7, 14 d, as well as thickened alveolar septum, damaged alveolar structure, and obvious pulmonary tissue fibrosis in 28 d after treatment with BLM were observed. (2) Immunohistochemistry: in normal control, VEGF expressed weakly in pulmonary tissue distributing mainly in AETII, bronchial epithelial cells, alveolar macrophages and leydig's cells. While in bleomycin treated groups, the expression of VEGF increased markedly. The expression in AETII, and pulmonary macrophage were significantly higher than that in control in 3 d to 28 d (P < 0.05, P < 0.01). The rat leydig's cells also had higher expression of VEGF in 7, 14, 28 d (P < 0.05, P < 0.01). CONCLUSION: The high expression of VEGF is related to vascular endothelial cells injury which may be one of important factors in the formation of bleomycin-induced pulmonary fibrosis.

Animals↗
PubMedDate not supplied

Simultaneous acral nodular eruption and flagellate erythema caused by bleomycin.

A 29-year-old male with AIDS was treated with bleomycin and vincristine for visceral Kaposi's sarcoma. Three days later, he developed two distinct eruptions simultaneously. One eruption was characterized by tender, erythematous, edematous plaques and nodules on the palmar and dorsal surfaces of the hands, forearms, and elbows. The other consisted of grouped, erythematous, hyperpigmented streaks on the trunk, buttocks, and extremities. The patient subsequently received a second treatment consisting of vincristine with adriamycin, without bleomycin, and no cutaneous effects were seen. Diagnoses of flagellate erythema and acral nodular eruption secondary to bleomycin were made and confirmed histopathologically. To our knowledge, this is the first report of two cutaneous side effects of bleomycin appearing simultaneously in a patient with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed2005

[The protective effects of Fufang Biejiafang on bleomycin-induced pulmonary fibrosis in rats].

OBJECTIVE: To explore the possible effects and mechanism of Fufang Biejiafang on a single intratracheal instillation (IT) of bleomycin-induced lung fibrosis model. METHOD: SD rats were treated with a single IT dose of bleomycin or control saline. Chinese medicine group were poured into the stomach after the first day of operation with high dosage, middle dosage and low dosage. On days 7, 14 and 28 following IT bleomycin or saline, 4 mL blood were taken from the abdominal aorta for arterial blood gas analysis. The left lung was fixed for routine light microscopic examination. Bronchoalveolar lavage fluid (BALF) from the right lung was tested the activity of pulmonary surfactant (PS) by the Whihelmy Film Balance, then the right lung was frozen immediately in liquid nitrogen for determination of hydroxyproline concentration. RESULT: Model rats had obviously changes of body weight and hypoxemia and dysfunction of PS on days 7 and improved on days 14. Compared with three dose groups, the middle dose group some degreely improved and PS function. It ameliorate fibrosis because of inhibition of inflammation. CONCLUSION: (1) PS dysfunction resulted in hypoxemia after bleomycin injured alveolar type II (AT II). Fufang biejiafang-middle dose-group ameliorate hypoxemia by remission AT-II injury. (2) Fufang biejiafang may inhibit exudation inflammation and ameliorate fibrosis.

Animals↗
PubMed2005

[Rat alveolar type II injured by bleomycin].

OBJECTIVE: To explore dysfunction mechanism of rat alveolar type II (AT-II) injured by bleomycin (BLM). METHODS: SD rats were injected with a single intratracheal dose of bleomycin or control saline. On day 7, 14, and 28 following intratracheal bleomycin or saline instillation, animals were killed under overdose of 1.5% sodium pentobarbital (0.25 ml/100 g, i.p.) and bronchoalveolar lavage fluid (BALF) from the lung was tested for the activity of pulmonary surfactant (PS) by the Whihelmy Film Balance. Several concentrations of bleomycin stimulated the culture of rat AT-II cells, and surfactant protein (SP) A, B, and aquaporin-1 (AQP) mRNA were analyzed by fluorescent quantitative polymerase chain reaction (FQ-PCR). RESULTS: The activity of PS and hypoxemia significantly decreased on day 7 and improved on day 14 and completely recovered to normal status on day 28. SP-A, B, and AQP-1 mRNA expression in BLM-stimulated group were significantly lower than those in the control group (P<0.001). CONCLUSION: BLM-injured AT-II cells decrease the levels of SP-A, B, and AQP-1 mRNA and cause PS dysfunction, resulting in hypoxemia and pneumonedema.

