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PubMed1997

Dermatography with bleomycin as a new treatment for verrucae vulgaris.

BACKGROUND: Common warts are caused by infection with human papillomaviruses (HPVs). Many, largely ineffective, treatment modalities have been tried in the past. The cytostatic drug bleomycin has been found to selectively affect squamous cell and reticuloendothelial tissue, but the method of its delivery directly into affected tissue such as warts has been of little efficacy. This study assessed the efficacy of a new mode of intralesional administration of bleomycin by dermatography. METHODS: The warts of patients were treated with increasing concentrations of bleomycin using the van der Velden Derma-Injector, a modified tattooing machine, under local or block anesthesia. The effects of the procedure were evaluated 1, 24, and 48 h later and the patients followed for up to 2 years. RESULTS: Thirteen patients with warts on the hands and/or feet, resistant to conventional therapy, were entered into the study, and two patients dropped out. Of the 11 remaining patients, seven went into full remission that was maintained for at least 2 years. One patient showed moderate progress and in three patients little progress was noted and dermatography was stopped. The dosage of bleomycin varied between 0.1 and 1.0 mg/mL. CONCLUSIONS: Dermatography proved to be an effective technique for intralesional administration of bleomycin in more than two-thirds of patients resistant to conventional therapy. Treatment failures in this study could in part be explained by a defective immune system in the patients. Dermatography is a technique that can be learned by any skillful dermatologist or plastic surgeon.

Adolescent↗
PubMed1999

Expression of transforming growth factor-beta1 and tumour necrosis factor-alpha in bronchoalveolar lavage cells in murine pulmonary fibrosis after intraperitoneal administration of bleomycin.

OBJECTIVE: We previously observed increased expression of interleukin-1beta, platelet-derived growth factor-A, and insulin-like growth factor-I in bronchoalveolar lavage (BAL) cells during the development of pulmonary fibrosis after an intraperitoneal administration of bleomycin in mice. The purpose of this study was to investigate the roles of tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 in this model. METHODOLOGY: We investigated the mRNA expression levels of TNF-alpha and TGF-beta1 in BAL cells of Institute for Cancer Research mice after 10 days of the intraperitoneal administration of bleomycin with or without treatment with a specific neutrophil elastase inhibitor, ONO-5046 x Na. RESULTS: On day 1 but not on days 15 and 29, the relative amount of TGF-beta1 mRNA in the bleomycin-treated mice was significantly decreased compared with control mice. In the mice treated with both bleomycin and ONO-5046 x Na intermediate values for TGF-beta1 were obtained. No significant differences in TNF-alpha expression were observed in any of the treatment groups. CONCLUSIONS: These results suggest that a reduced expression of TGF-beta1 in BAL cells in the early phase may be important during the development of murine pulmonary fibrosis induced by an intraperitoneal administration of bleomycin.

Animals↗
PubMed2000

A comparative study of pleurodesis using talc slurry and bleomycin in the management of malignant pleural effusions.

OBJECTIVE: Differing success rates of various pleurodesis agents have been reported in the management of malignant pleural effusions. A randomized clinical trial was conducted to compare the efficacy of two commonly used agents, talc and bleomycin, for the pleurodesis of malignant pleural effusions. METHODOLOGY: Inclusion in the study required proof of a malignant pleural effusion by fluid cytology or pleural biopsy. Exclusion criteria included trapped lung, loculated effusions, recurrent effusions and life expectancy < 1 month. Five grams of talc or 1 unit per kilogram bodyweight of bleomycin mixed in 150 mL of normal saline was administered via tube thoracostomy after complete drainage of the pleural effusion in each patient. Treatment success was defined as the absence of recurrent pleural effusion on the chest radiograph 1 month after pleurodesis. RESULTS: Treatment success was achieved in 16 out of 18 patients (89%) in the talc slurry group versus 14 out of 20 patients (70%) in the bleomycin group (P=0.168). Fever and pain were the only side-effects of pleurodesis in both groups. CONCLUSION: These results indicate that talc slurry is as effective as bleomycin in preventing early recurrence of malignant pleural effusions. Pleurodesis with talc instead of bleomycin can result in significant cost savings.

