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PubMed1996

Alterations in surfactant neutral lipid composition during the development of bleomycin-induced pulmonary fibrosis.

The purpose of this investigation was to correlate changes in the neutral lipids of pulmonary surfactant with previously observed changes in surfactant phospholipids and lung compliance in the rat model of bleomycin-induced pulmonary fibrosis. Bronchoalveolar lavage fluid (BAL) obtained at 0, 1, 3, 7, 14, 30 and 120 days after transtracheal instillation of bleomycin was used as a source of surfactant lipids. The mean concentration of neutral lipids in normal BAL was 439 nmol/lung and was composed of 55% cholesterol (CHO), 27% cholesterol ester (CE) and 19% free fatty acids (FFA). CHO was elevated at 1 day, reaching a maximum 4-fold increase in concentration at 14 days before subsiding to normal at 120 days. In contrast to CHO, CE and FFA were significantly reduced at 1 day after bleomycin with FFA below detectable levels. However, both these species were twice normal levels at 3-30 days before returning to normal at 120 days. The fatty acid composition of CE did not change; however, unsaturated fatty acids were significantly increased in FFA between 3 and 120 days. The data indicate that there are significant alterations in the neutral lipid composition of pulmonary surfactant at various stages of bleomycin induced lung injury. The significance of these changes are not fully understood; however, the possibility exists that an abnormal surfactant results which in turn affects lung function.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1978

Inhibition of replicative DNA synthesis and induction of unscheduled DNA synthesis in permeable sarcoma cell by bleomycin.

Unscheduled DNA synthesis was induced by bleomycin in isolated rat liver nuclei and in permeable mouse ascites sarcoma cells. ATP significantly enhanced the bleomycin effect of inducing unscheduled DNA synthesis. Replicative DNA synthesis in permeable mouse ascites sarcoma cells was inhibited by bleomycin. The apparent inhibition or stimulation by bleomycin of in vitro DNA synthesis was thought to be determined by a balance between inhibited DNA replicase activity and induced unscheduled DNA synthesis.

Animals↗
PubMed1983

Identification of a key structural feature of cobalt(III)-bleomycins: an exogenous ligand (e.g. hydroperoxide) bound to cobalt.

A series of cobalt(III) complexes of the anticancer antibiotic bleomycin has been prepared. Mass spectrometry and enzymatic analysis show that the green cobalt-bleomycin complex contains a hydroperoxide (-OOH) group bound to cobalt with unusual stability. Under appropriate conditions, cobalt-bleomycins containing other monodentate ligands to cobalt can be formed; fast-atom bombardment mass spectra of such complexes show peaks for cobalt-bleomycin at the expected mass, and also peaks for the intact complexes at the required higher mass.

Bleomycin↗
PubMed1983

Bleomycin-metal interaction: ferrous iron-initiated chemiluminescence.

Chemiluminescence often accompanies the spontaneous degradation of intermediates in an electronically excited state. The interaction of iron with bleomycin results in the activation of bleomycin to a reactive intermediate which can alter DNA or undergo self-inactivation. This report demonstrates that the interaction of ferrous iron with bleomycin results in chemiluminescence, that this response is iron-specific and that the presence of DNA prevents the generation of chemiluminescence. These observations suggest that the activated bleomycin intermediate may be in an electronically excited state.

Animals↗
PubMed1987

Ferrous iron-mediated enhancement of DNA damage and recovery potential in bleomycin-treated human cells.

Damage to cellular DNA is generally considered to be responsible for the antitumour activity of bleomycin. In view of the ferrous oxidase properties of the drug, ferrous iron supply has been manipulated to enhance bleomycin-induced DNA cleavage so that the relationship between the initial yield of DNA damage and cell survival could be explored in a human transformed fibroblast cell line. Bleomycin-induced DNA strand breaks were quantitated by either alkaline denaturation or neutral nucleoid sedimentation techniques. Exogenously supplied ferrous iron greatly enhanced the initial frequency of frank DNA strand breaks and alkali-labile lesions without affecting gross cellular repair capacity. Despite the increased levels of DNA damage, the presence of ferrous iron (greater than 3 microM) significantly increased (factor up to 2-fold; P less than 0.05) the survival capacity of drug-treated cells. It is concluded that the induction of DNA damage which can promote cellular recovery may contribute to the variability of the in vivo efficacy of bleomycin.

