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PubMed2002

Involvement of cell cycle control in bleomycin-induced mutagen sensitivity.

Bleomycin-induced chromosomal instability, generally referred to as mutagen sensitivity, is associated with an increased risk for the development of environmentally related cancer including head and neck squamous cell carcinoma and lung cancer. On average, the cultured lymphocytes of patients with these types of cancer show an increased number of chromatid breaks per cell after bleomycin exposure in the late S or G2 phase of the cell cycle as compared to lymphocytes from control persons. The aim of the present study was to investigate whether cell cycle regulation is involved in mutagen sensitivity. We determined cell cycle arrest after bleomycin-induced DNA damage in 21 lymphoblastoid cell lines that varied in mutagen sensitivity score. An ataxia telangiectasia (AT) cell line was included for comparison. Using a cut-off point of 0.70 breaks per cell, eight cell lines were classified as insensitive and 13 cell lines showed the hypersensitive phenotype. Compared to insensitive cell lines, bleomycin-treated hypersensitive cells remained at a relatively high level of DNA synthesis, as measured by thymidine incorporation, and showed a decreased accumulation of cells in G2 and M phase, as measured by flow cytometry. AT cells showed an extremely high mutagen sensitivity score, a high level of DNA synthesis, and a strong G2 block. In conclusion, mutagen sensitivity is associated with "damage-resistant growth," which is indicative of impaired cell cycle arrest. By which specific pathway(s) this checkpoint defect is explained has yet to be elucidated; however, it is probably distinct from the checkpoint defect in AT cells. Environ. Mol. Mutagen. 40:79-84, 2002.

Bleomycin↗
PubMed1991

Analysis of bleomycin-induced mutagenic functions related to the PSO4 (= xs9) gene of Saccharomyces cerevisiae.

In the present work we analyse some properties of the pso4-1 (= xs9) mutant of the yeast Saccharomyces cerevisiae, which is blocked in both reverse mutation and recombination. We have applied the "apparent survival test" as a method to characterize putative inducible error-prone repair activities related to the PSO4 gene. As the mutagenic agent we have used bleomycin, which is an antitumour radiomimetic antibiotic. Survival, reverse mutation yield, and reverse mutation frequency were determined as a function of bleomycin concentrations (1-60 micrograms/ml) in the logarithmic phase of growth. It is shown that the PSO4 gene product is poorly involved in bleomycin sensitivity and that reverse mutation induced by this mutagen is dramatically reduced in the pso4-1 lys2 mutant strain, as compared with the isogenic SC7K (lys2) strain. M(x) functions exhibit linear-quadratic courses for both the SC7K (lys2) and the pso4-1 lys2 strains. The apparent survival functions display "humps" in both strains, corresponding to the resistant components of the survival functions. These facts suggest that the mutagenicity of bleomycin depends on at least one inducible error-prone repair pathway and that the PSO4 gene product could act as a mutation triggering factor.

Bleomycin↗
PubMed1978

The pharmacokinetics of bleomycin in man.

A series of studies were carried out to investigate the pharmacokinetics of the antineoplastic antibiotic bleomycin in patients with neoplastic disorders. Drug was administered by long (four to five days) and short (10 minutes) zero-order infusions, and serial plasma and urine samples were collected. Serum and urine bleomycin concentrations were determined by radioimmunoassay. The disposition of bleomycin after the 10-minute infusion was described by a two-compartment open model. However, following multiple-day infusion estimates were obtained that were inconsistent with those from the short infusion. Parameters from the long infusions agreed with those from the short infusion when terminal plasma bleomycin levels less than 10 microunits/ml were excluded. The time to reach steady state following the long infusion (ca. 12 hours) was consistent with the half-life (3 hours) predicted by the short infusion and the long infusion excluding levels less than 10 microunits/ml. Possible explanations include assay interference by an unknown metabolite or strong binding of drug to tissues with release at a rate much less than the apparent rate of elimination of drug from the body.

Adult↗
PubMed1990

Comparative flow cytometric analysis of bleomycin toxicity on normal and tumour sheep cell kinetics in vitro.

