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PubMed1985

Comparison of the sequence specificity of bleomycin cleavage in two slightly different DNA sequences.

The sequence specificity of bleomycin damage was investigated utilising 340 bp alpha-DNA (a middle repetitive sequence in the human genome) as a target sequence. The following significant facts were found:- i) The dinucleotides GT and GC were cleaved on all occasions, GA most of the time, and AT, AC, GG and AA cleaved some of the time; ii) The base immediately 5' to the purine-pyrimidine dinucleotides was found to be statistically highly significant in determining the degree of damage caused by bleomycin, while other nearest neighbour bases had no significant effect; iii) The sequence specificity of bleomycin damage was determined on both strands and it was found that damage on either strand follows the above dinucleotide preference and is independent of the extent of damage on the opposite strand; iv) Bleomycin damage was compared between genomic 340 bp alpha-DNA and a cloned alpha-DNA with eleven base substitutions relative to the "consensus" sequence. There were forty-nine detectable differences in intensity of damage between these two DNA molecules. Although four of the differences can be directly attributed to changes in base sequence, the remaining differences were not at the base substitution sites. Some of the differences were over fifty base pairs from the nearest base substitution. We propose that the majority of these differences are due to microvariation in the structure of DNA with a slightly different DNA sequence.

Base Sequence↗

PubMed1993

DNA structure influences sequence specific cleavage by bleomycin.

We have examined the cleavage of several synthetic DNA sequences by iron(II)-bleomycin. We find that, although bleomycin cuts mixed sequence DNAs with a preference for GC = GT > GA >> GG, it efficiently cleaves regions of (AT)n cutting exclusively at ApT, not TpA. Isolated ApT steps show very little cleavage while blocks of three or more contiguous ATs are cut as efficiently as GpT. This cleavage is specific for (AT)n, since sequences of the type (TAA)n.(TTA)n and (ATT)n.(AAT)n are hardly cut at all. No cleavage is observed at ApC or CpA within sequences of the type (AC)n.(GT)n; regions of An.Tn are also not cut. Although the cobalt-bleomycin complex (which binds to but does not cleave DNA) yields good DNase I footprints at GT and GC sites, no footprints are observed within (AT)n, suggesting that although the cleavage reaction is efficient, the binding affinity is relatively weak. We propose a model in which bleomycin cleavage is determined by local DNA structure, while strong binding requires the presence of a guanine residue.

Base Composition↗

PubMed1995

Catalytic site-specific cleavage of a DNA-target by an oligonucleotide carrying bleomycin A5.

Oligonucleotide reagents have been created which are capable of catalytic site-specific cleavage of DNA-targets. The oligonucleotide reagent Blm-R-pd(CCAAACA) bearing the bleomycin A5 (Blm-RH) residue was used to degrade the DNA-target pd(TGTTTGGCGAAGGA). It has been shown that at equimolar reagent: target concentration the bleomycin oligonucleotide derivative can repeatedly cleave the target at G9, G7, T5, T4 and T3 in site-specific manner. This paper demonstrates that with a 10-fold excess of the DNA-target relative to the reagent 30% degradation of the target was observed primarily at a single position G7. The paper also shows that one reagent molecule containing bleomycin A5 residue was capable to degrade three molecules of the DNA-target. The catalytic activity of Blm-R-pd(CCAAACA) was the highest in the temperature range close to the melting temperature of the reagent-target complex, that is under conditions where the oligonucleotide reagent can form a complementary complex and easily dissociate to interact with the next molecule of the target. The number of target molecules degraded by the bleomycin reagent is limited by the degradation of the antibiotic residue itself.

Base Sequence↗

PubMed1995

Novel DNA photocleaving agents with high DNA sequence specificity related to the antibiotic bleomycin A2.