Aged↗
PubMed2005

Local bleomycin injection in the treatment of lymphangioma.

AIM: We report here our experience with local bleomycin injection in lymphangioma. PATIENTS AND METHODS: Nine patients with lymphangioma were treated with locally injected bleomycin and followed prospectively. We performed an ultrasound study in all cases to delineate the size, location, nature, and number of compartments of the cyst prior to the injection. Under ultrasound guidance, the content of the cystic cavity was aspirated and 1 - 3 mg/kg bleomycin were injected. The patients were revisited monthly. No attempt at re-injection was made as long as the mass continued to decrease in size. RESULTS: Patients consisted of 4 boys and 5 girls aged between 14 days and 6 years. The localisation of the mass was cervical in 6, cervical, sublingual, and lingual in 1, axillary in 1 and axillary and thoracic in 1. In six children, the mass disappeared totally after a single injection. In one patient a second injection was needed, and surgical excision was performed in two patients with residual solid component. No complication related to bleomycin was seen. CONCLUSION: Local application of bleomycin in children with lymphangioma is a simple, safe, and effective method. In the majority of cases, total healing may be achieved with a single injection.

Antimetabolites, Antineoplastic↗
PubMed1978

Interaction of bleomycin with DNA.

The sequence of oligonucleotides produced by the action of bleomycin and ferrous ion on double- and single-stranded DNA has been determined. In the presence of ferrous ion, bleomycin promotes cleavage at G-T and G-C sequences, while high concentrations of ferrous ion alone result in strand scission that is not base specific. In the presence of bleomycin and ferrous ion, pyrimidine bases located to the 3' side of guanosine are released preferentially and a low molecular weight product that forms a chromophore with thiobarbituric acid is produced from the deoxyribose moiety. Oligonucleotides produced by the action of bleomycin differ slightly in electrophoretic mobility from those produced by chemical or enzymatic cleavage. A model is proposed to explain the interactions of bleomycin with DNA.

Base Sequence↗
PubMed1990

NMR studies of the interaction of bleomycin with (dC-dG)3.

The interaction of bleomycin A2 and Zn(II)-bleomycin A2 with the oligonucleotide (dC-dG)3 has been monitored by nuclear magnetic resonance spectroscopy. Binding of the drug to the oligonucleotide is indicated by an upfield shift of the bithiazole proton resonances consistent with partial intercalation of this group between base pairs. The effect of temperature and ionic strength on the binding of both free bleomycin and the Zn(II) complex has been studied. Consistent with earlier studies on polynucleotides, the rate of exchange between the free drug and the drug-oligonucleotide complex is rapid on the 1H NMR chemical shift time scale. Binding of the oligonucleotide induced changes in resonances assigned to protons in the metal-binding region of Zn(II)-bleomycin. Intermolecular nuclear Overhauser effect enhancements between bleomycin and the oligonucleotide have not been detected.

Bleomycin↗
PubMed1999

Fluorescent labelling of closely-spaced aldehydes induced in DNA by bleomycin-Fe(III).

PURPOSE: To test the ability of FARPhC and FARP, two novel fluorescent reagents, to label aldehyde-containing sites (principally abasic sites) generated in DNA by the radiomimetic drug bleomycin, and to use fluorescent energy transfer from FARPhc (donor) to FARP (acceptor) to quantitate such closely-spaced sites. MATERIALS AND METHODS: FARPhc, 7-hydroxycoumarin-3-carboxylic acid (((((amino-oxymethyl) carbonyl) hydrazino) carbonylethyl) amide) was synthesized with a protocol similar to the one recently reported for FARP (a fluorescein-based probe). RESULTS: Both FARPhc and FARP form stable oxime bonds with the open-chain aldehydes generated upon acidic depurination of DNA. Plasmid DNA exposed to bleomycin-Fe(III)-ascorbate undergoes extensive strand breakage, and upon subsequent reaction with FARPhc and/or FARP it becomes fluorescently labelled, indicating the generation of aldehyde-containing sites. The binding of the probes to calf thymus or plasmid DNA results in significant fluorescent energy transfer among closely-spaced fluorophores, as revealed by the fluorescence increase following digestion of fluorescently labelled samples with nuclease P1. The fluorescent quenching is most evident when both FARPhc and FARP are used simultaneously to trap aldehyde sites. When single-stranded oligonucleotides engineered to contain either one or two closely spaced bleomycin binding sites are exposed to bleomycin and then fluorescently labelled, the oligonucleotides demonstrate significantly increased fluorescent energy transfer with two binding sites indicating a dependence of aldehyde site generation and clustering on the local sequence of a single strand. CONCLUSIONS: A new detection method for DNA damage induced by bleomycin following fluorescent labelling of aldehyde group-containing sites (FLAGS) and their clustering via fluorescent energy transfer is demonstrated. The method is applicable to any form of DNA. This work may lead to a general approach for the quantification of multiply damaged sites in DNA, a subset of DNA lesions that may have major biological significance.

