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PubMed2005

Role of the mismatch repair system and p53 in the clastogenicity and cytotoxicity induced by bleomycin.

The mismatch repair (MMR) system and p53 protein play a pivotal role in maintaining genomic stability and modulate cell chemosensitivity. Aim of this study was to examine the effects of either MMR-deficiency or p53 inactivation, or both, on cellular responses to bleomycin. The MMR-deficient colon carcinoma cell line HCT116 and its MMR-proficient subline HCT116/3-6, both expressing wild-type p53, were transfected with an expression vector encoding a dominant-negative p53 mutant, or with the empty vector. Four transfected clones, having the following phenotypes, MMR-proficient/p53 wild-type, MMR-proficient/p53 mutant, MMR-deficient/p53 wild-type, MMR-deficient/p53 mutant, were subjected to treatment with bleomycin. Loss of MMR function alone was associated with increased resistance to apoptosis, chromosomal damage and inhibition of colony formation caused by bleomycin. Loss of p53 alone resulted in abrogation of G1 arrest and increased sensitivity to apoptosis and chromosomal damage induced by the drug, but did not affect clonogenic survival after bleomycin treatment. Disabling both p53 and MMR function led to abrogation of G1 arrest and to a moderate impairment of drug-induced apoptosis. Chromosomal damage was reduced in the MMR-deficient/p53 mutant clone with respect to the MMR-proficient/p53 wild-type one, when evaluated 48 h after bleomycin treatment, but was comparable in both clones 96 h after drug exposure. Clonogenic survival of the MMR-deficient/p53 mutant clone was similar to that of the MMR-deficient/p53 wild-type one. The effects of MMR-deficiency on cellular responses to bleomycin were confirmed using the MMR-proficient lymphoblastoid cell line TK6 and its MMR-deficient subline MT1, both expressing wild-type p53. In conclusion, our data show that loss of MMR and p53 function exerts opposite and independent effects on apoptosis and chromosomal damage induced by bleomycin. Moreover, inactivation of MMR confers resistance to the cytotoxic activity of the anticancer agent in cells expressing either wild-type or mutant p53.

Antibiotics, Antineoplastic↗
PubMed2005

Increased and prolonged pulmonary fibrosis in surfactant protein C-deficient mice following intratracheal bleomycin.

Recent reports have linked mutations in the surfactant protein C gene (SFTPC) to familial forms of pulmonary fibrosis, but it is uncertain whether deficiency of mature SP-C contributes to disease pathogenesis. In this study, we evaluated bleomycin-induced lung fibrosis in mice with genetic deletion of SFTPC. Compared with wild-type (SFTPC+/+) controls, mice lacking surfactant protein C (SFTPC-/-) had greater lung neutrophil influx at 1 week after intratracheal bleomycin, greater weight loss during the first 2 weeks, and increased mortality. At 3 and 6 weeks after bleomycin, lungs from SFTPC-/- mice had increased fibroblast numbers, augmented collagen accumulation, and greater parenchymal distortion. Furthermore, resolution of fibrosis was delayed. Although remodeling was near complete in SFTPC+/+ mice by 6 weeks, SFTPC-/- mice did not return to baseline until 9 weeks after bleomycin. By terminal dUTP nick-end labeling staining, widespread cell injury was observed in SFTPC-/- and SFTPC+/+ mice 1 week after bleomycin; however, ongoing apoptosis of epithelial and interstitial cells occurred in lungs of SFTPC-/- mice, but not SFTPC+/+ mice, 6 weeks after bleomycin. Thus, SP-C functions to limit lung inflammation, inhibit collagen accumulation, and restore normal lung structure after bleomycin.

Animals↗
PubMed2001

PG490-88, a derivative of triptolide, blocks bleomycin-induced lung fibrosis.