Bleomycin↗
PubMed1989

Substrate specificity of bleomycin hydrolase.

Bleomycin (BLM) hydrolase is believed to protect both malignant and normal tissue from the toxicity of the antitumor drug BLM. Little is known about the substrate specificity of BLM hydrolase. Thus, we developed ion-paired reverse phase high speed liquid chromatography systems to assay for the metabolism of several BLM analogs. We found that BLM A2, BLM B2, tallysomycin S10b (TLM S10b), peplomycin (PEP), butylamino-3-propylamino-3-propylamine bleomycin (BAPP), deglyco bleomycin A2 (dgBLM A2) and bleomycinic acid were each metabolized by rabbit lung BLM hydrolase to a single metabolite. When compared to their corresponding parent compounds, these metabolites were 6- to 35-fold less potent in their ability to inhibit the proliferation of A-253 human head and neck squamous carcinoma cells in culture. Furthermore, we found that substitutions in various regions of the BLM molecule greatly affected the kinetic parameters of BLM hydrolase. For example, the Km with BLM B2 (0.056 +/- 0.005 mM) was 15-fold lower than that seen with BLM A2 (0.83 +/- 0.11 mM). In contrast, the Vmax was not affected markedly by these terminal amine substitutions but was influenced greatly by deletion of the carbohydrate groups of BLM. For example, a 4-fold higher Vmax was observed with dgBLM A2 compared to BLM A2. Thus, these results demonstrate that BLM hydrolase can recognize and metabolize a broad spectrum of BLM analogs regardless of their structural features. This enzymatic conversion resulted in the inactivation of the BLMs as demonstrated by a substantial decrease in their cytotoxicity. Furthermore, the terminal amine and carbohydrate regions, respectively, dictate the apparent affinity and the rate of metabolism of BLM hydrolase substrates.

Animals↗
PubMed1989

Activity of bleomycin in iron- and copper-deficient cells.

Three models were used to examine the requirement of bleomycin (Blm) for iron (Fe) to carry out its antitumor or cytotoxic activity. Mice were made iron deficient by dietary means. Animals with depressed iron stores in liver and low plasma and ascites fluid iron supported Ehrlich tumor growth as well as mice maintained on a control diet. Bleomycin was equally effective against this tumor in iron-deficient mice as it was against the tumor in iron-sufficient controls. Likewise, nutrient copper deficiency did not change the efficacy of the drug. Ehrlich cells in culture were treated with a non-growth inhibiting concentration of the chelating agent, 1,10-phenanthroline before or during their exposure to bleomycin. Again, the treated cells were as sensitive to drug as controls, despite the fact that this ligand reduces cellular iron and zinc and can extract iron from Fe(II)Blm. Lastly, it was demonstrated that iron-depleted Euglena gracilis cells growing at reduced rates were as sensitive to growth inhibition by bleomycin as control cells.

Animals↗
PubMed1981

Studies on the effects of the antitumor agent camptothecin and derivatives on DNA. Camptothecin potentiated cleavage of DNA by bleomycin in vitro.