The cytotoxic effects of bleomycin on cell proliferation, morphology and cycle progression were compared in a sheep tumour cell line and in normal sheep sinus cells. They were concentration and time dependent, irreversible, and were accompanied by increased cell diameter and cytosolic synthetic activity. Cell accumulation in the G2M phase, without much change in the cell cycle progression through the S phase, was observed using flow cytometry. Although the tumour cells showed a greater sensitivity to low bleomycin concentrations compared to the normal cells, both cell types exhibited equal sensitivity to higher drug concentrations. Provided that tumour cells are also preferentially affected by bleomycin in vivo, these findings raise the possibility that bleomycin cytotoxicity can be reduced or avoided in normal tissue.

Animals↗
PubMed1991

Application of alkaline unwinding to analysis of strand breaks induced by bleomycin in hamster lung DNA in vivo.

Strand breaks in hamster lung DNA were analyzed following in vivo exposure to bleomycin. An alkaline unwinding procedure involving separation of single-strand from double-strand DNA by hydroxylapatite chromatography followed by fluorescence detection of DNA with bisbenzimide was adapted for these studies. Procedures were developed that allowed preparation of DNA from lungs of control animals with a relatively low amount of single-strand DNA relative to double-strand DNA. Time dependence of unwinding was demonstrated using samples that were damaged deliberately by brief probe sonication. To verify that residual bleomycin remaining in lungs at the time of sacrifice did not cause strand breaks during sample preparation, bleomycin was added to minced lung in vitro. Under these conditions, the ratio of single-strand to double-strand DNA was not increased significantly. Substantial strand breaks were produced in vivo at 15 min and 1 h following intratracheal instillation of bleomycin into hamsters, as evidenced by a 5-6-fold increase in the ratio of single-strand to double-strand DNA relative to controls. The DNA damage appeared to be repaired within 1 day following exposure.

Animals↗
PubMed2007

Bleomycin-induced DNA damage and repair in Xenopus laevis and Xenopus tropicalis.

Microgel cell electrophoresis has been used with various species to measure breakage of DNA and DNA repair following exposure to the radiomimetic antibiotic, bleomycin. With humans, a high degree of DNA damage is considered to be predictive of cancer susceptibility. Non-isogeneic Xenopus laevis, the South African clawed toad, rarely develop spontaneous or induced cancers. Here, we investigate bleomycin-induced DNA damage and repair in splenic lymphocytes of this species to test consistency with cancer predictability. As X. laevis is pseudotetraploid in nature, while Xenopus tropicalis is diploid, we additionally explore the effect of polyploidy on DNA damage and repair in these vertebrates. The results show that higher doses of bleomycin are required to induce comparable levels of DNA damage in both Xenopus species, than in humans. X. tropicalis, the diploid, is more bleomycin-sensitive than is X. laevis. Additionally, repair rates of damaged DNA of X. laevis lymphocytes are more rapid than those of X. tropicalis, although both are hours slower than human leukocytes. While no data exist on cancer susceptibility in X. tropicalis, the results suggest greater susceptibility to cancer than X. laevis, but less than in humans. Thus, polyploidy serves as a protection against DNA damage and allows more rapid repair.

Animals↗
PubMed2003

Enhanced antitumor activity of a combination of MBD2-antisense electrotransfer gene therapy and bleomycin electrochemotherapy.

BACKGROUND: MBD2 is a methylated DNA-binding protein that has been previously suggested to have transcriptional silencing as well as DNA demethylase activities. We have previously shown that electrotransfer of an MBD2-antisense encoding plasmid inhibits tumor growth in vivo. In this study we tested whether a combination of MBD2-antisense gene therapy and bleomycin chemotherapy has an augmented antitumor effect in comparison with either monotherapy. METHODS: Mice bearing human non-small-cell lung carcinoma line H1299 xenoplants were treated with electrotransfer of either bleomycin or MBD2-antisense expression plasmid or a combination of both therapies and tumor growth following treatment was monitored. RESULTS: A combination of electrotransfer of MBD2-antisense and bleomycin electrochemotherapy has an additive inhibitory effect on the rate of tumor growth and a synergistic effect on the number of tumor-free animals when compared with either monotherapy. CONCLUSIONS: Our results suggest that a combination of MBD2-antisense electrotransfer gene therapy and chemotherapy with bleomycin is a candidate new approach to anticancer therapy.