In this study we evaluate the antifibrotic properties of PG-490-88, a water-soluble derivative of triptolide. Triptolide is an oxygenated diterpene that is derived from a traditional Chinese herb that has potent immunosuppressive and antitumor activity. We used the intratracheal bleomycin mouse model and found that PG490-88 inhibits fibrosis in the bleomycin group when given the same day or 5 days after bleomycin. PG490-88 also markedly reduced the number of myofibroblasts in the bleomycin treatment group. An enzyme-linked immunosorbent assay of transforming growth factor (TGF)-beta in the bronchoalveolar lavage fluid showed a significant decrease in TGF-beta in the PG490-88-treated groups compared to the bleomycin-treated group. Additionally, triptolide blocked bleomycin-induced increase in TGF-beta mRNA in cultured normal human lung fibroblasts. The efficacy of PG490-88 when administered late after bleomycin installation suggests a potential role in the treatment of idiopathic pulmonary fibrosis.

Animals↗
PubMed1986

Reduced dose of bleomycin in the treatment of recalcitrant warts.

The effectiveness of intralesional bleomycin (1 U/ml) in the treatment of warts refractory to conventional methods of treatment has been shown in well-controlled studies. We have now evaluated more dilute concentrations of bleomycin in the treatment of recalcitrant warts. Warts were assigned for therapy with intralesional bleomycin at a concentration of 0.25 U/ml, 0.5 U/ml, or 1 U/ml at 3-week intervals. If warts persisted after three injections or had recurred by 3 months' follow-up, treatment was considered a failure. Twenty-six patients whose warts had persisted after conventional treatment entered the study. Three patients had spontaneous regression of untreated warts during therapy and were not included in the results. Of seventy-nine warts treated with intralesional bleomycin, sixty-two (78%) were cured after one to three injections. Responding warts showed a hemorrhagic eschar even with the lower bleomycin concentrations and healed without complication. Almost all treated warts responded, although not all were cured. Treatment with bleomycin at 0.5 U/ml was as effective as treatment with 1 U/ml. Bleomycin at 0.25 U/ml is effective therapy but not enough warts were treated to permit a conclusion when compared with higher concentrations.

Adult↗
PubMed2002

Intratumoural bleomycin as a treatment for recurrent cystic craniopharyngioma. Case report and review of the literature.

INTRODUCTION: The majority of craniopharyngioma (CF) have a cystic component and only 10% are completely solid. In tumors with a large cystic component, stereotactic drainage or instillation of radioctive and/or chemotherapeutic agents have been used. Only several authors have reported the use of bleomycin for the treatment of cystic CF. CASE REPORT: The authors present the case of a nineteen years old patient with a recurrent cystic CF who was treated with intratumoral injections of bleomycin. The patient had been operated on three times before because of regrowth of the tumor. This last time he had a severe disturbance of his visual acuity and a huge regrowth of the cystic CF. An intracystic catheter stereotactically placed was connected to an Ommaya reservoir and, after assuring the impermeability of the cyst, bleomycin was administered through the reservoir up to a total dose of 45mg distributed in six doses. No complications were detected during and after the procedure. A MR performed 4 months after treatment showed a clear reduction in the size of the cyst but 10 months later a new regrowth of the cyst was detected by MR with no new signs or symptoms. A total dose of 30 mg divided in six doses was administered. No complications occurred. The MR 18 months after the first treatment showed the reduction in size of the tumor. The ophtalmological study showed almost normal visual acuity in both eyes. DISCUSSION: Although there is not an stablished protocol for the indication and the form of application of intracystic bleomycin, results with this treatment for cystic CF seem good in the literature. However, the risk of local complications after the administration of intratumoural bleomycin in these patients is around 10%, and some fatal toxic reactions have been recently reported. CONCLUSION: Intracystic administration of bleomycin is a valid option as adjuvant therapy for CF in patients with recurrences that are not surgical candidates because of the high risk of complications. The role of bleomycin as a primary treatment for CF and treatment protocols remain to be stablished with additional studies.

Adult↗
PubMed1984

Cobalt-bleomycins and deoxyribonucleic acid: sequence-dependent interactions, action spectrum for nicking, and indifference to oxygen.