We have designed and synthesized a series of novel DNA photocleaving agents which break DNA with high sequence specificity. These compounds contain the non-diffusible photoactive p-nitrobenzoyl group covalently linked via a dimethylene (or tetramethylene) spacer to thiazole analogues of the DNA binding portion of the antibiotic bleomycin A2. By using a variety of 5' or 3' 32P-end labeled restriction fragments from plasmid pBR322 as substrate, we have shown that photoactive bithiazole compounds bind DNA at the consensus sequence 5'-AAAT-3' and induce DNA cleavage 3' of the site. Analysis of cleavage sites on the complementary DNA strand and inhibition of DNA breakage by distamycin A indicates these bithiazole derivatives bind and attack the minor groove of DNA. A photoactive unithiazole compound was less specific inducing DNA breakage at the degenerate site 5'-(A/T)(AA/TT)TPu(A/T)-3'. DNA sequence recognition of these derivatives appears to be determined by the thiazole moiety rather than the p-nitrobenzoyl group: use of a tetramethylene group in place of a dimethylene spacer shifted the position of DNA breakage by one base pair. Moreover, much less specific DNA photocleavage was observed for a compound in which p-nitrobenzoyl was linked to the intercalator acridine via a sequence-neutral hexamethylene spacer. The 5'-AAAT-3' specificity of photoactive bithiazole derivatives contrasts with that of bleomycin A2 which cleaves DNA most frequently at 5'-GPy-3' sequences. These results suggest that the cleavage specificity exhibited by bleomycin is not simply determined by its bithiazole/sulphonium terminus, and the contributions from other features, e.g. its metal-chelating domain, must be considered. The novel thiazole-based DNA cleavage agents described here should prove useful as reagents for probing DNA structure and for elucidating the molecular basis of DNA recognition by bleomycin and other ligands.

Base Sequence↗

PubMed2006

Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation.

We have recently identified a gene named GITR (glucocorticoid-induced TNF receptor related gene). GITR is expressed in different cells and tissues such as T lymphocytes from thymus and spleen and lymph nodes, and also in the lung. GITR ligand (GITRL) is expressed in several cells including macrophages, B cells, dendritic cells, and endothelial cells. In the present study, by comparing the responses in wild-type (WT) mice (GITR+/+) and GITR-deficient mice (GITR-/-), we investigated the role played by GITR-GITRL interaction in the development of chronic lung injury caused by bleomycin instillation. When compared with bleomycin-treated GITR+/+ mice, bleomycin-treated GITR-/- mice exhibited a reduced degree of i) lung infiltration with polymorphonuclear neutrophils (MPO activity); ii) edema formation; iii) histological evidence of lung injury; iv) TNF-alpha and interleukin (IL)-1beta production; v) nitrotyrosine formation; and vi) NF-kappaB activation. The cotreatment of GITR+/+ mice with Fc-GITR fusion protein (6.25 microg/mouse) also significantly attenuated all of the above indicators of lung damage and inflammation. Our results clearly demonstrate that GITR-GITRL interaction plays an important role in the chronic lung injury induced by bleomycin in the mice.

Animals↗

PubMed1993

Bleomycin and mitoxantrone in the treatment of malignant pleural effusions. A comparative study.

Effusions are common in advanced cancer. Intracavitary instillation of various agents such as bleomycin has achieved control rates varying between 20% and 60%. However, serious side effects have also been observed, and cases of death due, for instance, to bleomycin have been reported. Mitoxantrone has been tested recently in the treatment of effusions, and preliminary results suggest high efficacy of this drug in the treatment of peritoneal, pericardial, and pleural effusions. Nevertheless, certain results have been conflicting. In the present study, 29 patients with pleural effusions were treated either with intracavitary bleomycin or intracavitary mitoxantrone. Effusions were controlled almost equally by both agents; 67% with mitoxantrone and 64% with bleomycin. We conclude that both agents can be used successfully in the treatment of pleural effusions.

Aged↗

PubMed1993

Low toxicity with continuous infusion of high-dose bleomycin in poor prognostic testicular cancer.

Bleomycin is a powerful antitumoral antibiotic whose utilization has been limited by pulmonary toxicity. At the Medical Oncology Department of the Hospital General de Mexico, SS, 17 patients with high-risk testicular cancer were treated with therapeutic regimens based on cisplatin and bleomycin in continuous infusion. The mean bleomycin dose was 813 mg. Adequate renal function was observed in all patients during and after chemotherapy. During a minimum 4-year follow-up period, no patient experienced pulmonary toxicity; 3 patients died due to tumoral progression. The remaining 14 patients are alive and none of them had shown x-ray abnormalities nor a significant reduction in pulmonary vital capacity (PVC) or carbon monoxide diffusion capacity (DLCO). Bleomycin in continuous infusion can be an appropriate alternative for reducing pulmonary toxic effects. Therefore, randomized controlled studies should be conducted in order to determine if this treatment regime could enhance the therapeutic index.

