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PubMed1983

Bleomycin interactions with DNA. Studies on the role of the C-terminal cationic group of bleomycin A2 in association with and degradation of DNA.

The role of the cationic dimethylsulfonium group of bleomycin A2 in the binding of the drug to poly(dA-dT) has been investigated by proton NMR studies on the S-demethylated derivative. In contrast to the parent drug, the demethyl congener shows no intercalation of the aromatic bithiazole group which is adjacent to the former cationic group. However, chemical studies show that the demethyl derivative retains the capability to degrade DNA in the presence of iron(II), albeit at a reduced rate and to a lesser extent than the intact bleomycin A2. Thus, the cationic group is necessary for the intercalation of the bithiazole portion of the drug molecule; however, intercalation is not essential for the degradation of DNA.

Animals↗
PubMed2003

Identification of the internal axial ligand of HO2-cobalt(III)-bleomycin: 1H[15N] HSQC NMR investigation of bleomycin, deglycobleomycin, and their hydroperoxide-cobalt(III) complexes.

The identity of the axial ligand contributed by the drug in hydroperoxide-Co(III)-bleomycin and hydroperoxide-Co(III)-deglycobleomycin has been in doubt. With each structure, a combination of (1)H[(15)N] HSQC and HMBC and (1)H COSY and NOESY NMR spectroscopy was used to observe and completely assign the nonaromatic (15)N chemical shifts of natural abundance bleomycin in the two hydroperoxide-Co(III) structures. Together with the (15)N assignments from a published 1D (15)N spectrum, the results permitted the assignment of the primary amine nitrogen to an axial ligand position in both structures.

Bleomycin↗
PubMed1983

Bleomycin analogues. Phenylthiazole models of the bithiazole moiety of bleomycin A2.

Amides of 2-phenylthiazole-4-carboxylic acid, 2'-phenyl-2,4'-bithiazole-4-carboxylic acid and 4,4'-biphenylcarboxylic acid containing the (3-aminopropyl)dimethylsulfonium chloride side chain of bleomycin A2 have been prepared and their binding to poly(dA-dT) has been studied by proton nuclear magnetic resonance spectroscopy. Both the phenylthiazole and phenylbithiazole derivatives exhibit high-field shifts for their hydrogens in the presence of the polynucleotide which are considerably larger than those observed in the analogous completely heterocyclic systems studied previously (Sakai, T.T.; Riordan, J.M.; Glickson, J.D. Biochemistry 1982, 21, 805). The intercalative nature of the binding of these analogues was further indicated by viscometric measurements using calf thymus DNA. The data show that a phenyl ring allows the aromatic systems to interact with the base pairs of the polynucleotide to a greater extent than a thiazole ring in the same position. Possible models for the interaction of these derivatives with DNA are considered. The hydrogens of the biphenyl derivative show an interaction that is substantially less than those observed in the heterocycle-containing systems, suggesting that the ring system is oriented improperly or that the ring system is nonplanar. The analogous phenyl (benzoyl) compound does not bind, showing the requirement for an extended aromatic system for intercalation. The utility of these observations for the design of possible synthetic analogues of the bleomycins is discussed. None of the derivatives exhibited toxicity when tested against L1210 leukemia cells in culture.

Animals↗
PubMed2006

Cryogenic photolysis of activated bleomycin to ferric bleomycin.

Activated bleomycin (ABLM) is a drug--Fe(III)-hydroperoxide complex kinetically competent in DNA attack (via H4' abstraction). This intermediate is relatively stable, but its spontaneous conversion to ferric bleomycin (Fe(III).BLM) is poorly characterized because no observable intermediate product accumulates. Light was shown to trigger ABLM attack on DNA in liquid at -30 degrees C, so ABLM was irradiated (at its 350 nm ligand-to-metal charge-transfer transition) at 77 K to stabilize possible intermediates. ABLM photolysis (quantum yield, Phi = 0.005) generates two kinds of product: Fe(III).BLM (with no detectable intermediate) and one or more minor (1-2%) radical O-Fe-BLM byproduct, photostable at 77 K. Adding DNA, even without its target H4', increases the quantum yield of ABLM conversion >10-fold while suppressing the observed radical yield. Since cryogenic solid-phase reactions can entail only constrained local rearrangement, the reaction(s) converting ABLM to Fe(III).BLM must be similarly constrained.