Light-induced strand scission of DNA by cobalt-bleomycins is more likely to occur at certain base sequences than others. By use of 32P-end-labeled DNA restriction fragments as the substrates for cleavage, products have been analyzed on high-resolution polyacrylamide gels and compared to those produced by iron-bleomycin. The results indicate that the sites of damage to DNA are similar in both cases: pyrimidine residues located at the 3' side of a guanine are preferentially attacked. Consistent with the observed nicking specificity, interactions between cobalt-bleomycin and guanine residues in the trinucleotide sequence GGT are revealed in a dimethyl sulfate methylation experiment. The action spectrum for the light-induced DNA cleavage reaction correlates with the absorption spectrum of cobalt-bleomycin in the wavelength range between 330 and 450 nm. In contrast to iron-bleomycin, the extent of DNA degradation by light-activated cobalt-bleomycins appears to be indifferent to the concentration of dissolved oxygen in the reaction medium, and little or no base propenal is produced. Bases (e.g., thymine) are released by both agents. Fluorescence quenching experiments show that apparent binding constants of cobalt-bleomycin complexes with DNA are in the 10(7) M-1 range in 25 mM tris(hydroxymethyl)aminomethane, pH 8, 1 mM NaCl, and 1 mM ethylenediaminetetraacetic acid at 25 degrees C.

Animals↗
PubMed1985

Diffusion-enhanced lanthanide energy-transfer study of DNA-bound cobalt(III) bleomycins: comparisons of accessibility and electrostatic potential with DNA complexes of ethidium and acridine orange.

Energy transfer in the "rapid-diffusion" limit reflects the equilibrium properties of a donor-acceptor system. Rates of energy transfer from freely diffusing terbium chelates to DNA-binding chromophores change dramatically when DNA is added; energy transfer from an electrically neutral chelate is reduced because the energy acceptor becomes partially buried in DNA, while energy transfer from a positive chelate is increased because of electrostatic attraction. The rate constants for energy transfer to DNA-bound chromophores from a positively charged terbium chelate, relative to those from a neutral chelate, were used to estimate the following values for the electrostatic potential near the surface of each DNA-bound acceptor at 298 K in the presence of 1.0 mM added salt (in units of -e/kT): acridine orange, 4.54 +/- 0.11; ethidium, 4.66 +/- 0.07; green Co(III) bleomycin A2, 4.06 +/- 0.11; orange Co(III) bleomycin A2, 3.11 +/- 0.10. Smaller numbers indicate less negative potentials; these can be due to a combination of (1) positive charge on the chromophore, (2) location of the chromophore [particularly Co(III) bleomycin] away from the DNA phosphates, and/or (3) separation of DNA phosphate negative charges by an intercalator. The magnitudes of the individual rate constants indicate that all the DNA-bound chromophores can be directly encountered by the terbium probes. Energy-transfer rate constants from a neutral terbium chelate to DNA-bound and free acceptors can provide a measure of the accessibility of the terbium probe to each bound chromophore. The ratios of these rate constants were as follows: acridine orange, 0.17 +/- 0.01; ethidium, 0.27 +/- 0.02; green form of Co(III) bleomycin A2, 0.48 +/- 0.06; orange form of Co(III) bleomycin A2, 0.71 +/- 0.06. These results are consistent with the probable differences in binding mechanisms for the intercalating chromophores (ethidium and acridine orange) as compared to the Co(III) bleomycins (in which the relevant chromophores are nonintercalating metal centers). In addition, all the results imply that the green Co(III) bleomycin chromophore binds closer to DNA than the orange; this provides a first step toward understanding the structural basis for the different biological properties of these metallobleomycins. Control experiments and theoretical considerations necessary to establish the validity of the results are also presented.

Acridine Orange↗
PubMed1996

Influence of chromatin structure on bleomycin-DNA interactions at base pair resolution in the human beta-globin gene cluster.