Adolescent↗

PubMed1996

A phase II trial of VP-16, ifosfamide, cisplatin, vinblastine, and bleomycin in advanced germ-cell tumors.

PURPOSE: A Phase II study to evaluate the effect of a five-drug regimen, VP-16, ifosfamide, cisplatin, vinblastine, and bleomycin (VIP/VB) on complete response rate, continuous disease-free survival, and toxicity in patients with advanced germ-cell tumor. PATIENTS AND METHODS: Twenty male patients with a histologic diagnosis of advanced-stage germ-cell cancer, previously untreated with chemotherapy, received the following: etoposide 75 mg/m2 i.v. days 1-5; ifosfamide (with mesna uroprotection) 1.2 g/m2 i.v. days 1-5; cisplatin 20 mg/m2 i.v. days 1-5; vinblastine 0.18 mg/kg i.v. day 1; bleomycin 30 units i.v. day 1; filgrastim 5 micrograms/kg days 7-16. Chemotherapy was given every 3 weeks (bleomycin weekly x 12) for four courses. RESULTS: All patients entered were evaluable for toxicity, response, and survival. Eleven of 20 (55%) achieved complete remissions with chemotherapy alone and an additional 5 (25%) were rendered disease-free with surgical resection of teratoma (3) or viable cancer (2). Two patients relapsed at 4 and 5 months from complete remission (CR). There was one treatment-related death, from bleomycin lung toxicity after thoracotomy. Thirteen patients (65%) are alive and continuously free of disease, with a median follow-up of 20 months and a minimal follow-up of 12 months. Hematologic toxicity was most common, with 16 patients (80%) having grade 3 or 4 leukopenia. CONCLUSIONS: VIP/VB appears to be a very active regimen in advanced disseminated germ-cell cancer. Hematological toxicity was severe but manageable.

Adult↗

PubMed1996

Electrochemotherapy with bleomycin in SA-1 tumor-bearing mice--natural resistance and immune responsiveness.

Electrochemotherapy is an antitumor treatment that utilizes locally delivered electric pulses to increase the effectiveness of chemotherapeutic drugs in cells and tissues. Electric pulses permeabilize tumor cells to allow nonpermeant drugs such as bleomycin to enter the cells. Although preclinical data indicate that immune responsiveness of the organism is important for obtaining cures of the tumors after electrochemotherapy with bleomycin, it is not known how electrochemotherapy affects the immune system of the organism. The aim of the study was to determine the effects of electrochemotherapy with bleomycin on natural resistance and immune responsiveness. Natural resistance was evaluated by phagocytic and intracellular killing activity (oxidative burst) in monocytes and polymorphonuclear granulocytes from venous blood, and immune responsiveness by blast transformation of spleen mononuclear cells to mitogens. The percentage of monocytes in venous blood able to elicit oxidative burst was significantly increased 7 days after the electrochemotherapy and returned to normal values after 14 days. In addition, increased blast transformation of spleen mononuclear cells by stimulation with concanavalin A (T lymphocytes activity) was found 14 days after electrochemotherapy treatment. The results of our study demonstrate that electrochemotherapy with bleomycin affects the immune system of the organism

Animals↗

PubMed1992

AIDS-associated mucocutaneous Kaposi's sarcoma treated with bleomycin.

OBJECTIVES: To evaluate efficacy and tolerance of bleomycin in AIDS-associated mucocutaneous Kaposi's sarcoma. A previous study showed that bleomycin was effective and well tolerated in this setting. DESIGN: A non-comparative, open, prospective study. METHODS: Seventy patients were treated with 5 mg per day intramuscular bleomycin on 3 consecutive days every 2 weeks. RESULTS: Two patients achieved a complete response and 50 a partial response (overall response rate, 74%). Median time to treatment response was 4 weeks (range, 2-12 weeks) and median time to relapse 10 weeks (range, 2-36 weeks). Dose-limiting toxicity consisted of cutaneous adverse reactions. CONCLUSION: Bleomycin is active against AIDS-associated mucocutaneous Kaposi's sarcoma; relapse occurs after discontinuation of therapy.

