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PubMed2002

Comparing transforming growth factor-beta2, talc and bleomycin as pleurodesing agents in sheep.

BACKGROUND: Transforming growth factor (TGF)-beta2 can produce effective pleurodesis in animals, but its efficacy has not been compared with commonly used pleurodesing agents in sheep, which have a thick pleura resembling that of humans. The acute physiological effects and the level of systemic TGF-beta absorption after its intrapleural administration have not been studied. The aims of the present study were to compare: (i) the effectiveness of TGF-beta2, talc and bleomycin in producing pleurodesis in sheep; (ii) the acute side-effects and systemic TGF-beta levels following the intrapleural administration of these agents; and (iii) histological changes after intrapleural injections of these agents. METHODOLOGY: Twelve sheep were divided into three groups and were given a single intrapleural dose of TGF-beta2 (0.25 microg/kg), talc slurry (5 g) or bleomycin (60 IU) via a chest tube. Saline or buffer was injected into the contralateral side, which served as the control. Arterial blood gases and respiratory and heart rates were monitored for the first 24 h. Plasma levels of TGF-beta1 and TGF-beta2 were measured. Pleurodesis was graded macroscopically from 1 (none) to 8 (symphysis > 50% of hemithorax) at day 14. RESULTS: At day 14, the pleurodesis score of the TGF-beta2 group (7.7+/-0.6) was similar to that of the talc (7.0+/-1.7) group and significantly higher than that of the bleomycin group (3.3+/-2.3; P < 0.05). No significant differences were seen in arterial blood gas analysis, vital signs and plasma TGF-beta1 and TGF-beta2 concentrations among the three groups. CONCLUSIONS: Transforming growth factor-beta2 was as effective as talc and more so than bleomycin in inducing pleurodesis in sheep. Intrapleural administration of TGF-beta2 appeared safe. No acute changes in gaseous exchange or macroscopic abnormalities were seen following intrapleural TGF-beta2. Importantly, there was no evidence of an increase in systemic TGF-beta levels following its intrapleural administration.

Analysis of Variance↗
PubMed1981

Proton NMR studies of the Zn(II)--bleomycin-A2--poly(dA-dT) ternary complex.

Proton NMR spectra demonstrate the formation of a ternary complex, Zn(II)--bleomycin-A2--poly(dA-dT), which serves as an analog of the putative active complex, Fe(II)--bleomycin-A2--DNA. Specific sites of metal--drug and drug--nucleic acid interaction have been delineated on the basis of chemical shift perturbations. On the basis of this criterion there appear to be three distinct regions of the drug: (i) the NH2 terminus up to and including the disaccharide and hydroxyhistidine residues, whose resonances are perturbed only by metal interactions; (ii) the COOH-terminal dipeptide, whose resonances are displaced only by nucleic acid interactions; and (iii) the methylvaleric acid-threonine dipeptide, which links these domains and whose resonances are sensitive to both types of interactions. The spectral perturbations in the first and second domains are very similar to changes observed in the corresponding binary complexes--i.e., Zn(II)--bleomycin-A2 and bleomycin-A2--poly(dA-dT), respectively.

Bleomycin↗
PubMed1983

Alteration and activation of sequence-specific cleavage of DNA by bleomycin in the presence of the antitumor drug cis-diamminedichloroplatinum(II).

The antitumor drug cis-diamminedichloroplatinum(II) dramatically alters the sequence-specific cleavage of the bleomycin A2-iron(II)-O2 system. Preferred bleomycin cleavage sites adjacent to oligo(dG) regions on two restriction fragments of plasmid pBR322 DNA were masked by pretreatment with cis-diamminedichloroplatinum(II). trans-Diamminedichloroplatinum(II), which is inactive as an antitumor drug, showed similar but not identical behavior. The DNA-cleaving activity of bleomycin was substantially modified by cis-diamminedichloroplatinum(II), and a number of specific new cutting sites in guanine-rich parts of the sequence were activated by both isomers of the platinum complex. The results further emphasize the possibility that the synergism found when cis-diamminedichloroplatinum(II) and bleomycin are used in combination chemotherapy may be due to interactions at the level of DNA-drug binding.