Animals↗
PubMed1990

Plasma membrane perturbations of KB3 cells induced by the bleomycin-iron complex.

The effect of the anticancer drug bleomycin on acyl chain order of KB cell membranes was examined by electron paramagnetic resonance and fluorescence polarization spectroscopies using respectively, the 5-doxyl stearic acid spin probe and the 1,6-diphenyl-1,3,5-hexatriene and the 1-[4-(trimethylammonio)phenyl]-6-phenyl-1,3,5-hexatriene fluorescent probes. Measurements of the order parameter, S, by the two techniques showed a perturbation of the plasma membrane fluidity with bleomycin-iron, while no effect was observed with bleomycin or iron alone. A kinetic study of the location of the 1,6-diphenyl-1,3,5-hexatriene fluorescent probe into the cell was followed by fluorescence microscopy. Lipid peroxidation measurements were also performed using isolated unsaturated lipids, intact cells, or isolated plasma membranes whose purity was checked by electronic microscopy. These membrane perturbation effects not observed with bleomycin-iron in the presence of a hydroxyl radical scavenger, dimethyl thiourea, or a chelating agent, desferrioxamine, were correlated with the ability of the complex to generate highly reactive oxygen species.

Bleomycin↗
PubMed1990

Accumulation of hyaluronan in bronchoalveolar lavage fluid is independent of iron-, complement- and granulocyte-depletion in bleomycin-induced alveolitis in the rat.

Previous studies on bleomycin-induced alveolitis in rats have demonstrated a transient histological accumulation of hyaluronan (hyaluronate or hyaluronic acid) in the alveolar interstitium, corresponding to increases in hyaluronan (HA) levels in bronchoalveolar lavage (BAL) fluid and lung tissue extracts. The accumulation of HA was related to the influx of inflammatory cells, especially polymorphonucleated cells (PMNs) in BAL fluid and the increase in lung water. In this study we have investigated the influence of iron, complement and PMN dependent mechanisms on the early connective response of the lung in the bleomycin rat model. Iron depletion had no effect on HA or the cellular composition of lavage fluid recovered on day 4 post bleomycin. Treatment of bleomycin-injured rats with cobra venom factor (CVF), totally neutralized complement haemolytic activity but had no effect on lavage HA or the cell invasion in BAL. Treatment with anti-neutrophil serum (ANS), reduced blood and lavage PMN by 70-80%, but had no influence on HA levels in BAL. These results suggest that regulatory mechanisms other than those dependent on iron, complement activation or PMN recruitment are responsible for HA accumulation in this fibrosing alveolitis animal model.

Animals↗
PubMed1991

[Bleomycin and pulmonary function changes in children with malignant lymphomas].

In 25 patients under 18 years of age with Hodgkin's disease or non-Hodgkin lymphoma treated with bleomycin as part of the treatment with several cytostatics, the diffusion capacity of the lung for carbon monoxide (DLCO) was determined before, during and after this treatment to investigate the damaging effect of bleomycin on the lungs. The DLCO decreased in 18 of the 25 children; the degree of decrease depended both on the total dosage (max. 120 mg/sq.m body surface) and on the dose per administration (5 or 10 mg/sq.m). Eight of these 18 children were followed up for some time after discontinuation of bleomycin treatment. During the relatively brief follow-up period of one year on average, complete recovery of pulmonary function was seen in none of these children; in two, partial recovery occurred. It is necessary to study the changes of DLCO for a longer period after bleomycin treatment, as well as the factors that influence recovery of pulmonary function in children.