Amides↗
PubMed1999

The neutral cysteine protease bleomycin hydrolase is essential for epidermal integrity and bleomycin resistance.

The papain superfamily member bleomycin hydrolase (Blmh) is a neutral cysteine protease with structural similarity to a 20S proteasome. Bleomycin (BLM), a clinically used glycopeptide anticancer agent, is deaminated in vitro by Blmh. We used gene targeting to generate mice that lack Blmh and demonstrated that Blmh is the sole enzyme required for BLM deamination. Although some Blmh null mice were viable and reproduced, only about 65% of the expected number survived the neonatal period, revealing an important role for Blmh in neonatal survival. Mice lacking Blmh exhibited variably penetrant tail dermatitis that resembled rodent ringtail. The histopathology of the tail dermatitis was similar to skin lesions in humans with pellagra, necrolytic migratory erythema, and acrodermatitis enteropathica. Compared with controls, Blmh null mice were more sensitive to acute BLM lethality and developed pulmonary fibrosis more readily following BLM treatment. Thus, we have established that Blmh is an essential protectant against BLM-induced death and has an important role in neonatal survival and in maintaining epidermal integrity.

Aging↗
PubMed1996

Different conformations and site selectivity of HO-2-Co(III)-bleomycin A2 and Co (III)-bleomycin A2 bound to DNA oligomers.

Conformational properties of HO2(-)-Co(III)-bleomycin A2 (Form I) and Co(III)-bleomycin (Form II) bound to DNA oligomers offering either principal cleavage site for the drug, d(GGAAGCTTCC)2 or d(AAACGTIT)2, have been studied by NMR methods. Form I binds in slow exchange to these oligomers. It retains most of its solution nuclear Overhauser effects (NOEs) upon binding to either oligomer. Pyrimidinyl methyl protons from the metal domain of the drug make an NOE connection with a G5 2-amino proton on DNA. The bithiazole intercalates between base pairs involving either C6 and T7 or T6 and T7 of the two DNA molecules, according to NOE connections between the bithiazole protons and protons from these bases and changes in the positions of their chemical shifts. Form II also retains most of its solution NOEs upon association with the first oligomer. However, in contrast to Form I it binds to DNA in fast exchange on the NMR time scale over the temperature range of 5-35 degrees C and does not break the degeneracy of the DNA proton chemical shifts. No intermolecular NOEs between Form II and the 10-mer have been detected. Likewise, the major perturbation in chemical shift of the histidine H2 and guanine G5 protons seen in Form I-DNA adducts is absent in Form II-DNA. The association constant of Form II with d(GGAAGCTTCC)2 in 20 mM HEPES buffer at pH 7.4 and 25 degrees C is 1.7 x 10(5) M(-1), and 1.0 mol of Form II bind per mol of 10-mer.

Antibiotics, Antineoplastic↗
PubMed1997

Experience with bleomycin, etoposide, cisplatin (BEP) and alternating cisplatin, cyclophosphamide, doxorubicin (CISCA(II))/vinblastine, bleomycin (VB(IV)) regimens of chemotherapy in poor-risk nonseminomatous germ cell tumors.