Animals↗
PubMed1990

Site-specific cleavage of RNA by Fe(II).bleomycin.

Bleomycin is an antitumor agent whose activity has long been thought to derive from its ability to degrade DNA. Recent findings suggest that cellular RNA may be a therapeutically relevant locus. At micromolar concentrations, Fe(II)-bleomycin readily cleaved a Bacillus subtilis tRNAHis precursor in a highly selective fashion, but Escherichia coli tRNA(Tyr) precursor was largely unaffected even under more forcing conditions. Other substrates included an RNA transcript encoding a large segment of the reverse transcriptase from human immunodeficiency virus 1. RNA cleavage was oxidative, approximately 10-fold more selective than DNA cleavage, and largely unaffected by nonsubstrate RNAs. RNA sequence analysis suggested recognition of RNA tertiary structure, rather than recognition of specific sequences; subsets of nucleotides at the junction of single- and double-stranded regions were especially susceptible to cleavage. The ready accessibility of cellular RNAs to xenobiotic agents, the high selectivity of bleomycin action on RNAs, and the paucity of mechanisms for RNA repair suggest that RNA may be a therapeutically relevant target for bleomycin.

Bacillus subtilis↗
PubMed1998

Immunodetection of the murine chemotactic protein CP-10 in bleomycin-induced pulmonary injury.

The murine S-100 protein designated CP-10 is a potent chemotactic factor for phagocytic cells, exhibiting optimal activity in the picomolar range. We assessed the role of this cytokine in the inflammatory response to pulmonary injury following intratracheal administration of bleomycin to mice. In the lungs of normal animals, strong cytoplasmic immunostaining for CP-10 was demonstrable in all recognisable neutrophil leucocytes sequestered within alveolar capillaries. Following induction of pulmonary inflammation in susceptible C57BL/6 mice, numerous CP-10-positive neutrophils were observed, but many of the recruited neutrophils did not exhibit staining for CP-10. No other cells were immunoreactive. The concentration of CP-10 in bronchoalveolar lavage (BAL) fluids from normal mice and mice administered intratracheal saline was below the level of detection by enzyme immunoassay. In contrast, nanomolar levels of CP-10 were detected in unconcentrated BAL fluids from C57BL/6 mice after bleomycin-induced injury, and the presence of monomeric CP-10 was demonstrable by Western blotting. Elevation of CP-10 levels correlated with the influx of inflammatory cells in C57BL/6 mice, but was not demonstrable in BAL fluids from BALB/c mice, which are resistant to pulmonary injury by bleomycin. We conclude that CP-10 may contribute to the recruitment of inflammatory cells in bleomycin-induced lung damage.

Animals↗
PubMed2002

Increase in the beta chain of hepatocyte growth factor (HGF beta) precedes c-met expression after bleomycin-induced lung injury in the rat.

After lung injury the regeneration of the alveolar epithelium is highly dependent on the proliferation of type II alveolar epithelial cells (AECs). Hepatocyte growth factor (HGF), a potent epithelial cell mitogen, is present as a single chain in normal tissue, but after injury HGF is converted to an active form composed of an alpha and a beta chain. In this study it was demonstrated that there was an increase in the beta chain of HGF 4 days after bleomycin administration, coinciding with the time of maximal type II AEC proliferation. Bronchoalveolar lavage fluid (BALF) obtained 4 days after bleomycin administration was maximally mitogenic to L2 cells, a nontransformed rat alveolar epithelial cell line. Type II cells isolated from normal rats do not express the HGF receptor, c-met. However, 4 days after bleomycin injury, using Western blot analysis, an increase in c-met was detected in AEC protein extracts. HGF induced c-met expression by L2 cells and neutralizing antibodies to HGF inhibited the mitogenic activity in the BALF. These findings suggest that HGF may regulate its own receptor on AECs and is an important mitogen for AECs 4 days after bleomycin administration.