Adolescent↗
PubMed1990

Bleomycin-iron complexes and DNA radiation damage.

Radiation in the form of high-energy electrons dose-dependently activates bleomycin-Fe3+ in oxygen-containing DNA solutions. This activation causes a DNA fragmentation and a release of oxidative degradation products from the DNA. During irradiation, bleomycin-chelated Fe3+ is reduced to Fe2+. The kinetics of DNA base propenal-formation (measured by reaction with thiobarbituric acid) and iron-reduction (measured by bathophenanthroline chelation) are similar, with a yield of 1 mol base propenal/6 mol Fe3+ reduced. The activation of bleomycin-Fe3+ by irradiation could be instrumental in the synergistic action of radiotherapy and bleomycin observed on simultaneous administration in vivo.

Bleomycin↗
PubMed1991

Protective effect of liposome-entrapped superoxide dismutase and catalase on bleomycin-induced lung injury in rats. I. Antioxidant enzyme activities and lipid peroxidation.

The influence of liposome-entrapped catalase and/or superoxide dismutase on bleomycin-induced rat lung injury was studied. Liposome-entrapped catalase and/or superoxide dismutase increase antioxidant enzyme activities in the lung tissue of bleomycin-treated rats. The level of lipid peroxidation products (malondialdehyde, conjugated dienes, lipid hydroperoxides) was significantly lower in liposome-entrapped catalase and/or superoxide dismutase supplemented rats with bleomycin-injured lungs. It is suggested that liposomes are good vectors for drugs in the treatment of bleomycin-induced lung fibrosis.

Animals↗
PubMed1985

Etoposide and cisplatin with or without bleomycin as first-line chemotherapy for patients with small-volume metastases of testicular nonseminoma.

Between December 1981 and September 1982, a phase II study of etoposide and cisplatin was carried out in 17 patients with small-volume metastases of testicular nonseminoma to see whether the toxicity associated with bleomycin could be avoided without loss of therapeutic effect. Of 16 evaluable patients followed for 13-23 months (median, 18.5), four failed to achieve complete remission and three had disease progression. Conversely, all 18 equivalent patients treated with bleomycin, etoposide, and cisplatin between January 1981 and November 1982 (observation time, 12-34 months; median, 25) achieved complete remission and have been continuously disease-free since treatment (P = 0.07). The results suggest that bleomycin contributes significantly to the combination chemotherapy for testicular nonseminoma, and although its omission led to a marked reduction in toxicity, loss of therapeutic activity was also apparent. Prolongation of the intervals between cycles of etoposide and cisplatin from 3 to 4 weeks may significantly reduce the effectiveness of the two-drug combination, whereas no evidence of this was seen in patients treated with bleomycin, etoposide, and cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

[Effect of iron concentrations on the DNA-degradation reaction by bleomycin].

DNA-degradation reaction by bleomycin was conducted with form I of SV40 DNA as the substrate under "iron-limited conditions" and "iron-sufficient conditions". For "iron-limited conditions", the iron ions in reaction mixtures were derived from contaminant iron in the bleomycin preparation, the molar ratio of bleomycin/iron being 1/0.05. For "iron-sufficient conditions", Fe(II) was added to reaction mixtures to attain the molar ratio of bleomycin/iron at 1/1 to 1/29. DNA-degradation reaction by Fe(II) without bleomycin, or "Fe(II) alone", was also run for comparison. In any case, the reaction was allowed to proceed at such low rates that other products than form II and form III, due to further fragmentation, were negligible. The mass of DNA in each form was quantitatively determined by spectrofluorometry after agarose gel electrophoresis and staining with ethidium bromide. "Iron-limited conditions" and "iron-sufficient conditions" showed similar reaction characteristics as follows. As form I decreased with incubation time, form II increased faster than form III, hit a plateau (ca. 65% of total DNA) and decreased gradually thereafter. Form III kept increasing throughout the incubation. The reaction was dependent on incubation time and on doses of both bleomycin and Fe(II) but rather independent of temperature. The reaction was inhibited by acidic pH, Tiron (a specific chelator of iron) and Cu(II) but not EDTA. Octanucleotides with specific base sequence inhibited the reaction. DNA-degradation reaction by "Fe(II) alone" showed different characteristics as follows. The reaction proceeded rapidly at first, but ceased within 2 minutes. The extent of reaction was dependent on dose of Fe(II). The reaction product was form II accompanied by little amount of form III. The reaction was highly dependent on temperature, inhibited by EDTA, and not inhibited by Cu(II) and acidic pH. Octanucleotides, irrespective of their base sequences, inhibited the reaction.