Animals↗
PubMed1981

High-performance liquid chromatographic determination of components of bleomycin preparations.

A fast and sensitive method was developed for the quantitative determination of at least 10 components of pharmaceutical bleomycin sulfate preparations. The method is based on the reversed-phase high-performance liquid chromatographic (HPLC) separation of the components on a muBondapak C18 column with a mobile phase having a linear gradient of 10--40% methanol in aqueous 0.005 M 1-pentanesulfonic acid at pH 4.3. With this assay, the average standard deviations for components A2 and B2 are 0.92 and 0.87, respectively, for a 7.5--22.5 x 10(-3)-mg sample. Regulatory agencies presently use the official Code of Federal Regulations (CFR) method, which is based on CM-Sephadex column chromatography. It was demonstrated that this CFR method does not separate the bleomycin A2 component from some other minor bleomycin components. After elution from the CM-Sephadex column, the "A2 component" was separated into five components by the HPLC method. Bleomycin A2 is stable under these HPLC conditions.

Bleomycin↗
PubMed1987

Intracavitary bleomycin and tetracycline in the management of malignant pleural effusions: a randomized study.

Both bleomycin and tetracycline have been suggested as the sclerosing agent of choice in the management of malignant pleural effusions. To determine if one drug is superior to the other in this role, patients with malignant pleural effusions were randomly assigned to receive either bleomycin or tetracycline in the previously evacuated pleural space through a thoracostomy tube. Following instillation of the assigned agent, the tube was clamped for 8 hours and then reattached to suction. When the chest tube drainage had slowed to less than 40 ml in a 24-hour period or if 7 days had passed, the tube was removed. Pleural sclerosis was attempted 42 times in 34 patients. No statistically significant differences were found between the two treatment groups when prevention of effusion reaccumulation and time to removal of the chest tube (efficiency) were compared. Side effects including pleural pain and fever, occurred with both agents, but were manageable. Since one drug was not clearly superior to the other, and bleomycin is more costly, we suggest that tetracycline rather than bleomycin be used when pleural sclerosis is needed to manage malignant pleural effusions.

Bleomycin↗
PubMed1979

Bleomycin in combination chemotherapy of metastatic Wilms tumor: a late recurrent case, refractory to conventional therapy.

A patient with a late recurrence (13 years) of Wilms tumor is presented. After relapse with conventional chemotherapy, an objective partial remission was obtained with bleomycin, vinblastine, cyclophosphamide, and cis-platinum. Stable disease was noted when bleomycin was withheld. Bleomycin in this combination appeared to effect a good response, and further studies of chemotherapy of Wilms tumor should include bleomycin in combination with other active agents.

Antineoplastic Agents↗
PubMed1978

Ultrastructural study of bleomycin-induced pulmonary changes in mice.

The pulmonary changes produced in mice given bleomycin intraperitoneally (twice weekly for 4 weeks, total dose 240 mg/kg) were examined by light and electron microscopy. Bleomycin damaged the pulmonary vessels and produced type I pneumocyte necrosis, resulting in non-uniform pulmonary fibrosis. The sequence of events leading to pulmonary fibrosis may be arbitrarily divided into three phases: firstly, a focal perivascular lesion consisting of interstitial oedema with plasma cell and lymphocyte infiltration; followed by the middle proliferative phase characterised by type I pneumocyte necrosis, intra-alveolar fibrin deposition, an increase in the numbers of type II pneumocytes and fibroblasts and an overall decrease in the alveolar diameter. The third phase consisted of organisation, with intra-alveolar and interstitial collagen formation and the synthesis of elastin. These phases, although occurring sequentially, did not bear a constant time relationship to the dosage schedule, for new early focal lesions continued to appear throughout the period of the experiment. These ultrastructural changes are not specific for bleomycin, but represent a general reaction of the lung to injury. The exact mechanism whereby bleomycin produces the lung damage has yet to be ascertained.

Animals↗
PubMed2003

Codon 64 of K-ras gene mutation pattern in hepatocellular carcinomas induced by bleomycin and 1-nitropyrene in A/J mice.

