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PubMed1982

Labelled bleomycin as a tumour-localizing agent. II. The effect of dose loading of the different forms of 57Cobalt-bleomycin A2, B2, and pepleomycin on the tissue distribution and tumour uptake in tumour-bearing rats.

The different forms of 57cobalt-bleomycin (57C0-blm) A2 and B2 as well as 57Co-pepleomycin (57Co-pep), were investigated in tumour-localizing properties of both forms of 57Co-blm are identical if 57Co-blm is injected as a bleomycin solution without carrier cobalt. Differences between the biological behaviour of the various cobalt complexes (which differ in ligand arrangement) were found if these complexes were injected together with inactive cobalt bleomycin complexes of the same form. In this case Co-blm B2 form I and Co-pep form I localize better than Co-blm b2 form II and Co-pep form II respectively. Such a decrease in uptake by the tumour, compared with form I, was not observed for Co-blm A2-II.

Absorption↗

PubMed1982

Bleomycin pulmonary toxicity: production of fibrosis by bithiazole-terminal amine and terminal amine moieties of bleomycin A2.

We have previously demonstrated that endotracheal administration of the terminal amines of several bleomycins, when administered as the free amines, produce pulmonary fibrosis of severity comparable to the intact drug. In the present report, bleomycin A2 and its sulfonium ion-containing terminal substituents, with and without the bithiazole rings, were administered to mice endotracheally. The incidence and severity of epithelial metaplasia was greater with the intact drug in comparison to the terminal substituents. In contrast, the terminal substituents and intact drug produced similar degrees of fibrosis. These results underscore the importance of the variable bleomycin terminal substituents in the pathogenesis of pulmonary fibrosis.

Animals↗

PubMed1987

Bleomycin-induced pulmonary nodules: a variant of bleomycin pulmonary toxicity.

Bleomycin has been associated with pulmonary toxicity which is typically manifested as an interstitial pneumonitis resulting in fine, diffuse reticular or reticulomicronodular infiltrates. Attention is drawn to an additional radiologic appearance where discrete pulmonary nodules are seen and representative of bleomycin-induced change. The pitfalls of interpreting such changes as toxic effects versus metastatic disease and proposed mechanisms of bleomycin pulmonary toxicity are discussed.

Adolescent↗

PubMed2002

Structures of HO(2)-Co(III)bleomycin A(2) bound to d(GAGCTC)(2) and d(GGAAGCTTCC)(2): structure-reactivity relationships of Co and Fe bleomycins.

HO(2)-Co(III)bleomycin is a model for HO(2)-Fe(III)bleomycin, which initiates single and double strand cleavage of DNA. In order to enlarge the understanding of its structure and reactivity, three-dimensional structures of HO(2)-Co(III)bleomycin bound to two DNA oligomers, d(GAGCTC)(2) (I) and d(GGAAGCTTCC)(2) (II), that have 5'-GC-3' binding sites, have been determined by nuclear magnetic resonance (NMR) methods. Besides previously recognized determinants of binding selectivity, a probable hydrogen bond was detected between the pyrimidinyl acetamido NH(2) and the carbonyl of cytosine base paired to G at the recognition site. Another hydrogen bond between the NH of the dimethylsulfonium R group and N7 of guanine opposite cytosine at the GC site may contribute to specification of the pyrimidine. Substitution of G with inosine shifted HO(2)-Co(III)Blm A(2)[bond]I and Fe(III)Blm[bond]I into fast exchange on the NMR time scale, supporting the role of the 2-amino group in site specification for each molecule. The conformationally stable metal-domain linker established a close-packed adduct with the minor groove in which the hydroperoxide ligand occupies a sterically constrained pocket that is isolated from the solvent. The hydroperoxide group is directed toward one of the two cytosine H4' hydrogens but is sterically blocked from access to the other by the drug. These findings enlarge the structural understanding of selective binding of Co(III)/Fe(III)Blm species at G-pyrimidine sites. They also rationalize the instability of a number of ligands bound to Co(III)/Fe(III)Blm at specific binding sequences and the relative unreactivity of Fe(III)Blm[bond]I with ascorbate as well as its lack of interaction with spin labels.