Animals↗
PubMed2004

Heart angiotensin-converting enzyme activity increased after intraperitoneal bleomycin administration in rat.

Angiotensin-converting enzyme (ACE) generates angiotensin II and degrades bradykinin. This ectopeptidase acts as a marker in pathologic conditions, showing tissue and vascular damage. In order to evaluate serum and tissue ACE activity in bleomycin-associated lung damage, the authors studied morphological and enzymatic alterations as well as blood pressure in male Sprague-Dawley rats. Animals were treated intraperitoneally with bleomycin (5 mg/kg) 3 times for 1 week. This subacute and therapeutic dose produced morphologically evident pulmonary damage characterized by alveolar septum thickness and collagen deposition. Bleomycin also had significantly lowered lung and aorta N-acetyl-beta-D-glucosaminidase (NAG) activity, whereas heart and serum NAG activity increased significantly. Serum ACE activity was significantly lower in the treated animals, and heart ACE activity increased significantly. Lung ACE activity and blood pressure did not change during the study. The authors conclude that heart ACE activity increased faster than pulmonary ACE and serum ACE is a good indicator of damage even in subacute therapeutic bleomycin doses.

Animals↗
PubMedDate not supplied

Variability of interalveolar septal remodeling after bleomycin treatment in mice.

Although bleomycin-induced cellular injury in the lung parenchyma is followed by the development of patchy fibrosis, the authors hypothesized that remodeling of the interalveolar septum (IAS) following bleomycin is a diffuse process not limited to the formation of discrete fibrotic areas. To determine the spectrum of changes in the IAS induced by bleomycin treatment, lungs were harvested from mice at 1, 2, 3, and 4 weeks following intratracheal administration of 0.04, 0.06, or 0.08 units of bleomycin. Light microscopy with quantitative morphometric techniques and electron microscopy were used to evaluate the IAS alterations. At 4 weeks after treatment, there was evidence of diffuse IAS remodeling. By morphological analysis, two types of structural remodeling of the IAS were observed. One type showed thickening with extracellular matrix deposition and hyperplasia of lining epithelial cells. The other type showed localized thinning of the interstitium with capillary loss and reduction in number and in size of epithelial cells. The authors have defined these variants as septal thickening and septal atrophy, respectively. The findings indicate that studies investigating the pathogenesis of lung fibrosis should focus on septal remodeling as well as analysis of fibrotic foci and measurement of collagen content.

Animals↗
PubMed1997

A prospective, randomised study comparing the efficacy of talc slurry and bleomycin in the treatment of malignant pleural effusions.

In comparative studies with other agents, insufflated talc has been shown to be the most effective agent in achieving chemical pleurodesis in patients with malignant pleural effusions. The objective of this study is to compare the efficacy of talc administered as slurry (5 g in 50 mL saline) via tube thoracostomy with that of bleomycin (1 mg/kg in 50 mL saline) (which is the most effective agent other than talc). In a randomised, prospective comparative study, twenty-six consecutive patients with proven malignant pleural effusions (recurrent after at least two pleuroscenteses) in whom no pleurodesis attempt had yet been made, and who were symptomatic, had a Karnovski index < or = 50, and an expected survival of one year or less, were included. Therapeutic failure was defined as recurrent pleural fluid > or = 50% of initial volume or requiring pleurocentesis. Recurrence rates (25% vs 21.4%, NS), fever (25% vs 35.7%, NS), pain (0% both groups) and survival (3.75 +/- 3 vs 5.82 +/- 7.15 months, NS) did not differ between bleomycin or talc treated patients. There were no major complications (e.g., empyema) or side-effects. In conclusion, talc slurry and bleomycin are equally effective in achieving chemical pleurodesis via thoracostomy in patients with malignant pleural effusions, and the safety profile of both agents is similar. Since talc is substantially less expensive than bleomycin, talc slurry probably represents the agent of choice for chemical tube thoracostomy pleurodesis.