The DNA sequence specificity of bleomycin was examined in human cells and in purified genomic DNA. In each case, DNA damage sites were determined at nucleotide resolution in the human single-copy beta-globin promoter and the locus control region (LCR) hypersensitive site 2 (HS-2). Exponential amplification of gene-specific genomic fragments was achieved by ligation-mediated PCR, and labeled reaction products were analyzed directly by sequencing gel electrophoresis. Bleomycin was found to cleave DNA preferentially at GC, GT, and GA dinucleotides. This study represents the first occasion that the sequence specificity of bleomycin has been determined in intact human cells at the single-copy gene level. The intensity of bleomycin damage sites in the LCR HS-2 was found to differ substantially between intact cells and purified DNA at putative transcription factor binding sites. Bleomycin activity was greatly reduced in cells at a tandem NF-E2/AP1 DNA sequence element. This footprint was strongest in K562 cells where the nuclear factor-erythroid 2 (NF-E2) is thought to bind. Protection and enhancement were also observed at other sequence elements in the HS-2 that associate with erythroid-specific and ubiquitous transcription factors. These results suggest that the activity of bleomycin is significantly reduced at the site of protein-DNA interactions in intact cells. This property of bleomycin is extremely useful in genomic "footprinting", where it has significant advantages over other commonly used agents.

Base Composition↗
PubMed1997

Mapping of the cleavage-associated bleomycin binding site on DNA with a new method based on site-specific blockage of the minor groove with N2-isobutyrylguanine.

Although the binding of various forms of bleomycin to DNA has been studied extensively, the transient nature of the activated bleomycin species which ultimately attacks DNA has largely precluded direct examination of its physical interactions with DNA. In an attempt to map the minimum binding site required for this species to effect DNA cleavage, several oligonucleotide duplexes were synthesized, each of which contained a single N2-isobutyrylguanine moiety at a specific position in the sequence. These duplexes were end-labeled, and sequence-specific bleomycin-induced cleavage was assessed in each strand of each duplex. Isobutyrylguanine substitution immediately 5' to a primary bleomycin target site suppressed bleomycin-induced cleavage by more than 10-fold. Substitution two bases 5' to a target site suppressed cleavage by about 4-fold, and substitution directly opposite the target site suppressed cleavage by 7-fold. Substitution immediately 3' to the target site, or at other more distant positions 3' or 5', had little or no effect. In cases where cleavage at a primary site was strongly suppressed, cleavage at the corresponding secondary site (the putative site of the second break in a bleomycin-induced double-strand break) was also inhibited, even when the secondary site was several bases away from the isobutyrylguanine substitution. The results suggest that the binding site required for bleomycin-induced DNA cleavage spans a region of approximately 2 or 3 bp in the minor groove, including the base associated with the sugar attacked and one or two bases to its 5' side. Computer-based molecular modeling indicated that these results are consistent with the predictions of recently proposed models in which the bithiazole is intercalated immediately 3' to the cleavage site, and the iron coordination site binds in the minor groove immediately 5' to the cleavage site. Both the empirical data and the modeling studies suggest that N2-isobutyrylguanine substitution effectively blocks the minor groove, but without significantly disturbing DNA secondary structure. Thus, it is proposed that site-specific incorporation of N2-isobutyrylguanine may provide a general method for mapping binding sites of minor groove-binding ligands on DNA.

Binding Sites↗
PubMed2000

Bleomycin: new perspectives on the mechanism of action.

The bleomycin group antitumor antibiotics have long been of interest as a consequence of their efficacy in the treatment of certain tumors, not to mention their unique structures and properties in mediating dioxygen activation and sequence selective degradation of DNA. At a chemical level, the structure originally assigned to bleomycin was subsequently reassigned and the new structure has been confirmed by total synthesis. Through the elaboration of structurally modified bleomycin congeners and fragments, synthetic efforts have also facilitated an understanding of the contribution of individual structural domains in bleomycin to sequence selective DNA binding and cleavage, and have also provided insights into the nature of the chemical processes by which DNA degradation takes place. Within the last several years, it has also become apparent that bleomycin can mediate the oxidative degradation of all major classes of cellular RNAs; it seems entirely plausible that RNA may also represent an important locus of action for this class of antitumor agent. In parallel with ongoing synthetic and mechanistic efforts using classical methods, the study of bleomycins attached to solid supports has been shown to provide important mechanistic insights, and the actual elaboration of modified bleomycins by solid phase synthesis constitutes a logical extension of such efforts.