Antibiotics, Antineoplastic↗

PubMed1999

Metal complexes of bleomycin: evaluation of [Rh-105]-bleomycin for use in targeted radiotherapy.

Bleomycin has been used as a carrier for several radioisotopes; however, its potential for clinical use has been limited either by the in vivo stability of the complexes or the half-life of the isotope used. The chemical, biological, and radiological properties of 105Rhodium appear to make it an ideal choice for targeted radiotherapy. The synthesis and purification of a hereto unreported 105Rhodium-bleomycin (105Rh-BLM) complex is described. The stability of this complex in plasma is sufficient to allow targeted delivery of the radioisotope. 57Cobalt-bleomycin was studied under identical conditions for comparative purposes. The suitability of 105Rh-BLM for targeted therapy, which appears to be limited by the renal clearance of this agent, is discussed.

Animals↗

PubMed1982

Models of bleomycin interactions with poly(deoxyadenylylthymidylic acid). Fluorescence and proton nuclear magnetic resonance studies of cationic thiazole amides related to bleomycin A2.

The interaction of eight 2-substituted thiazole-4-carboxamides, structurally related to cationic terminus of bleomycin A2, with poly(deoxyadenylylthymidylic acid) [poly(dA-dT)] has been studied by using proton nuclear magnetic resonance and fluorescence spectroscopy. These analogues have been used as probes of the complex formed between the parent drug molecule and poly(dA-dT). Aliphatic substituents on the 2' position of 2,4'-bithiazole derivatives restrict the ability of the aromatic ring system to intercalate in the double-helical form of the polynucleotide. Absence or partial removal of the 2' substituent enhances intercalation of the bithiazole system. The cationic side chain does not appear to be involved in the stabilization of any of these complexes, although it may be necessary for their formation. A 2,4':2',4"-terthiazole derivative shows a substantial degree of intercalation which is accompanied by extensive immobilization of the cationic side chain. This suggests that insertion of the aromatic system into the nucleic acid causes the cationic side chain to be pulled in also. Monothiazole analogues do not appear to bind, indicating that at least two thiazole rings are necessary for binding or that proper spacing between the two side chains on either side of the thiazole system is important for binding. The relation of the interactions of these analogues to the biochemical and biological properties of the parent bleomycins is discussed as is the possible use of these data in the design of synthetic bleomycin derivatives having varying affinities and specificities for DNA.

Bleomycin↗

PubMed1983

Studies on bleomycin-DNA and bleomycin-iron interactions.

The bleomycins, a group of antitumor antibiotics (Figure 1), cause the degradation of DNA by a process requiring iron(II) and dioxygen (1,2). DNA degradation appears to involve two steps: association of the drug with the nucleic acid and degradation of the DNA. As part of studies directed toward achieving an understanding of how the bleomycins degrade DNA, we have examined various properties of the drug using a variety of chemical and physico-chemical techniques, including NMR and Mössbauer spectroscopy. We have studied both the interaction of the antibiotic with its target (DNA) as well as its association with its metal ion cofactor. This work has been performed on the intact drug and its derivatives as well as on synthetic models of the parent drug. This paper reviews and updates the recent work from this laboratory on the bleomycins.

Binding Sites↗

PubMed1988

Phase II studies of bleomycin, cyclophosphamide, doxorubicin and cisplatin, and bleomycin and cisplatin in advanced cervical carcinoma.

In a randomized phase II trial of two cisplatin-based chemotherapy regimens, 45 patients with advanced cervical carcinoma received a combination of bleomycin, cyclophosphamide, doxorubicin, and cisplatin (BCAP), and 45 others received bleomycin plus cisplatin (BP). BCAP was repeated every 4 weeks, and BP was given at 3-week intervals. Although 19 of 43 (44%) evaluable patients receiving BCAP and 16 of 42 (38%) evaluable patients receiving BP experienced tumor regression, only 22% of those receiving BCAP and 21% of those on BP survived 1 year after beginning treatment. Among bidimensionally measurable patients, 15 of 27 (56%) and 8 of 25 (32%) receiving BCAP and BP, respectively, achieved tumor regression. One patient died of bleeding resulting from severe myelosuppression on BCAP, and two others succumbed to pulmonary toxicity of bleomycin on the BP regimen. Although active against cervical carcinoma, these regimens have limited therapeutic value at this advanced stage of the disease.