Adult↗
PubMed1986

Intraperitoneal bleomycin for ventriculoperitoneal spread of a hypothalamic astrocytoma.

A pediatric patient is presented in whom malignant ascites developed after ventriculoperitoneal shunt placement for a suprasellar astrocytoma. Paracentesis followed by intraperitoneal bleomycin resulted in decreased fluid re-accumulation with minimal side effects. A review of the literature shows that intracavitary chemotherapy, including bleomycin, can result in safe, effective relief of malignant effusion associated with adult tumors. We have demonstrated that such treatment is also applicable to the pediatric population. In this case, the effectiveness of intracavitary bleomycin may be related to its direct action against brain glioma cells. The need for effective treatment of malignant effusions in pediatric patients is growing because of their increased survival time with tumor. We propose that intracavitary bleomycin may provide relief from this potential complication of childhood solid tumors.

Astrocytoma↗
PubMed1988

Pulmonary toxicity after treatment with bleomycin alone or in combination with hyperoxia. Studies in the rat.

Female Wistar rats (n = 11) received bleomycin 10 mg kg-1 i.p. three times weekly for 6 weeks. Four weeks later part of the group (n = 7) were exposed to 50% oxygen in air for 4 h; the others served as unexposed controls. A further control group (n = 5) received physiological saline i.p. and was not exposed to oxygen. One week after the hyperoxia treatment all animals were sacrificed and the lungs prepared for histological and biochemical determinations. Although the average body weight of the bleomycin-treated rats decreased significantly compared with the saline-treated controls, no significant alterations in lung histology were found in regard to the occurrence of oedema, fibrosis, and type II pneumocytes. Intra-alveolar macrophages were significantly increased. Subsequent hyperoxia did not lead to a more pronounced effect, except for macrophage accumulation. The activities of superoxide dismutase and glutathione peroxidase were not changed either after administration of bleomycin alone or after combination with hyperoxia. It is concluded that bleomycin i.p. in doses comparable to those encountered clinically, administered alone or combined with hyperoxia, does not result in pulmonary damage in female Wistar rats.

Animals↗
PubMed1990

Aphidicolin-sensitive DNA repair synthesis in human fibroblasts damaged with bleomycin is distinct from UV-induced repair.

Human fibroblasts repair DNA damaged by bleomycin through both short-patch and long-patch pathways, mediated by an aphidicolin-resistant (beta) and aphidicolin-sensitive (delta) DNA polymerase respectively (DiGiuseppe, J.A. and Dresler, S.L. (1989) Biochemistry, 28, 9515-9520). Despite certain similarities, aphidicolin-sensitive repair synthesis induced by bleomycin can be distinguished genetically and biochemically from that elicited by UV radiation. Permeable xeroderma pigmentosum fibroblasts of complementation groups A and G, completely deficient in UV-induced repair, display aphidicolin-sensitive repair synthesis dependent upon dose of bleomycin. Furthermore, the ribonucleotide dependence of long-patch repair induced by bleomycin differs from that of UV repair with respect to substrate specificity and apparent Km for ATP. This novel ATPase activity mediates a step prior to polymerization. By contrast, short-patch repair synthesis does not require ATP. These data suggest that, in addition to short-patch repair, human cells possess two distinct long-patch excision repair pathways. We propose that these pathways represent strand-break, base and nucleotide excision repair respectively.

Adenosine Triphosphate↗
PubMed1992

Initiation by bleomycin of hepatocellular foci in the rat.