Antibiotics, Antineoplastic↗
PubMed1998

Fatal bleomycin pulmonary toxicity in the west of Scotland 1991-95: a review of patients with germ cell tumours.

We conducted a retrospective review of fatal bleomycin pulmonary toxicity in patients treated for germ cell tumours during 1991-95 at the Beatson Oncology Centre, Glasgow. Case notes of patients treated with bleomycin were reviewed with respect to cumulative bleomycin dose, renal impairment, exposure to supplemental oxygen, thoracic radiotherapy and age. A total of 194 patients underwent chemotherapy, of whom 180 received bleomycin-containing regimens. Five fatal cases of pulmonary toxicity were identified, an incidence of 2.8%. These cases were older than the remaining patients (P < 0.001), with a median age at diagnosis of 55 vs 33 years. The incidence of fatal pulmonary toxicity increased with each decade of life above age 30. Renal function also differed between the two groups, with the worst glomerular filtration rate recorded at the time of bleomycin administration for each patient, lower in the fatal group, median 69 vs 107 ml min(-1) (P < 0.001). There was no difference with respect to cumulative bleomycin dose or exposure to supplemental oxygen. For patients aged over 40 years, especially those with renal function in the lower range of normal, the risk of developing fatal toxicity may exceed 10%. The benefits of bleomycin could be questioned for this age group.

Adult↗
PubMedDate not supplied

Differential expression of transforming growth factor-beta type I and II receptors by pulmonary cells in bleomycin-induced lung injury: correlation with repair and fibrosis.

In a rat model of lung injury induced by the antineoplastic antibiotic, bleomycin, there is loss of type I alveolar epithelial cells (AECs) followed by infiltration of activated inflammatory cells, type II AEC proliferation, and fibrosis. At 4 and 7 days after bleomycin administration alveolar macrophages have increased production and release of active transforming growth factor (TGF)-beta1, an inhibitor of epithelial cell proliferation. Paradoxically at these same time intervals there is a concomitant induction of type II AEC proliferation. For TGF-beta-mediated signal transduction to occur, the expression of both TCF-beta receptor types I (TbetaR-I) and II (TbetaR-II) must be present. Using immunohistochemistry and in situ hybridization, 4 and 7 days after bleomycin administration the expression of TbetaR-I on AECs was reduced whereas that of TbetaR-II was unaltered. However, 14 and 28 days after bleomycin injury, when there is decreased proliferation and induction of differentiation of type II AECs, there was a return of TbetaR-I expression on AECs. In contrast, TbetaR-I and TbetaR-II were observed on interstitial fibroblasts at all time intervals after bleomycin administration. Because both TbetaR-I and TbetaR-II are required for signal transduction, the reduction of TbetaR-I levels on the alveolar epithelium may alter the sensitivity of AECs to the antiproliferative effects of TGF-beta1 present in increased quantities following bleomycin injury. The loss of an antiproliferative response to TGF-beta1 may be important for the regeneration of the alveolar epithelium by proliferation while the expression of both receptors onfibroblasts would result in TGF-1 signaling for the synthesis of connective tissue proteins. Ourfindings suggest that during bleomycin-induced pulmonary fibrosis, the effects of TGF-beta1 on cells may be regulated by the expression of TbetaRs.

Activin Receptors, Type I↗
PubMed2003

Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours.