Base Sequence↗
PubMed1985

Central nervous system toxicity and cerebrospinal fluid pharmacokinetics of intraventricularly administered bleomycin in beagles.

The neurotoxic effects and cerebrospinal fluid (CSF) pharmacokinetics of bleomycin were evaluated in beagles after chronic intraventricular administration twice a week for 8 consecutive weeks. Bleomycin was reasonably well tolerated at doses of 0.067 to 0.3 mg/week. Doses higher than 0.3 mg/week produced marked elevation of CSF protein levels and a necrotizing vasculitis within the central nervous system. Pharmacokinetic studies were performed approximately 1 month after the completion of the toxicity studies. [3H]inulin was used as a reference compound. Both [3H]inulin and bleomycin were cleared from the CSF more slowly than in previous studies and more slowly than in normal dogs, which suggests that bulk CSF absorption was reduced by the drug, probably secondary to protein-induced blockage of the arachnoid granulations through which CSF is normally absorbed. Because a "minimally toxic" dose of bleomycin (approximately 0.1 mg/week) produces a CSF C X t of only 1.9 mg/min/ml, we believe that a Phase I clinical trial would be too dangerous given the limited therapeutic potential that a dose of 0.1 mg/week could achieve.

Animals↗
PubMed1985

The sequence specificity of bleomycin-induced DNA damage in intact cells.

Bleomycin causes lesions to DNA in intact cells and in purified DNA under appropriate conditions. Using a middle repetitive DNA sequence called alpha-DNA as a target sequence, we have compared the sequence specificity of bleomycin-induced DNA cleavage in intact human cells and in purified human DNA. Bleomycin induces numerous cleavage sites in alpha-DNA which vary widely in intensity and give rise to a complex pattern of bands on a DNA sequencing gel. Unexpectedly, the intensity and position of bleomycin-induced DNA cleavage sites are very similar in intact human cells and in purified human DNA.

Base Sequence↗
PubMed1985

Endolymphatic application of bleomycin oil suspension in dog model.

To explore the potential usefulness of a cytostatic agent deposited directly in lymph nodes, 4ml Bleomycin oil suspension (Oil-Bleo) was injected over one hour into hind leg lymphatics of seven dogs. Five of these dogs received a second, identical dose one week later into lymphatics of the contralateral hind leg. Peak serum concentration of Oil-Bleo after the first injection (7 dogs) was 12.3 micrograms/ml but after the second injection (5 dogs) was slightly lower (10.8 micrograms/ml). Maximum level of Oil-Bleo in blood was 12% of the endolymphatic dose and represented the "spillover" from lymph transport. In a control experiment, in which 60mg of aqueous Bleomycin was injected, the serum spillover was one-third higher. Large amounts of Oil-Bleo were stored in popliteal and retroperitoneal lymph nodes for several weeks. Twenty-four hours after injection the weight of "treated" lymph nodes was 73% greater than "untreated" nodes and one month later treated lymph nodes were still 37% heavier. After 24 hours, 4.7% of Oil-Bleo instilled was distributed within extracted lymph nodes, and one month later 0.12% was still detectable. By contrast, after aqueous Bleomycin infusion, only 0.05% was detected in these lymph nodes after only six hours. In general, lymph nodal architecture was preserved after Oil-Bleo. Together the findings suggest that Bleomycin oil suspension may be a useful agent for treatment of lymph nodal metastases by endolymphatic infusion.

Animals↗