Aldehydes↗
PubMed2000

Nitric oxide-dependent activation of p53 suppresses bleomycin-induced apoptosis in the lung.

Chronic inflammation leading to pulmonary fibrosis develops in response to environmental pollutants, radiotherapy, or certain cancer chemotherapeutic agents. We speculated that lung injury might be mediated by p53, a proapoptotic transcription factor widely implicated in the response of cells to DNA damage. Intratracheal administration of bleomycin led to caspase-mediated DNA fragmentation characteristic of apoptosis. The effects of bleomycin were associated with translocation of p53 from the cytosol to the nucleus only in alveolar macrophages that had been exposed to the drug in vivo, suggesting that the lung microenvironment regulated p53 activation. Experiments with a thiol antioxidant (N-acetylcysteine) in vivo and nitric oxide (NO) donors in vitro confirmed that reactive oxygen species were required for p53 activation. A specific role for NO was demonstrated in experiments with inducible nitric oxide synthase (iNOS)(-/)- macrophages, which failed to demonstrate nuclear p53 localization after in vivo bleomycin exposure. Strikingly, rates of bleomycin-induced apoptosis were at least twofold higher in p53(-/)- C57BL/6 mice compared with heterozygous or wild-type littermates. Similarly, levels of apoptosis were also twofold higher in the lungs of iNOS(-/)- mice than were observed in wild-type controls. Consistent with a role for apoptosis in chronic lung injury, levels of bleomycin-induced inflammation were substantially higher in iNOS(-/)- and p53(-/)- mice compared with wild-type controls. Together, our results demonstrate that iNOS and p53 mediate a novel apoptosis-suppressing pathway in the lung.

Acetylcysteine↗
PubMed1988

Absence of an additional fibrotic response caused by oxygen in the lungs of rats after the intratracheal administration of bleomycin.

Bleomycin 0.4, 0.6, 1.0 or 3.5 mg/kg body weight was administered via the trachea in rats. After various time intervals some of the animals were exposed to 50% oxygen for either 4 or 24 h. The rats were then sacrificed at different times. Control rats remained untreated or received physiological saline. Lung histology was studied by light microscopy. In a number of rats the lung content of hydroxyproline was determined. Mild reactions, namely increases in pneumocytes type II and macrophages, oedema and prefibrotic alterations were observed after the instillation of bleomycin. The reactions were comparable to those observed after additional hyperoxia alone. Lung hydroxyproline concentration was not increased after bleomycin plus oxygen as compared with bleomycin alone. We conclude that no added toxicity is caused by 50% oxygen supplied for 4 or 24 h subsequent to doses of bleomycin that lead to mild pulmonary abnormalities in the absence of hyperoxia.

Animals↗
PubMed2002

Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice.