Adult↗

PubMed1994

Inactivation of bleomycin by an N-acetyltransferase in the bleomycin-producing strain Streptomyces verticillus.

Bleomycin-producing Streptomyces verticillus ATCC15003 possesses a bleomycin acetyltransferase which inactivates the drug in the presence of acetyl coenzyme A. The site of acylation in enzymically prepared acetylbleomycin A2 was determined by nuclear magnetic resonance analysis; the primary amino group of the beta-aminoalanine moiety of bleomycin was acetylated Acetylbleomycin A2 had no detectable antibacterial activity and did not induce in vitro DNA degradation.

Acetyltransferases↗

PubMed1976

Bleomycin in advanced squamous cell carcinoma: a random controlled trial. Report of Medical Research Council Working Party on Bleomycin.

Bleomycin was compared with conventional cytotoxic drugs in the treatment of 70 patients with advanced squamous cell carcinoma; the primary deposit was in the head and neck in 50 patients and in the perineum or skin in 20. Thirty-four patients received bleomycin while 36 received other cytotoxic drugs. No significant difference was detected between the two groups either in the proportion showing tumour regression or in the survival rates. If bleomycin is to advance the treatment of squamous cell carcinoma it can be only in combination with other drugs or with radiotherapy.

Adult↗

PubMed1983

[Comparative study of 2 chemotherapy induction protocols. Cisplatinum-methotrexate-bleomycin and oncovin-methotrexate-bleomycin].

A prospective randomized study was conducted in 77 patients with stages III and IV epidermoid carcinomas of the buccal cavity, oropharynx, and pharyngolaryngeal regions to compare effects of two induction chemotherapy regimens: cisplatinum, methotrexate, bleomycin, and oncovin, methotrexate, bleomycin. Tumoral response and complications were analyzed as a function of the regimen, the tumoral site, and the stage. Chemotherapy including cisplatinum provided a tumoral response in 58.8 p.cent of stage III pharyngolaryngeal epitheliomas as against 38.4 p.cent with oncovin, methotrexate, bleomycin, but with a higher frequency of complications.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1984

A new tumor imaging agent--111In-bleomycin complex. Comparison with 67Ga-citrate and 57Co-bleomycin in tumor-bearing animals.

We have found a new 111In-bleomycin complex (BLMC), which has high affinity to tumor, does not bind to transferrin and is stable in vivo. Distribution in animals bearing glioma, hepatoma, or mammary adenocarcinoma at 48 hours showed: the ratios of tumor to blood, brain, heart, lung, liver, pancreas, stomach, and femur were 1.4-22.4 times as high for 111In-BLMC as for 67Ga-citrate. In mammary adenocarcinoma, 111In-BLMC bound more to viable and 57Co-Bleomycin (BLM) more to necrotic tumor. In viable tumor, the concentration of 111In-BLMC was similar to that of 57Co-BLM. The ratios of tumor to stomach and pancreas were higher, to blood, brain, muscle, heart, and femur were lower for 111In-BLMC than those for 57Co-BLM. The ratios of tumor to lung, liver, spleen, skin, and kidney were similar for the two compounds. Tumors were imaged more distinctly with the new 111In-BLMC and 57Co-BLM than with 67Ga-citrate. 111In-BLMC is promising for tumor imaging.

Animals↗

PubMed1994

Randomized study for the treatment of adult advanced Hodgkin's disease: epirubicin, vinblastine, bleomycin, and dacarbazine (EVBD) versus mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD).

Seventy patients with previously untreated advanced Hodgkin's disease and without bulky disease were entered in a prospective randomized clinical trial comparing epirubicin in combination with vinblastine, bleomycin, and dacarbazine (EVBD) with a regimen containing mitoxantrone, vinblastine, bleomycin, and dacarbazine (MVBD). Both groups were comparable for the variables of age, sex, stage, and presence of B symptoms and histology. Thirty-one (88%) of EVBD-treated patients achieved a pathologically documented complete remission (CR) compared to the 24 cases (68%) of the MVBD-treated group. After a median follow-up of 36 months, duration of CR is better in the EVBD-treated patients with an actuarial 5-year duration of CR of 80%, statistically different to the MVBD group: 53% (P < 0.01). Both regimens showed the same gastrointestinal toxicity, but the patients treated with the MVBD regimen shown most and severe hematological and cardiac toxicities. Also, biochemical alterations in hepatic test were observed in these patients. The alternative use of epirubicin in combination chemotherapy appears to be as effective in advanced Hodgkin's disease without bulky disease, with reduced clinical toxicity. Mitoxantrone containing regimen was not found to have an equivalent efficacy and clinical toxicity was most frequent and severe. We felt that mitoxantrone could be consider a second-line drug in the treatment of advanced Hodgkin's disease.