Addition of sodium camptothecin (2a, Fig. 1) in comparable low concentrations to the glycopeptide antitumor antibiotic bleomycin (BLM) leads to enhanced rates of single-strand scission of PM2-covalently closed circular DNA, whereas sodium camptothecin alone has no effect. A similar enhancement of DNA scission by sodium camptothecin is produced with the 1 : 1 bleomycin-iron complex alone or in conjunction with NADPH as an additional reductant. The interpretation that camptothecin may substitute for the reducing requirement of the antibiotic is supported by its oxidation at 37 degrees C by the 1 : 1 bleomycin iron complex, by iron salts or more efficiently by hydrogen peroxide to the known hemiacetal (3, Fig. 1). Electrochemical studies of 2a, its analogues and selected model compounds established that the alpha-pyridone ring D is most susceptible to a one-electron reduction at a reversible potential of -0.95 +/- 0.01 V. The reduced camptothecin is a transient species readily capable of donating an electron. This process may by compatible with a coupled reduction of the sequestered Fe(III) in the glycopeptide antibiotic necessary for the expression of antibiotic and antitumor properties. The results may provide a mechanistic rationale for the observed potentiation of the antitumor activity of bleomycin by camptothecin in vivo.

Bleomycin↗
PubMed1984

The effect of bleomycin on DNA in Escherichia coli K12 cells.

In Escherichia coli cells treated to reduce colony-forming ability to about 10%, bleomycin causes fewer than six randomly located DNA single-strand breaks or three double-strand breaks per genome. This is many fewer than produced by strand-breaking agents such as ionizing radiations in cells with similar loss of colony-forming ability. Bleomycin treatment to this level of colony-forming ability does affect the intracellular DNA, as shown by a change in the sedimentation rate of the chromosomal structure found in lysates made with sodium dodecyl sulfate. Bleomycin may act on only a limited part of the chromosome of such cells, perhaps the part associated with the outer cell membrane, or it may make strand breaks that are less repairable than those formed by ionizing radiations. Extensive DNA degradation in heavily treated cells (colony-forming ability 1% or less) could be from the action on DNA of bleomycin entering freely through membranes which are no longer intact, or from enzymatic degradation in heavily damaged cells.

Bleomycin↗
PubMed1988

A biphasic nature of the bleomycin-mediated degradation of DNA.

The bleomycin-mediated digestion of DNA in the presence of ferrous ion, molecular oxygen, and dithiothreitol is characterized by a fast initial reaction, which is followed by a much slower process. The fast degradation is due to the fast activation of the bleomycin-Fe(II) complex and the subsequent fast reaction of the activated complex with DNA. The rate determining step for the slow process is reactivation of the bleomycin-Fe(III) complex. The apparent rate constants for both reactions increase with increasing ionic strength. The latter, unusual results are interpreted in terms of inhibition of bleomycin turnover by binding of cationic species with DNA at low ionic strength.

Bleomycin↗
PubMed1984

Radioiodinated bleomycin: stoichiometry of iodination and structural characterization by 1H-nuclear magnetic resonance.

Bleomycin was iodinated by reaction with iodine monochloride (ICl). A direct relationship was found to exist between the average number of iodine atoms bound per molecule of bleomycin and the ICl: bleomycin molar ratio. Characterization by 1H-NMR analysis denoted that mono, di-, tri- and tetraiodobleomycin are formed when the reacting molar ratios, respectively, are 2:1, 4:1, 6.8:1 and 8.5:1 or greater. The sites of iodination of the bleomycin molecule have been identified to be the imidazole ring which iodinates first, followed by the bithiazole ring system which iodinates last.

Bleomycin↗
PubMed1987

Calmodulin antagonist W 13 prevents DNA repair after bleomycin treatment of human urological tumor cells growing on extracellular matrix.

1. The combined application of DNA strand-scission agents (bleomycin) and inhibitors of recovery from lethal damage (calmodulin antagonist W-13) could be a novel and potentially important approach to cancer therapy. 2. As determined by alkaline elution, both DNA-DNA and DNA-protein cross-links in bleomycin-treated cells were revealed by the presence of the proteinase K assay. 3. This lethal effect could be potentiated by the addition of calmodulin antagonist W-13 that prevents the repair of DNA strand breaks and DNA cross-links caused by bleomycin. 4. The results indicated that combinations of bleomycin and W-13 were more effective than treatment with either single agent. Isobologram analysis suggests synergistic effect of these drugs. 5. Therefore, the rational use of combinations of DNA-strand-scission agents and inhibitors of recovery from lethal damage based on mechanistic considerations should result with improved therapeutic regimens for the treatment of cancer.