Susceptibility to pulmonary fibrosis following environmental insults or cytotoxic cancer therapies has a genetic component. In mouse strains differing in susceptibility to bleomycin-induced lung fibrosis, we show highly significant linkage to only two loci. The first locus on chromosome 17 in the major histocompatibility complex (MHC), LOD = 17.4, named Blmpf1, is highly significant in both males and females, and accounts for approximately 20% of the phenotypic variance. We confirmed the presence of Blmpf1 in MHC congenic mice and narrowed the region to 2.7 cM in a reduced MHC congenic strain. The second locus on chromosome 11, LOD = 5.6, named Blmpf2, is significant in males only. A model including an interaction between Blmpf1 and Blmpf2 best fit the data in males. We confirmed Blmpf2 in a chromosome substitution strain, C57BL/6J-11(C3H), and found that its presence reduces the severity of fibrosis. Functional studies of bleomycin hydrolase activity indicate that this enzyme modulates bleomycin-induced pulmonary fibrosis, suggesting that it may be a candidate gene for Blmpf2. The data suggest sex-specific models of susceptibility to bleomycin-induced lung fibrosis, with an interaction between Blmpf2 and Blmpf1 for the more susceptible males and Blmpf1 as the major locus in females. A putative mechanism for the interaction between the two loci in males is that bleomycin hydrolase functions as an MHC class I epitope-processing protease.

Animals↗
PubMed1977

Bleomycin: mammalian cell lethality and cellular basis of optimal schedule.

Experiments on the dose- and time-dependent changes in the survival of Ehrlich ascites tumor cells exposed to bleomycin were done to determine a useful regimen for the effective inactivation of the tumor cells. The experimental results on time-dependent changes in survival of bleomycin-treated cells indicated that two phenomena were involved in the survival increase observed after single bleomycin treatment: 1) The bleomycin-treated cells were resistant to the second injection when the interval between the two successive doses was within 2 hours (induced resistance), and 2) the survival was increased as a function of time when the interval between treatments was prolonged (repair of potentially lethal damage). The effect of the fractionated treatments was then investigated for the regimen that minimized the induced resistance and repair of potentially lethal damage. The results indicated that administration of a lower dose of bleomycin at shorter intervals was more effective than other fractionation schedules, and, on the basis of the same dose rate, the continuous infusion regimen was more effective than fractionation regimens for the sterilization of Ehrlich ascites tumor cells.

Animals↗
PubMed1999

Analysis of bleomycin-induced chromosomal aberrations in Chinese hamster primary embryonic cells by FISH using arm-specific painting probes.

Chinese hamster primary embryonic cells (at G1 phase) were treated with 1.0 or 3.0 microg/ml bleomycin and chromosomal aberrations in first division metaphases were analysed by fluorescence in situ hybridization (FISH) using arm-specific painting probes for chromosomes 3, 4, 8 and 9. We observed that bleomycin induced all classes of chromosome-type aberrations very efficiently. The interesting findings were: (i) the frequency of induced interstitial translocations (i.e. insertions) was approximately equal to that of reciprocal translocations; (ii) the frequency of induced pericentric inversions was higher than that of centric rings. In our earlier studies, we found that X-rays induced a low frequency of interstitial translocations in comparison with reciprocal translocations and equal frequencies of centric rings and pericentric inversions. These data suggest that bleomycin differs from X-rays with respect to the induction of some specific types of aberrations. The results of a chi2 test examining the hypothesis that formed aberrations among the chromosomes or chromosome arms are randomly distributed on the basis of their relative lengths revealed a differential involvement of these chromosomes in the aberrations following exposure to bleomycin. In general, chromosome 8 was found to be more involved in induced aberrations than expected, chromosome 4 was randomly involved, whereas chromosomes 3 and 9 were less involved. This study demonstrates the utility of arm-specific painting probes for efficient detection of a large variety of chromosomal aberrations induced by bleomycin.

Animals↗
PubMed2000

The bleomycin amplification assay in V79 cells predicts frameshift mutagenicity of intercalative agents.

We have recently reported on the use of a cell-based bleomycin amplification assay for the detection of DNA intercalating agents. In order to further validate this assay, two series of proprietary compounds were evaluated for frameshift mutagenesis in the Ames bacterial reversion system and for bleomycin amplification in the Chinese hamster V79 micronucleus system. It is shown that 10 of 11 frameshift-positive compounds were bleomycin amplifiers. These studies indicate that positive frameshift mutagenicity findings are consistent with expectations from the results of the bleomycin amplification assay, providing additional validation of the amplification assay for the detection of DNA intercalating agents. The studies also demonstrate that intercalation is necessary but not sufficient for frameshift mutagenesis since bleomycin amplifiers lacking frameshift mutagenic activity were also identified.