Acquired Immunodeficiency Syndrome↗

PubMed1987

Proton relaxation times in bleomycin-induced lung injury.

Pulmonary fibrosis and inflammation induced in mice by biweekly injection of low doses (20 mg/kg) of bleomycin chronically administered subcutaneously was associated with a significant increase in T2 values measured in vitro (54.6 +/- 20.7 ms vs. 36.2 +/- 3.8 ms in controls). T1 values, however, were not altered significantly (613 +/- 124.6 ms vs. 666 +/- 105.7 ms in controls). Lung water content did not change (79.1 +/- 2.5% vs. 78.4 +/- 0.98% in controls, NS). Water content to dry weight ratio in the control group (3.63 +/- 0.212) did not differ significantly from that in the experimental group clinically treated with bleomycin (3.84 +/- .618). However, morphometric and histologic analysis indicated that in 71% of the chronically treated mice, there was marked pulmonary fibrosis (mean area of involvement 3.5 +/- 8.1% vs. 0.25 +/- 0.15% in controls, P less than .01). In addition, there was marked increase in pulmonary cellularity and infiltration by lymphocytes and macrophages (mean area of macrophage infiltration 8.71 +/- 13.256% vs. 1.17 +/- 1.404% in controls). The alteration in T2 in bleomycin damaged lung occurred in the absence of change in overall water content. However, the change in cellularity indicates an alteration of water distribution between the cellular, intravascular, and interstitial components induced by the measurable fibrotic and inflammatory response to bleomycin.

Animals↗

PubMed1997

Effective treatment of B16 melanoma by direct delivery of bleomycin using electrochemotherapy.

Electrochemotherapy (ECT), chemotherapy administered in combination with electric fields, has the potential to be an effective localized treatment for cutaneous malignancies. Bleomycin's cytotoxicity was enhanced by exposing tumour cells to electrical fields following intravenous injection of the chemotherapeutic agent. Two issues associated with this procedure are the existence of a narrow but optimal time-window for effective treatment and the fact that a systemic drug dose is administered for a localized therapy. In order to address these issues, a study was initiated to examine the effectiveness of administering bleomycin by intratumoural injection. A dose-response relationship for intratumoural injection was determined. In addition, the minimal effective field strength necessary for ECT was established. Results of this study indicated drastic reductions in tumour volume for ECT-treated groups. In addition, ECT-treated groups showed increased survival over control groups. The minimum effective dose for the ECT intratumour bleomycin group was 0.025 units. The minimum effective field strength was found to be 1250 V/cm. The results demonstrate that intratumoural injection of bleomycin in combination with electric pulses is effective, and this information will be used to initiate clinical trials.

Animals↗

PubMed1982

Plasmid R46-mediated protection against bleomycin is poLA+-dependent.

Strains of Escherichia coli deficient in post-replication recombination repair were more sensitive to bleomycin than wild-type, repair-proficient strains. Mutants lacking excision repair functions were no more sensitive to bleomycin than the wild-type strains, indicating that this pathway is not involved in the repair of bleomycin-damaged DNA. Plasmid R46 not only protected repair-proficient strains but also those with recB, recC, uvrA or lig genotypes, suggesting that R46 protection against bleomycin is independent of these host repair functions. However, R46 protection was abolished in recA or polA strains, indicating that these gene functions are necessary for plasmid-mediated protection. It is suggested that protection may be due to a recA+-dependent interaction of a plasmid-encoded product with host DNA polymerase I, resulting in an increase in the DNA repair capacity of cells.

Bleomycin↗

PubMed1990

Synergistic effect in culture of bleomycin-group antibiotics and N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine, a synthetic isoprenoid.