The antitumor antibiotic, bleomycin, was tested for activity as an initiator of hepatocellular foci and neoplasms in rats. The compound was administered in a single dose via the portal vein 4 h after the proliferative stimulus of a two-thirds partial hepatectomy. Rats were subsequently fed diet containing phenobarbital for up to 41 weeks to promote the development of initiated hepatocytes. Bleomycin-treated livers displayed significantly increased frequencies of basophilic hepatocellular foci and hepatocellular foci which retain glycogen during fasting. Foci that express glutathione-S-transferase (placental form) were not initiated by bleomycin. Hepatocellular neoplasms were infrequently seen in bleomycin-treated livers (5% incidence). The results suggest that oxygen radical-mediated DNA damage may initiate, within populations of proliferating hepatocytes, new lineages of altered hepatocytes that form foci but have low probability of progressing to neoplasms during promotion with phenobarbital.

Animals↗
PubMed1998

Serum creatinine level during chemotherapy for testicular cancer as a possible predictor of bleomycin-induced pulmonary toxicity.

BACKGROUND: Bleomycin is one of the key drugs used in induction chemotherapy for testicular cancer. Pulmonary toxicity is the major and potentially fatal adverse side-effect of this drug. METHODS: To evaluate the risk factors for bleomycin pulmonary toxicity, we retrospectively analyzed the cases of 20 men treated for metastatic testicular cancer at Tsukuba University Hospital between 1990 and 1996. All patients were treated with two to four cycles of a PVB regimen or BEP regimen. Recombinant human granulocyte colony-stimulating factor was used in all but one case. With a logistic procedure, we evaluated the age, total bleomycin dose, total cisplatin dose, renal injury, leukocytosis, smoking history, lung metastases and drug regimen as risk factors for a decrease in the diffusing capacity. RESULTS: Diffusing capacity was decreased to below 75% of the predicted values in nine patients. Elevation of the serum creatinine level was the most significant risk factor (P = 0.018) by the chi-squared test. A logistic regression analysis also indicated that the elevation of serum creatinine level was an independent risk factor for a decrease in the diffusing capacity (odds ratio 22.3, 95% Cl 1.02-487.3, P = 0.049). CONCLUSIONS: We recommend a pulmonary function assessment of patients receiving a relatively low dose of bleomycin, especially when an elevated serum creatinine level is seen during chemotherapy.

Antibiotics, Antineoplastic↗
PubMed1999

Inherited susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes.

BACKGROUND: Susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes may reflect the way a person deals with carcinogenic challenges. This susceptibility (also referred to as mutagen sensitivity) has been found to be increased in patients with environmentally related cancers, including cancers of the head and neck, lung, and colon, and, in combination with carcinogenic exposure, this susceptibility can greatly influence cancer risk. The purpose of this study was to assess the heritability of mutagen sensitivity. METHODS: Heritability was determined by use of a maximum likelihood method that employed the FISHER package of pedigree analysis. Bleomycin-induced breaks per cell values for 135 healthy volunteers without cancer were determined. These individuals were from 53 different pedigrees and included 25 monozygotic twin pairs (n = 50), 14 pairs of dizygotes (twin pairs and siblings, n = 28), and 14 families selected on the basis of a first-degree relative who was successfully treated for head and neck cancer and who had no sign of recurrence for at least 1 year. All data were analyzed simultaneously, and different models of familial resemblance were fitted to the data. All P values are two-sided. RESULTS: Our results showed no evidence for the influence of a shared family environment on bleomycin-induced chromatid breaks. Genetic influences, however, were statistically significant (P =. 036) and accounted for 75% of the total variance. CONCLUSIONS: The high heritability estimate of the susceptibility to bleomycin-induced chromatid breaks indicates a clear genetic basis. The findings of this study support the notion that a common genetic susceptibility to DNA damage--and thereby a susceptibility to cancer--may exist in the general population.

Antimetabolites, Antineoplastic↗
PubMed1998

Induction of apoptosis by bleomycin in resting and cycling human lymphocytes.