Forty poor-risk patients with metastatic nonseminomatous germ cell tumors were treated with a chemotherapy regimen that consisted of either the BEP protocol (bleomycin + etoposide + cisplatin) or the CISCA(II)/VB(IV) regimen (cyclophosphamide + doxorubicin + cisplatin/vinblastine + bleomycin). There was no randomization. Among 17 patients who received the CISCA(II)/VB(IV) protocol, three early deaths, four primary failures, and 10 complete responses were observed. Two relapses and one acute myeloid leukemia were subsequently noted. Nine (53%) of 17 patients remain free of disease 15-38 months after the end of therapy. In the group of patients treated with the BEP regimen, one early death, one primary failure, one toxic death, one partial response, and 19 complete responses were observed. There were eight relapses. Sixteen (70%) of 23 patients remain free of disease 26-52 months after the end of therapy. Myelosuppression and mucositis were clearly more severe with the CISCA(II)/VB(IV) regimen. However, no septic death was registered, whereas one patient died of septic shock after the fourth cycle of BEP. Investigators of the Genitourinary Group of the French Federation of Cancer Centers have now embarked on a prospective randomized trial of BEP versus CISCA(II)/VB(IV) in poor-risk patients.

Adolescent↗
PubMed1998

Crystallization and preliminary X-ray diffraction studies of bleomycin-binding protein from bleomycin-producing Streptomyces verticillus.

A bleomycin-binding protein (BLMA) produced by bleomycin-producing Streptomyces verticullus was crystallized in a form suitable for X-ray diffraction analysis using the vapor-diffusion method. Crystals were grown at pH 5.7, in 0.2 M NH4 actate and 0.1 M Na acetate, using 30% PEG 4000 as a precipitant. They belong to the orthorhombic system, with space group P21212, cell dimensions a = 54. 90, b = 67.94, c = 35.60 A, and one BLMA molecule in the asymmetric unit. The crystals diffract X-rays well and the diffraction intensity data was collected up to 1.5 A resolution with a merging R value of 0.054 at beamline 6B of the Photon Factory. The diffraction data set is 94% complete.

Bacterial Proteins↗
PubMed1983

[Etretinate (Ro 10-9359, Tigason) and CCNU (1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea) and bleomycin versus CCNU and bleomycin in the treatment of advanced squamous cell carcinoma of the bronchus (Working group on Internal Medicine Oncology Study BS1/78)].

Forty-six evaluable patients with advanced squamous cell carcinoma of the lung were treated in a randomized fashion with either etretinate, CCNU and bleomycin in combination (ECB) or with CCNU and bleomycin (CB). There were no complete and no partial responses. Minor responses occurred in 5 patients (24%) with ECB and in 3 patients (12%) with CB independently of histological grade. No change was observed in 9 patients (43%) with ECB and in 13 patients (52%) with CB. There was no survival difference between the two groups. Reversible side-effects of skin and mucous membranes were more frequent under ECB. The antitumor efficacy of CB is marginal and could not be improved by the addition of the vitamin-A-derivative etretinate.

Adult↗
PubMed2003

Three cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or epirubicin, bleomycin, vinblastine, and methotrexate (EBVM) plus extended field radiation therapy in early and intermediate Hodgkin disease: 10-year results of a randomized trial.

From 1990 to 1996, a total of 386 adult patients with early/intermediate Hodgkin disease (HD) were randomly assigned to receive 3 cycles of adriamycin, bleomycin, vinblastine, dacarbazine (an alkylating agent), and methylprednisolone (ABVDm, arm A) or epirubicin, bleomycin, vinblastine, methotrexate, and methylprednisolone (EBVMm, arm E), a combination without alkylating agent. Responding patients received extended field radiation therapy (RT). Postchemotherapy complete remission and 10-year freedom from progression rates were higher in arm A (79.5% and 91.4%) than in arm E (70.4%, P =.04, and 80%, P <.002). HD mortality (HDM), treatment-related mortality (TRM), and overall survival (OS) were similar in both arms (A, 2.1%, 7.5%, and 90.4%; B, 3.9%, 5.5%, and 90.3%). However TRM and OS rates were lower in patients aged 40 years or older (P <.005), reflecting the increasing incidence of background fatal events with increasing age. Finally, event-free survival (EFS) was higher in arm A (84.6%) than in arm E (74.9%, P <.02). In patients aged younger than 40 years in arm A (74%), 10-year EFS and OS rates were 88.9% and 95.4% with HDM and TRM rates as low as 0.7% and 3%. Three courses of ABVDm plus RT are the best available option for treating early or intermediate HD.