Bleomycin↗
PubMed1989

Stimulatory effect of phosphate, ATP and ADP on iron transfer from Fe(III)-bleomycin to apotransferrin.

1. The rate of ferric ion transfer from Fe(III)-bleomycin to apotransferrin was increased in the presence of orthophosphate, ATP and ADP, while AMP was without effect. 2. Ortho phosphate activation probably involves formation of a Fe(III)-bleomycin-phosphate complex. The optical absorption of Fe(III)-bleomycin at 450 nm is enhanced in the presence of phosphate. 3. ATP and ADP remove the ferric ion from the iron-drug complex; thus making the ferric ion readily available for uptake by apotransferrin. 4. Low concentrations of ATP, ADP and AMP, also enhance the 450 nm absorption of the iron-drug complex. Higher ATP and ADP concentrations reduce both the 450 and 384 nm absorption of Fe(III)-bleomycin.

Adenosine Diphosphate↗
PubMed1985

The response of normal and ataxia-telangiectasia cells to bleomycin: relationships between chromosome damage, cell cycle delay and cell killing.

In agreement with our earlier observation (Scott and Zampetti-Bosseler, 1982) on X-irradiated normal and ataxia-telangiectasia (A-T) fibroblasts, we now report that after bleomycin or neocarzinostatin treatment also, A-T cells exhibit less G2 delay than normal cells. We confirm that A-T cells sustain more chromosome damage and lethality than normal cells after bleomycin. These observations support the hypothesis (Painter and Young, 1980) that A-T cells are defective in the recognition of certain lesions which normally lead to delays in progression through the cell cycle, during which they are repaired, and which, if unrepaired, lead to cell-lethal chromosome damage. However, we find that after bleomycin, as opposed to X-rays, the contribution of this type of lesion to cell death is minimal. The predominant lesions leading to cell death after bleomycin are not manifested at chromosome aberrations and do not lead to G2 delay or DNA-synthesis inhibition. A-T cells are defective in the recognition and/or repair of both types of lesion.

Ataxia Telangiectasia↗
PubMed1989

Cytogenetical characterization of Chinese hamster ovary X-ray-sensitive mutant cells xrs 5 and xrs 6. III. Induction of cell killing, chromosomal aberrations and sister-chromatid exchanges by bleomycin, mono- and bi-functional alkylating agents.

Two X-ray-sensitive mutants of CHO-K1 cells, xrs 5 and xrs 6, were characterised with regard to their responses to genotoxic chemicals, namely bleomycin, MMS, EMS, MMC and DEB for induction of cell killing, chromosomal aberrations and SCEs at different stages of the cell cycle. In addition, induction of mutations at the HPRT and Na+/K+ ATPase (Oua) loci was evaluated after treatment with X-rays and MMS. Xrs 5 and xrs 6 cells were more sensitive than wild-type CHO-K1 to the cell killing effect of bleomycin (3 and 13 times respectively) and for induction of chromosomal aberrations (3 and 4.5 times). In these mutants a higher sensitivity for induction of chromosomal aberrations to MMS, EMS, MMC and DEB was observed (1.5-3.5 times). The mutants also showed increased sensitivity for cell killing effects of mono- and bi-functional alkylating agents (1.7-2.5 times). The high cell killing effect of X-rays in these mutants was accompanied by a slight increase in the frequency of HPRT mutation. The xrs mutants were also more sensitive to MMS for the increased frequency of TGr and Ouar mutants when compared to wild-type CHO-K1 cells. Though bleomycin is known to be a poor inducer of SCEs, an increase in the frequency of SCEs in xrs 6 cells (doubling at 1.2 micrograms/ml) was found in comparison to no significant increase in xrs 5 or CHO-K1 cells. The induced frequency of SCEs in all cell types increased in a similar way after the treatment with mono- or bi-functional alkylating agents. MMS treatment of G2-phase cells yielded a higher frequency of chromatid breaks in the mutants in a dose-dependent manner compared to no effect in wild-type CHO-K1 cells. Treatment of synchronised mutant cells at G1 stage with bleomycin resulted in both chromosome- and chromatid-type aberrations (similar to the response to X-ray treatment) in contrast to the induction of only chromosome-type aberrations in wild-type CHO-K1 cells. The frequency of chromosomal aberrations chromosome and chromatid types) also increased with MMC treatment in G1 cells of xrs mutants. DEB treatment of G1 cells induced mainly chromatid-type aberrations in all cell types. The possible reasons for the increased sensitivity of xrs mutants to the chemical mutagens studied are discussed and the results are compared to cells derived from radiosensitive ataxia telangiectasia patients.