Bleomycin is a radiomimetic antitumor agent with unique genotoxic properties. 1-nitropyrene is an environmental mutagen and carcinogen that undergoes both oxidative and reductive metabolism. In the present study, hepatocellular carcinomas were induced in male A/J mice by the intraperitoneal injection of bleomycin (120 mg/kg) followed by the intraperitoneal administration of 1-nitropyrene (total dose: 1,575 mg/kg). In order to understand the mechanism by which these two compounds induce hepatocellular carcinomas, the incidence and spectrum of mutations in the K-ras proto-oncogene in these hepatocellular carcinomas were analyzed. The hepatocellular carcinomas were induced by the administration of bleomycin and 1-nitropyrene were evaluated for point mutations in exon 1 and exon 2 of the K-ras gene by the polymerase chain reaction and a sequencing analysis. No mutation was found in the hotspots regions of the K-ras gene codon 12, 13, or 61. However, the codon 64 of the K-ras gene mutation was identified in 10 of 10 (100%) hepatocellular carcinomas. All mutations showed the same pattern, which was TAC-CAC transition. Codon 64 of the K-ras gene mutation may thus play an important role in the induction of hepatocellular carcinomas by bleomycin in the existence of 1-nitropyrene. As far as we know, this is the first report of a codon 64 mutation in the K-ras gene in a chemically induced tumor.

Animals↗
PubMed1993

Cytotoxic effect of free bleomycin A5-iron (II) complex and its conjugates with concanavalin A, insulin and calcitonin on mouse thymocytes.

The possibility of using the antibiotic bleomycin as a part of a hybrid molecule consisting of a targeting fragment and a generator of reactive oxygen species has been investigated. The bleomycin-iron (II) complex was shown to destroy the plasma membrane of thymocytes by producing reactive oxygen species. Antioxidants protected the cells from destruction thus pointing to its free-radical mechanism. The protective effects of catalase and superoxide dismutase indicate that superoxide radical and hydrogen peroxide being formed during autooxidation of the complex are involved in cell damage. The covalent binding of bleomycin to targeting molecules (concanavalin A, insulin, and calcitonin) enhanced the ability of the bleomycin-iron (II) complex to destroy the plasma membrane of thymocytes.

Animals↗
PubMed1999

Bleomycin, etoposide, and cisplatin combination therapy of ovarian granulosa cell tumors and other stromal malignancies: A Gynecologic Oncology Group study.

OBJECTIVES: The objectives of this study were to assess efficacy and toxicity of the combination of bleomycin, etoposide, and cisplatin (BEP) in this Phase II trial as first-line therapy for ovarian stromal malignancies. METHODS: Patients with incompletely resected Stages II-IV or recurrent cancer underwent surgical debulking. There were two bleomycin-related deaths early in the trial; thus, the initial schedule of bleomycin (20 units/m2 x 9 weeks for a maximum dose of </=30 units x 9) was changed, without subsequent mortality. The final dose schedule was 20 units/m2 bleomycin iv push day 1 every 3 weeks x 4, 75 mg/m2 etoposide days 1-5 every 3 weeks x 4 and 20 mg/m2 cisplatin days 1-5 every 3 weeks x 4. The frequency of negative second-look surgery was the primary outcome measure. RESULTS: Seventy-five women were entered; 18 were excluded. Grade 4 myelotoxicity occurred in 61% of the patients. The end point used for response was negative second-look laparotomy. Thirty-seven percent (14/38) of the patients undergoing second-look laparotomy had negative findings. The six complete responders were of long median duration (24.4 months). Patients with measurable disease were at the highest risk of progression and death. CONCLUSIONS: BEP appears to be an active combination regimen for first-line chemotherapy of malignant tumors of the ovarian stroma. Myelotoxicity was tolerable.

Adult↗
PubMed2001

Bleomycin, methotrexate, and CCNU in locally advanced or recurrent, inoperable, squamous-cell carcinoma of the vulva: an EORTC Gynaecological Cancer Cooperative Group Study. European Organization for Research and Treatment of Cancer.