Adolescent↗
PubMed2004

Severe pulmonary toxicity in patients with advanced-stage Hodgkin's disease treated with a modified bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, and gemcitabine (BEACOPP) regimen is probably related to the combination of gemcitabine and bleomycin: a report of the German Hodgkin's Lymphoma Study Group.

PURPOSE: To investigate a new effective, nonleukemogenic polychemotherapy regimen, BAGCOPP (bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone, gemcitabine) in a phase I/II dose-escalation study in patients with advanced-stage Hodgkin' s disease (HD). PATIENTS AND METHODS: Patients in clinical stages IIB with risk factors III and IV were enrolled in this nonrandomized, multicenter trial aimed at defining the maximum-tolerated dose of gemcitabine within a modified escalated BEACOPP regimen. Gemcitabine was given at a starting dose of 800 mg/m(2) on days 1 and 4 of each cycle. RESULTS: Twenty-seven patients (eight female, 19 male) were enrolled with a median age of 33 years (range, 19 to 65 years). Due to a higher than expected hematotoxicity, the day-4 application of gemcitabine was omitted after 14 patients were included and 59 cycles were given. A total of eight patients developed lung toxicity, mainly pneumonitis (six of eight), which led to the termination of the study. With a median follow-up of 27 months, 25 patients are in continuing complete remission. CONCLUSION: The substitution of etoposide by gemcitabine in the escalated BEACOPP schema is not feasible and leads to severe pulmonary toxicity. This toxicity is probably related to the concomittant application of gemcitabine and bleomycin.

Adolescent↗
PubMed1991

Interaction of bleomycin with deoxyribonucleic acid oligomer: proton nuclear magnetic resonance titration study using novel bleomycin complexes with Ni2+ and VO3+.

Two metal complexes of bleomycin (BLM), BLM-Ni2+ and BLM-VO3+ are used for studying interactions between BLM and deoxyribonucleic acid (DNA) by nuclear magnetic resonance. Although these BLMs do not mediate DNA strand scission under the usual conditions, they bind to DNA in the same manner as the active metal complexes of bleomycin (BLM-Fe2+ and BLM-Co3+). A self-complementary dodecanucleotide, d(CCCCAGCTGGGG), having a single site for cleavage was synthesized. d(CCCCAATTGGGG), which contains no -GpC- sequence, was also synthesized. The BLM-metal complexes were shown to bind specifically to the GpC site by circular dichroism and fluorescence titration studies. We assigned all the resonances for imino protons and phosphorus, and most of the nonexchangeable proton resonances of d(CCCCAGCTGGGG). No substantial change in the chemical shifts of these signals was observed upon titration with either BLM-Ni2+ or BLM-VO3+. This result is not consistent with a model of the strong intercalation of the BLMs between the base-pairs. The BLMs bind to DNA in a different manner, and DNA does not change its conformation upon binding with BLMs.

Base Sequence↗
PubMed1992

[Bleomycin emulsion for intralesional instillation in advanced oropharyngeal carcinomas. A case report on local bleomycin application].

Local therapy of head and neck cancer using a special bleomycin emulsion as an intratumoral applicarted cytotoxic agent is not established in regular antitumor therapy. It's use only is supposed to be regarded as an "ultima ratio" possibility when other usual methods like surgery, radiotherapy or systemic cytostatic therapy have failed. The procedure of intralesional bleomycin emulsion application will be described and the advantages and disadvantages will be discussed by means of a long-term case report.

Adult↗
PubMed1989

Characteristics of bleomycin-resistant phenotypes of human cell sublines and circumvention of bleomycin resistance by liblomycin.