BACKGROUND: Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials of bleomycin in the 1960s. Postulated risk factors include cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised creatinine, older age and supplemental oxygen exposure. PATIENTS AND METHODS: From our prospectively collected testicular cancer research database, we reviewed 835 patients treated at the Royal Marsden NHS Trust (Sutton, UK) with bleomycin-containing regimens for germ-cell tumours between January 1982 and December 1999, to identify those with BPT. RESULTS: Fifty-seven (6.8%) patients had BPT, ranging from X-ray/CT (computed tomography) changes to dyspnoea. There were eight deaths (1% of patients treated) directly attributed to BPT. The median time from the start of bleomycin administration to documented lung toxicity was 4.2 months (range 1.2-8.2). On multivariate analysis, the factors independently predicting for increased risk of BPT were GFR <80 ml/min [hazard ratio (HR) 3.3], age >40 years (HR 2.3), stage IV disease at presentation (HR 2.6) and cumulative dose of bleomycin >300,000 IU (HR 3.5). CONCLUSIONS: Patients with poor renal function are at high risk of BPT, especially if they are aged >40 years, have stage IV disease at presentation or receive >300,000 IU of bleomycin. In such cases alternative drug regimens or dose restriction should be considered.

Adolescent↗
PubMed1992

Haemodynamic sequelae of pulmonary fibrosis following intratracheal bleomycin in rats.

OBJECTIVE: Intratracheal instillation of bleomycin in rats has been extensively used as an animal model of pulmonary fibrosis in humans, although it produces a patchy, airway based response. We proposed that the haemodynamic sequelae of the bleomycin model might be less severe than those associated with more diffuse lung injury. METHODS: Pulmonary and systemic haemodynamic indices were examined in adult Sprague-Dawley rats (approximately 400 g, n = 10) both at rest and during submaximal exercise on a rodent treadmill, approximately 60 days after intratracheal bleomycin (6 units.kg-1), and the results compared to a control group (n = 6). RESULTS: Compared to controls, mean pulmonary artery pressure (PPA) was increased by intratracheal bleomycin (p = 0.02) both at rest [24.5 (SEM 2.6) v 18.2(0.9) mm Hg] and during exercise [34.7(3.0) v 26.7(0.7) mm Hg]. PPA-pulse product was also increased, with a similar trend in right ventricular work index, but cardiac index was not altered. Right ventricular hypertrophy was noted on necropsy examination. Consistent with pulmonary fibrosis, lung dry weight, total protein, and hydroxyproline were also raised, and these values correlated strongly with (mean) PPA at rest (r2 = 0.86, 0.81, 0.69, respectively) and during exercise (r2 = 0.81, 0.79, 0.65, respectively). Packed cell volume was increased by intratracheal bleomycin, at 49(1) v 45(1)%, p = 0.02. CaO2 tended to decrease with exercise in the bleomycin group, although this was not statistically significant, while systemic oxygen delivery and consumption were not altered. CONCLUSIONS: Pulmonary hypertension and right ventricular hypertrophy occur in this model of lung fibrosis, and correlate with the severity of fibrosis. However, these sequelae were less severe than those previously demonstrated in association with crotalaria ingestion. We suggest that the haemodynamic sequelae of the intratracheal bleomycin model are consistent with patchy, airway based fibrosis, but reflect less well the haemodynamic sequelae of more diffuse fibrotic injury associated with systemic processes.

Animals↗
PubMed1983

Marker rescue from bleomycin-treated Chlamydomonas reinhardi.

A new method has been developed for gene transfer in eukaryotic cells. Chlamydomonas reinhardi, a unicellular eukaryotic alga, was treated with a lethal dose of bleomycin, an agent that induces chromosome breakage. Bleomycin-treated cells were mated with untreated cells, and the mixture was plated onto selective agar medium. The progeny that arose contained the genetic markers from the untreated parent plus a subset of the genetic markers from the bleomycin-treated parent. Those markers derived from the untreated parent were stable, whereas those recovered from the bleomycin-treated parent were often unstable. Markers closely linked in the bleomycin-treated parent were usually rescued or lost together, whereas distantly linked or unlinked markers were rescued or lost independently. These results suggest that bleomycin treatment of C. reinhardi leads to the formation of chromosome fragments, and fusion of bleomycin-treated cells to untreated cells results in the rescue of some of these fragments. This procedure provides a new means of gene transfer that may be useful for genetic mapping, genetic engineering and for the study of genetic organization.