Bleomycin induces DNA and chromosome breakage. The differential sensitivity to the drug has been used in vitro to identify individuals at high risk of developing tumours. However, there are limited reports on the ability of bleomycin to induce apoptosis. In this study we tested induction of apoptosis in human peripheral lymphocytes by bleomycin at different concentrations and different culture times using various parameters, such as nuclear fragmentation and DNA fragmentation, evaluated either in situ with terminal transferase and labelled nucleotides (TUNEL) or by flow cytometry analysis. We demonstrate that bleomycin induces apoptosis without previous permeabilization of the cell membrane. Cell death occurs mainly by apoptosis and not by necrosis, with significant alteration of membrane lipoperoxidation (evaluated by luminescence).

Adult↗
PubMed1999

A comparison of bleomycin-induced damage in lymphocytes and primary oral fibroblasts and keratinocytes in 30 subjects.

The number of chromatid breaks in peripheral blood lymphocytes (PBL) after exposure to bleomycin in the S/G2 phase of the cell cycle (in the literature referred to as 'mutagen sensitivity') is associated with an increased risk of environmentally related cancers, including oral cancer. The aim of this study was to elucidate whether mutagen sensitivity measured in lymphocytes actually reflects chromosomal instability of normal cells in the areas in which tumors develop. Therefore, bleomycin-induced chromosomal damage in and growth inhibition of cultured oral fibroblasts and oral keratinocytes from 30 persons were compared with the standard mutagen sensitivity score in PBL. A correlation was found for the percentage of aberrant metaphases between PBL and oral fibroblasts but not for the number of breaks per cell. These data do not allow a conclusion to be drawn on the use of fibroblasts to study cancer risk. Within the fibroblasts it was found that a high number of breaks per cell was associated with less growth inhibition, indicative of damage-resistant growth. Oral keratinocytes were extremely sensitive to bleomycin, as indicated by a strong cell cycle block which resulted in a mitotic index too low to determine chromosomal breaks. Moreover, in the cell proliferation assay keratinocytes were found to be 100 times more sensitive as compared with fibroblasts. There was no correlation between bleomycin sensitivity of keratinocytes compared with fibroblasts from a single patient as measured by growth inhibition. This may be due to the strong influence of alcohol consumption by the subjects, which was found to increase the sensitivity of keratinocytes but not of PBL and fibroblasts. In conclusion, oral fibroblasts but not keratinocytes can be used to measure sensitivity for chromatid breaks. The apparent influence of environmental factors on keratinocytes makes them a useful source to study exposure characteristics but limits their application for the determination of genetic factors.

Adult↗
PubMed1999

Bleomycin genotoxicity alteration by glutathione and cytochrome P-450 cellular content in respiratory proficient and deficient strains of Saccharomyces cerevisiae.

The genotoxic effects of the antiblastic drug bleomycin were studied in the D7 strain of Saccharomyces cerevisiae and on its derivative mitochondrial mutant rho degree at different cellular concentrations of two drug metabolizing systems, glutathione (GSH) and cytochrome P-450. Bleomycin mutagenic activity was evaluated as frequencies of mitotic gene conversion, reversion and total aberrations under different physiological conditions. In the D7 strain, petite mutant induction was also detected. This is important due to the role of the mitochondrial genome in cancer induction, ageing and degenerative diseases. Both strains showed higher convertant than revertant induction. At high cytochrome P-450 levels, bleomycin-induced gene conversion was enhanced in both strains although mitochondrial functionality showed a detoxicant role while cellular GSH content decreased the induction of convertants only in the respiratory proficient strain. Cell metabolic conditions, such as cell cycle, aerobic/hypoxic conditions of the cell and content of drug metabolizing enzymes, appeared to interact with the genotoxic effectiveness of bleomycin. Moreover, the usefulness of S.cerevisiae as a model organism for drug assessment for mutagenicity was emphasized.

Bleomycin↗