Alkylating Agents↗
PubMed1989

Correlation between the anti-oxidant enzyme activities of blood fractions and the yield of bleomycin-induced chromosome damage.

The concentration of the anti-oxidant enzymes catalase (CAT), peroxidases (POD) and superoxide dismutases (SOD) in different blood fractions, and the chromosomal sensitivity of lymphocytes to bleomycin-induced free radicals (expressed as frequency of dicentrics per bleomycin dose) were analyzed in 10 normal human donors. Our results demonstrate that the physiological concentration of the enzymes as well as the chromosomal sensitivity exhibited a wide interindividual variability. An inverse correlation between chromosomal sensitivity to bleomycin and SOD concentration in whole blood, plasma and red cells was found. On the other hand, no correlation between the yield of bleomycin-induced dicentrics and the concentration of CAT or POD was detected in any of the blood fractions analyzed. These findings suggest that the concentration of SOD may play an important role in the cellular susceptibility to DNA damage by free radicals.

Adult↗
PubMed1994

Anticlastogenic effects of galangin against bleomycin-induced chromosomal aberrations in mouse spleen lymphocytes.

Galangin, a flavonoid derivative, was tested for its anticlastogenic effect against the induction of chromosome aberrations by bleomycin. For an in vitro assay, galangin (0, 2 x 10(-8), 2 x 10(-7), and 2 x 10(-6) M) was added to mouse spleen lymphocyte cultures together with bleomycin (3 microgram/ml) at 24 h after Con A initiation of cultures. In an in vivo/in vitro experiment, galangin (0, 0.1, 1, 10, and 100 mg/kg) was administered to mice orally twice with a 24-h interval. Mice were killed 8 h later. Spleen lymphocytes were isolated and cultures were made. Bleomycin (3 microgram/ml) was added to the mouse spleen lymphocyte cultures at 24 h after Con A initiation. Both in vitro and in vivo/in vitro cultures were harvested at 42 h after initiation. The harvested cells were used for cytogenetic analyses. The results showed that in vitro or in vivo treatment of lymphocytes with galangin suppressed the induction of chromosome aberrations by bleomycin in a galangin dose-dependent manner. The galangin doses used were non-clastogenic to cells. The data from our in vitro and in vivo/in vitro studies confirmed each other and indicate that galangin is an anticlastogenic agent. The in vivo/in vitro protocol may be a useful means to assay the chemoprotective effects of chemicals in humans.

Animals↗
PubMed1994

Potentiation of bleomycin by the aminothiol WR-1065 in assays for chromosomal damage in G0 human lymphocytes.

The aminothiol radioprotector WR-1065 potentiates the induction of chromosome aberrations and micronuclei by the chemotherapy drug bleomycin in G(0) human lymphocytes. Potentiation by 5 mM WR-1065 was observed at bleomycin concentrations from 0.1 to 100 micrograms/ml in a 2-h treatment. The frequencies of micronuclei induced by bleomycin in the presence of WR-1065 reached that of 500-fold higher concentrations of bleomycin alone. The potential therapeutic implications of these findings are discussed.

Adult↗