Animals↗
PubMed1996

In vitro detection of endonuclease IV-specific DNA damage formed by bleomycin in vivo.

Endonuclease IV of Escherichia coli has been implicated by genetic studies in the repair of DNA damage caused by the antitumor drug bleomycin, but the lesion(s) recognized by this enzyme in vivo have not been identified. We used the sensitive primer activation assay, which monitors the formation of 3'-OH groups that support in vitro synthesis by E.coli DNA polymerase I, to determine whether endonuclease IV-specific damage could be detected in the chromosomal DNA of cells lacking the enzyme after in vivo treatment with bleomycin. Chromosomal DNA isolated after a 1 h bleomycin treatment from wild-type, endonuclease IV-deficient (nfo-) and endonuclease IV-overproducing (p-nfo; approximately 10-fold) strains all supported modest polymerase activity. However, in vitro treatment with purified endonuclease IV activated subsequent DNA synthesis with samples from the nfo- strain (an average of 2.6-fold), to a lesser extent for samples from wild-type cells (2.1-fold), and still less for the p-nfo samples (1.5-fold). This pattern is consistent with the presence of unrepaired damage that correlates inversely with the in vivo activity of endonuclease IV. Incubation of the DNA from bleomycin-treated nfo- cells with polymerase and dideoxynucleoside triphosphates lowered the endonuclease IV-independent priming activity, but did not affect the amount of activation seen after endonuclease IV treatment. Primer activation with DNA from the nfo- strain could also be obtained with purified E.coli exonuclease III in vitro, but a quantitative comparison demonstrated that endonuclease IV was > or = 5-fold more active in this assay. Thus, endonuclease IV-specific damage can be detected after in vivo exposure to bleomycin. These may be 2-deoxy-pentos-4-ulose residues, but other possibilities are discussed.

Antibiotics, Antineoplastic↗
PubMed1983

Bleomycin and cis-platinum with or without mitomycin C in 110 previously untreated patients with head and neck cancer.

Between November 1979 and October 1981, 110 consecutive patients with previously untreated, biopsy-proven squamous cell carcinoma of the head and neck, were treated by chemotherapy prior to scheduled surgery and/or radiotherapy. Two regimens of chemotherapy were used. The first 57 patients received cis-platinum, 20 mg/m2/day for 5 consecutive days and bleomycin 5 mg/m2/day as a continuous infusion over the same 5 days every 3 weeks (Regimen A). The next 53 patients received the same schedule and dose of cis-platinum, bleomycin 2.5 mg/m2 every 12 hours for the same 5 consecutive days and mitomycin C6 mg/m2 on day 1 of each cycle every 3 weeks (Regimen B). The number of courses administered prior to surgery and/or radiotherapy ranged from 1-4 depending on the otorhinolaryngologist's assessment of the optimal time for locoregional treatment. The overall response rate in regimen A was 78% (45/57) compared to 90% for regimen B (48/53). Complete responses were seen in 10/57 (18%) and 13/53 (25%) patients in regimens A and B, respectively. Eight of 57 patients in regimen A and 6/53 in regimen B refused further treatment and follow-up, and 7/53 patients in regimen B chose to pursue chemotherapy (in which methotrexate replaced bleomycin) rather than undergo surgery and/or radiotherapy. Five of these seven patients are surviving disease-free from 7-12 months. In regimen A, 31/57 patients are surviving with a median survival exceeding 15 months. In regimen B, 46/53 patients are surviving up to 14 months. Nausea and vomiting induced by cis-platinum were the major side effects, seen to a variable degree in all patients. No cis-platinum-induced renal toxicity was observed with the 5-day regimen and none of the patients had symptomatic bleomycin-induced pneumonitis. One patient had a bleomycin-induced skin rash which did not require discontinuation of therapy.

Adult↗
PubMed1986

Intravenous bleomycin does not alter the toxic effects of hyperoxia in rabbits.