OBJECTIVE: To investigate tumor response rate and treatment toxicity of a modified combination chemotherapy consisting of bleomycin (B), methotrexate (M), and CCNU (C) for patients with locally advanced, squamous-cell carcinoma of the vulva (not amenable to resection by standard radical vulvectomy) or recurrent disease (after incomplete resection). Tumor resectability was reassessed in patients who had responded to chemotherapy. METHODS: The regimen consisted of bleomycin 5 mg intramuscular (im) days 1-5, CCNU 40 mg per os (po) days 5-7, and methotrexate 15 mg po days 1 and 4 during the first week. During weeks 2-6 the patient was administered bleomycin 5 mg im days 1 and 4, and methotrexate 15 mg po on day 1 of the week. This 6-week cycle was repeated at 49-day intervals. RESULTS: Twenty-five eligible patients with a median age of 66 years (range, 39-82 years) were entered in this phase II trial. Twelve patients had primary locally advanced disease, 13 patients had a locoregional recurrence, and all received up to three BMC cycles. Two complete and twelve partial responses were observed (response rate, 56%; 95% confidence limits, 35-76%). The BMC regimen was associated with major hematological side effects and mild signs of bleomycin-related pulmonary toxicity. At a median follow-up of 8 months, 3 patients were alive, 18 had died due to malignant disease, 2 had died due to toxicity, and 2 had died due to intercurrent disease and unknown cause. The median progression-free survival was 4.8 months and the median survival was 7.8 months. The 1-year survival was 32% (95% confidence limits, 13-51%). CONCLUSION: The present data confirm the therapeutic activity of the BMC regimen in locoregionally advanced or recurrent squamous-cell carcinoma of the vulva. Following neoadjuvant chemotherapy, the overall response rate was 56%. BMC is an outpatient treatment that may play a role in the palliative therapy of advanced or recurrent vulva cancer.

Adult↗
PubMed1978

A review of the bleomycin experience in the United States.

As bleomycin has up to now proved effective when used alone, the main thrust of current clinical investigations predominantly concerns its use in combination with other drugs. This has occurred along three broad patterns: 1) combination with vinca alkaloids which has been mainly in testicular carcinoma; 2) as part of multidrug regimens where bleomycin added for its lack of myelosuppression. This has occurred in the malignant lymphomas, lung cancer, and head and neck cancer; 3) in combination with radiotherapy which has taken place mostly in head and neck cervix cancer. To date, the combination of velban and bleomycin has had a major impact in improving the ability to induce complete remissions in advanced testicular carcinoma. Other drugs such as cis-platinum diaminedichloride and actinomycin D have been added and no definitive combination has been established. In the lymphomas the addition of bleomycin to the MOPP or CVP regimen has given higher complete response rates, but long-term survival data are still awaited.

Bleomycin↗
PubMed1981

Current status of PEP bleomycin studies in Japan.

1. The therapeutic effects of pepleomycin seem superior to those achieved with bleomycin against squamous cell carcinoma and malignant lymphoma. 2. In basal cell epithelioma, carcinoma in situ (e.g., actinic keratosis, Bowen's disease), adenocarcinoma (e.g., mammary and genital Paget's disease), and adult soft tissue sarcoma, pepleomycin as well as bleomycin was clinically ineffective. 3. Of the two cases of stage IV malignant melanoma, pepleomycin combined with MeCCNU and VCR exerted a moderate effect against multiple disseminated skin metastases in one, and a slight effect against a VI rib metastasis in the other. 4. The sorts of side effects of pepleomycin were almost the same as those of bleomycin. Lung toxicities were less frequent under pepleomycin treatment than those under bleomycin treatment.

Adolescent↗
PubMed1976

57-cobalt-bleomycin as a tumor scanning agent in primary hepatocellular cancer.

57Co-bleomycin and 99mTc-sulfur colloid scans were performed in 13 southern African black patients with primary hepatocellular cancer (PHC) and 3 patients with other space-occupying hepatic lesions. Selective concentration of 57Co-bleomycin in the defect or defects seen on the 99mTc-sulfur colloid scan occurred in only 4 of the 13 (31%) patients with PHC. In the remaining PHC patients, as well as in the 2 patients with metastatic liver disease and the 1 patient with an amebic liver abscess, the 57 Co-bleomycin and 99mTc-sulfur colloid scans were identical. 57Co-bleomycin appears to have only a limited place as a tumor-seeking agent in the diagnosis of PHC in southern African blacks.

Bleomycin↗