Three bleomycin (BLM)-resistant sublines were isolated from a human head and neck squamous cell carcinoma cell line (A-253); these sublines (C-10, D-10, and G-11) were 4-, 9-, and 21-fold resistant to BLM A2, respectively. These sublines were selectively resistant to other members of the BLM class, namely BLM B2, peplomycin, talisomycin S10b, and bleomycinic acid; none of the sublines displayed cross-resistance to vincristine, doxorubicin, cis-diamminedichloroplatinum or melphalan; only one subline (G-11) was cross-resistant to X-irradiation. None of the BLM-resistant cell lines demonstrated resistance to the novel BLM analogue liblomycin, which contains a lipophilic terminal amine. The cell cycle distributions of the clonally derived BLM-resistant cell populations were similar to the distribution of the parental cell population. In vitro BLM hydrolase activity in homogenates of D-10 and G-11 BLM-resistant cell lines was two- to threefold higher than that in homogenates of A-253 or C-10 cells. Nonetheless, no deamido BLM A2 was found associated with any cell type or in the culture medium and more than 80% of the radioactivity in all cells appeared as unmetabolized BLM A2 by high pressure liquid chromatography. Thus, the appearance of large quantities of the deamido BLM metabolite was not a prominent feature of acquired resistance to BLM in these human tumor cells. The cellular accumulation of radiolabeled BLM A2 by C-10 and G-11 cells during a 1-h incubation with [3H]BLM A2 was 1/2 that seen with A-253 and D-10 cells. C-10 cells maintained a lower nuclear content of radioactivity than A-253, G-11, or D-10 cells. Initial single strand DNA damage, based upon alkaline elution analysis, also was lower in C-10 cells compared to A-253 cells. D-10 cells, in contrast, exhibited high initial genomic DNA damage but demonstrated a greater repair rate than either A-253 or C-10 cells. Thus, multiple BLM-resistant phenotypes can be obtained from a population of human squamous carcinoma cells, and modification of the terminal amine in the BLM molecule can produce compounds capable of circumventing all of these BLM-resistant phenotypes. Liblomycin, which appears to be a nonclassical BLM, may be a useful therapeutic agent with a spectrum of activity distinct from other members of the BLM class.

Antineoplastic Agents↗
PubMed2000

The 1.5 A crystal structure of a bleomycin resistance determinant from bleomycin-producing Streptomyces verticillus.

Bleomycin (Bm)-binding protein, designated BLMA, which is a Bm resistance determinant from Bm-producing Streptomyces verticillus, was crystallized in a form suitable for X-ray diffraction analysis. The diffraction intensity data were collected up to a resolution of 1.5 A with a merging R-value of 0.054 at a completeness of 94 %. The BLMA structure, determined by the single isomorphous replacement method including the anomalous scattering effect (SIR-AS) at a resolution of 2.0 A, was refined at 1.5 A resolution. The final R-factor was 19.0 % and R(free) was 22.1 % including 91 water molecules. The crystal packing showed a dimer form, which was generated by arm exchange. The 1.5 A high-resolution experiment allowed an analysis of the side-chain disorder of BLMA. The structural comparison of BLMA with a homologous protein from Streptoalloteichus hindustanus, designated Shble protein, showed that a Ser100-Gly103 loop was farther from the groove, which is a Bm-binding site, in BLMA than in the Shble protein. Furthermore the hydrophobicity of the groove in BLMA is much lower than that in the Shble protein. The structural differences between these proteins may be responsible for the observation that a half-saturating concentration (K(1/2)) of Bm is higher for BLMA than for the Shble protein.

Acetyltransferases↗
PubMed1994

Induction of bleomycin resistance in a human oral squamous carcinoma cell line and characterisation of bleomycin-resistant and -sensitive clones.