The purpose of this study was to test the hypothesis that bleomycin administration enhances the toxic effects of oxygen on the respiratory system. Twenty-one rabbits, with no evidence of respiratory disease, received intravenous injections of 45 units of bleomycin (Blenoxane), twice a week, for a total dose of 300 units. Fifteen rabbits received an equal volume of saline and served as controls. Treatment with bleomycin resulted in failure to thrive, weight loss, and 30% mortality from nonpulmonary causes, as indicated by the lack of respiratory distress or cyanosis, during or shortly after the injection period. The remainder of the animals were allowed to recover for 21 days following the last injection. At that time, no differences were found between the experimental and the control groups with respect to arterial blood gases, total lung capacity, compliance, and hydroxyproline content. Histologic examination of lung tissue revealed normal lung architecture. When exposed to 100% O2, bleomycin-treated rabbits developed arterial hypoxemia and died from respiratory failure at the same rate as the controls. It was concluded that pretreatment of healthy rabbits with 300 units of intravenous bleomycin did not result in the development of significant amounts of lung fibrosis or enhance the toxic effects of oxygen on the respiratory system.

Animals↗
PubMed1992

Bleomycin-induced acute lung injury in the rat does not influence pulmonary vascular responsiveness in vitro.

OBJECTIVE: To investigate the effects of the intratracheal and iv administration of bleomycin on the contraction and endothelially dependent vasodilation of rat pulmonary arteries in vitro. DESIGN: Prospective pharmacologic study. SETTING: National Heart and Lung Institute, London, UK. INTERVENTIONS: Intratracheal saline, intratracheal and iv bleomycin. MEASUREMENTS AND MAIN RESULTS: Rats treated with intratracheal bleomycin developed a significant increase in mean lung wet/dry weight ratio (5.6 +/- 0.4 [SEM] vs. 3.9 +/- 0.1, p less than .05) when compared with saline-treated control animals, confirming the development of pulmonary edema. However, these rats displayed normal relaxant responses to the endothelially dependent vasodilator acetylcholine and a normal contractile response to phenylephrine in vitro. Intravenous bleomycin had no effect on either wet/dry weight ratio or the response to either drug. CONCLUSIONS: Despite evidence for the loss of endothelial integrity that characterizes lung injury after intratracheal bleomycin, isolated pulmonary artery rings in vitro showed no loss of endothelial cell function. The role of the endothelium in modulating pulmonary ventilation/perfusion matching after lung injury is unclear.

Animals↗
PubMed1997

Reduction of bleomycin-induced acute DNA injury in the rat lung by the 21-aminosteroid, U-74389G.

OBJECTIVE: To determine whether pretreatment with a 21-aminosteroid, U-74389G, can prevent subsequent DNA injury in bleomycin-exposed lungs. SUBJECTS: Thirty-six adult male Sprague-Dawley rats. DESIGN: Controlled animal laboratory investigation of DNA injury in vivo. INTERVENTIONS: Animals were treated with 21-aminosteroid (10 mg/kg) or vehicle and subsequently received intratracheal instillation of bleomycin (1.75 U) or normal saline. MEASUREMENTS AND MAIN RESULTS: Twenty-four hours after bleomycin exposure, the 21-aminosteroid-treated animals had decreased evidence of DNA injury, expressed as percentage of DNA fragmentation normalized to the control group (113.5 +/- 6 [SEM] vs. 132 +/- 3.9%, p < or = .05), and activity of the DNA repair enzyme poly ADP-ribose synthetase (3.4 +/- 0.2 vs. 5.6 +/- 0.9 pmol nicotinamide adenine dinucleotide/min/mg protein, p < or = .05). Only bleomycin-exposed (+ vehicle) animals demonstrated significant evidence of increased DNA injury vs. the intratracheal saline-exposed control groups. CONCLUSIONS: The 21-aminosteroid pretreatment decreases subsequent pulmonary DNA injury induced by bleomycin exposure. This finding is likely due to the 21-aminosteroid's iron-chelating and cell-permeating abilities, and suggests that these agents may be effective in other diseases where iron-dependent free radical reactions occur.

Animals↗