Bleomycin↗
PubMed1996

Bleomycin resistance in Staphylococcus aureus clinical isolates.

Among clinical isolates of Staphylococcus aureus tested for resistance to the antibiotic bleomycin, 197 were found to be resistant; most of them were also resistant to tobramycin and contained plasmids. DNA dot-blot hybridization analysis of the bleomycin resistant isolates with an 171 bp probe derived from the plasmid pUB110 indicated that 43 strains (22%) carried pUB110-like bleomycin resistance DNA sequences. Analysis of bacterial cell lysates derived from the bleomycin resistant isolates indicated that many contained bleomycin-binding properties (BBP), that prevent DNA damage by the antibiotic. Of 13 strains that were analysed by DNA gel electrophoresis and Southern blot DNA hybridization, six were found to carry pUB110-like bleomycin resistance DNA sequences. These studies indicate that there may be more than one genetic determinant for bleomycin resistance in S. aureus whose DNA is protected.

Acetyltransferases↗
PubMed1988

Effect of various oxygenation conditions and fluosol-DA on cytotoxicity and antitumor activity of bleomycin in mice.

In an attempt to improve the antitumor efficacy of bleomycin, the effects of the oxygen-carrying emulsion Fluosol-DA and increased levels of inspired oxygen were tested in the mouse FSaIIC fibrosarcoma system. The dose-dependent cytotoxicity of bleomycin toward the FSaIIC cells in vitro was significantly decreased under hypoxic conditions, but it increased in a 95% O2-5% CO2 (carbogen) atmosphere as compared with the cytotoxicity of bleomycin in normally oxygenated cells. Investigations on the FSaIIC tumor in vivo also demonstrated that growth delays induced by bleomycin (10 mg/kg ip given on days 6, 10, 13, and 16) were significantly increased when one of the following treatments was given with each bleomycin injection: carbogen breathing for 2 hours (4.7 days), carbogen breathing for 6 hours (5.7 days), and breathing 3 atm of hyperbaric oxygen (6.3 days) versus normal air (3.3 days). When Fluosol-DA (12 mL/kg iv) was administered just before each bleomycin injection, the following growth delays were produced: 4.8 days with air breathing, 14.6 days with carbogen breathing for 2 hours, 14.9 days with carbogen breathing for 6 hours, and 19.7 days with breathing 100% O2 at 3 atm for 1 hour. Excision studies on the FSaIIC tumor also demonstrated that the cytotoxicity increased approximately fivefold when Fluosol-DA and carbogen breathing for 2 hours were combined with a single treatment with 10 mg of bleomycin/kg. In contrast, no measurable bone marrow toxicity was evident with this combined regimen. These results suggest that the use of Fluosol-DA plus carbogen breathing could add substantially to the clinical antitumor effects of bleomycin.

Animals↗
PubMed1983

Effect of bleomycin on lipid peroxides, glutathione peroxidase and collagenase in cultured lung fibroblasts.

Bleomycin-Cu(II) complex tended to increase the lipid peroxide level in cultured lung fibroblasts, though neither free bleomycin nor free cupric ion increased the level. Simultaneous addition of DL-alpha-tocopherol decreased the level significantly. Bleomycin-Cu(II) complex decreased glutathione peroxidase activity remarkably, though free bleomycin reduced the activity only slightly. Collagenase activity was not decreased but rather increased by both free bleomycin and bleomycin-Cu(II) complex. Accordingly, the accumulation of collagen induced by bleomycin could be explained not by a decrease in collagenase activity, but by the occurrence of cross-linking of collagen due to the increased lipid peroxides.

Bleomycin↗