We examined the change of sensitivity to antitumour agents by repeated treatment with bleomycin (BLM) using two oral squamous carcinoma cell lines, SCCTF and SCCKN. SCCTF exhibited minimal sensitivity to BLM and strong heterogeneity in BLM sensitivity, whereas SCCKN was highly sensitive to BLM and showed weak heterogeneity. When SCCTF was treated continuously with low-dose BLM (0.1 microgram/ml) but not intermittently with high-dose BLM (1 microgram/ml), the BLM sensitivity was rapidly decreased to acquire drug resistance. On the other hand, SCCKN was completely killed by the same treatments. To investigate the mechanism of induction of resistance in SCCTF, BLM-sensitive and -resistant clones, TF-S and TF-R, were isolated and analysed. Consequently, TF-R showed decreased cellular accumulation and retention of BLM, increased BLM hydrolase activity and elevated DNA repair activity concomitant with increased poly(ADP-ribose) polymerase activity as compared with TF-S. Therefore, it was suggested that antitumour drug-resistant clones were selectively grown from heterogeneous tumour cell population.

Antineoplastic Agents↗
PubMed1999

Internalisation of the bleomycin molecules responsible for bleomycin toxicity: a receptor-mediated endocytosis mechanism.

Bleomycin (BLM) does not diffuse through the plasma membrane but nevertheless displays cytotoxic activity due to DNA break generation. The aim of the study was to describe the mechanism of BLM internalisation. We previously provided evidence for the existence of BLM-binding sites at the surface of DC-3F Chinese hamster fibroblasts, as well as of their involvement in BLM cytotoxicity on DC-3F cells and related BLM-resistant sublines. Here we report that A253 human cells and their BLM-resistant subline C-10E also possessed a membrane protein of ca. 250 kDa specifically binding BLM. Part of this C-10E cell resistance could be explained by a decrease in the number of BLM-binding sites exposed at the cell surface with respect to A253 cells. The comparison between A253 and DC-3F cells exposing a similar number of BLM-binding sites revealed that the faster the fluid phase endocytosis, the greater the cell sensitivity to BLM. Moreover, the experimental modification of endocytotic vesicle size showed that BLM cytotoxicity was directly correlated with the flux of plasma membrane area engulfed during endocytosis rather than with the fluid phase volume incorporated. Thus, BLM would be internalised by a receptor-mediated endocytosis mechanism which would first require BLM binding to its membrane receptor and then the transfer of the complex into intracellular endocytotic vesicles, followed by BLM entry into the cytosol, probably from a nonacidic compartment.

Animals↗
PubMed2001

Expression of thioredoxin in bleomycin-injured airway epithelium: possible role of protection against bleomycin induced epithelial injury.

Bleomycin (BLM) is an anticancer drug, administration of which leads to severe lung injury, in which the generation of intracellular reactive oxygen species (ROS) is thought to participate in that. Thioredoxin (TRX) has been found to function as a powerful antioxidant by reducing ROS, and thus protecting against ROS-mediated cytotoxicity. However, a protective role of TRX in BLM-induced lung injury has not been determined. In the present study, we therefore attempted to clarify this issue. Human TRX-transfected L929 murine fibrosarcoma cells were more resistant to BLM-induced cytotoxicity than the parental and the control transfected cells, indicating that TRX plays the protective role in BLM-induced cytotoxicity. Next, we examined TRX expression in the lung of in vivo model of BLM-induced lung injury and BLM-stimulated bronchial epithelial cells in vitro to clarify the role of TRX in BLM-induced lung injury. In the lungs of BLM-treated mice, the expression of TRX was strongly induced in bronchial epithelial cells. TRX expression was also up-regulated at both the mRNA and protein levels in cultured BEC with the treatment with BLM. However, the expression of other major antioxidants, such as Cu/Zn-SOD, Mn-SOD, catalase and glutathione peroxidase, was not affected by BLM. These observations suggest that the cellular reduction and oxidation (redox) state modified by TRX is involved in the BLM resistancy and the induction of TRX in bronchial epithelial cells might play a protective role in BLM-induced lung injury.

Animals↗