Like bleomycin and peplomycin, libromycin, a newly developed bleomycin-group antibiotic, was potentiated 130-fold against Chinese hamster V79 cells (V79/S) and 47-fold against its multidrug-resistant mutant (V79/ADM) by N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB-ethylenediamine) at 10 and 3 micrograms/ml, respectively. But neocarzinostatin, known to cause DNA strand scission as bleomycins do, was potentiated only twofold. This suggests that the high potentiation by SDB-ethylenediamine is unique to the bleomycin-group antibiotics. Isobologram analysis revealed that the combined effect of peplomycin and SDB-ethylenediamine was highly synergistic. SDB-ethylenediamine did not increase the intracellular accumulation of [3H]peplomycin in V79/S cells. Analyses by an alkaline elution method demonstrated that single strand scission in DNA of intact V79/S cells caused by 1-h incubation with peplomycin was greatly stimulated by pre- and co-existence of SDB-ethylenediamine, but DNA strand breaks in isolated nuclei were not affected. Apparently some cytoplasmic constituent(s) is involved in the potentiation mechanism. SDB-ethylenediamine did not block the DNA repair which occurred after the removal of peplomycin from the medium. Two fragments of SDB-ethylenediamine, solanesol (polyprenoid moiety) and a diamine component (verapamil-like moiety), were not synergistic with peplomycin, even when they were mixed together. This indicates that the steric conformation of the intact SDB-ethylenediamine molecule is important for the activity.

Animals↗

PubMed1984

The treatment of resistant warts with intralesional bleomycin: a controlled clinical trial.

A controlled double-blind trial was carried out on fifty-nine matched pairs of hand warts in a group of twenty-four patients, with proven resistance to treatment, to study the effectiveness of the intralesional injection of 0.1% solution of bleomycin sulphate in normal saline, compared with a normal saline placebo injected into the paired warts in the same patient. We found that 87.5% of patients showed a more favourable response to bleomycin (P less than 0.001); 76% of the fifty-nine warts treated with bleomycin were cured by one to three injections of up to 0.2 ml of solution. Subsequently 75% of thirty-two patients with resistant hand warts and 66% of fifteen patients with mosaic plantar warts were cured of all their warts. No patient received more than 4 mg of bleomycin. No toxicity was experienced. Local pain was on the whole well tolerated. This form of treatment for resistant warts is reliable, safe and acceptable to patients.

Adolescent↗

PubMed2006

Bleomycin and the skin.

Bleomycin is frequently used as a chemotherapeutic agent to treat various kinds of malignancy. However, the cytotoxic effects of bleomycin cause a number of adverse responses, in particular in the lung and the skin. Bleomycin is used by dermatologists as a treatment for various skin cancers, recalcitrant warts, keloid and hypertrophic scars. This article discusses the use of bleomycin for various skin disorders, as well as the risk factors and cutaneous side-effects resulting from its use.

Antibiotics, Antineoplastic↗

PubMed1991

Low dose bleomycin with etoposide and cisplatin for metastatic testicular teratoma.

Thirty-nine men with metastatic testicular teratoma were treated with a combination of bleomycin, etoposide and cisplatin (BEP). Unlike the usual regimen of these 3 agents, bleomycin and cisplatin were given on day 1 only of the cycle, with etoposide for 3 days. Thirty patients (77%) are alive and disease-free after a median follow-up of 31 months--24/25 (96%) with disease confined to lymph nodes but only 6/14 (43%) patients with lung involvement. Modified BEP chemotherapy is a well tolerated alternative to standard BEP chemotherapy for small volume nodal disease; it minimises in-patient time, hospital visits and the risk of bleomycin lung toxicity. However, omission of the weekly doses of bleomycin and shortening of the administration schedule of cisplatin and etoposide may be detrimental in patients with more extensive disease, for whom more intensive therapy may be necessary.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Inhibitors of poly(ADP-ribose) polymerase modulate signal transduction pathways and the development of bleomycin-induced lung injury.

Poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA, plays an important role in the tissue injury associated with inflammation. The aim of our study was to evaluate the therapeutic efficacy of in vivo inhibition of PARP in an experimental model of lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury and apoptosis (measured by Annexin V coloration). An increase of immunoreactivity to nitrotyrosine and PARP, as well as a significant loss of body weight and mortality, was observed in the lung of bleomycin-treated mice. Administration of the two PARP inhibitors 3-aminobenzamide (3-AB) or 5-aminoisoquinolinone (5-AIQ) significantly reduced the 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) edema formation, and 5) histological evidence of lung injury. Administration of 3-AB and 5-AIQ also markedly reduced nitrotyrosine formation and PARP activation. These results demonstrate that treatment with PARP inhibitors reduces the development of inflammation and tissue injury events induced by bleomycin administration in the mice.

Animals↗