Actuarial Analysis↗

PubMed1983

Stability of 111In-bleomycin in vivo--properties compared with 57Co-bleomycin.

111Indium-bleomycin (111In-BLM) and 57Co-bleomycin (57Co-BLM) were prepared and their distributions were compared in the tissues, blood, and urine in tumor-bearing and in untreated mice and rats. Autoradiographs of electrophoresis gels showed that patterns for urine from untreated and tumor-bearing animals, collected 1-3 h or 48 h after injection of 111In-BLM were similar to those for in vitro mixtures of urine and 111In-BLM, but differed from the patterns obtained with 111InCl3 under in vivo or in vitro conditions. In rats bearing mammary adenocarcinoma, 48 h after administration of the radiopharmaceutical, the activity ratio of tumor to eleven different tissues was 1.2-4.6 times higher for injected 111In-BLM than for 111InCl3 (P less than or equal to 0.001 or P less than or equal to 0.05). Imaging with a gamma camera depicted tumors in mice more distinctly with 111In-BLM than with 111InCl3. These findings were interpreted as reflecting the stability of 111In-BLM in vivo. The tumor concentration (%dose/g) was higher for the viable area than for the necrotic area for 111In-BLM, but the reverse was true for 57Co-BLM.

Adenocarcinoma↗

PubMed1994

Involvement of membrane bleomycin-binding sites in bleomycin cytotoxicity.

The authors have recently shown the existence of bleomycin (BLM)-binding sites at the surface of DC-3F cells. In order to study the involvement of these sites in the sensitivity of the cells to bleomycin several BLM-resistant cell lines from DC-3F cells were analysed. These mutants were obtained by electrotransfection of the Sh ble gene (D/BlmI cells) or the Sh ble-beta Gal fusion gene (D/BlmII cells) and/or by continuous culture in the presence of BLM (D/BlmIR and D/Blm40 cells). The resistance levels of the D/BlmII and D/Blm40 cells were 50- and 22-fold, respectively, determined at the EC50 level. The D/BlmI cells were only 2-fold resistant, whereas D/BlmIR cells were so resistant that almost no cytotoxicity was detected up to 200 microM BLM external concentration. Electropermeabilization was used in an attempt to bypass the plasma membrane of the cells and permit the distinction between internal resistance and membrane resistance. The former was observed when the products of the transfected genes were present. With respect to membrane resistance, differences were detected in the number of BLM-binding sites in several mutant cell lines, which could account for the differences in cell sensitivity to BLM. This suggests that the BLM-binding sites found at the cell surface may play a crucial role in BLM internalization and consequently in its cytotoxicity.

Animals↗

PubMed1995

Overproduction of the bleomycin-binding proteins from bleomycin-producing Streptomyces verticillus and a methicillin-resistant Staphylococcus aureus in Escherichia coli and their immunological characterisation.

The bleomycin-binding proteins designated BLMA and BLMS, which confer resistance to bleomycin (Bm), from Bm-producing Streptomyces verticillus ATCC15003 and a methicillin-resistant Staphylococcus aureus B-26, respectively, were overexpressed in Escherichia coli. The present study showed that both BLMA and BLMS quench the antibacterial activity of Bm by the binding to the drug. To immuno-characterize the Bm-binding proteins, we constructed a monoclonal antibody against BLMA. The antibody, designated 893-12, did not cross react to BLMS and another Bm-binding protein from tallysomycin-producing Streptoalloteichus hindustanus. Although the ability of Bm to cleavage DNA was eliminated by a binding of BLMA to Bm, as shown by Sugiyama et al. [Gene 151 (1994) 11-15], the Bm-induced DNA degradation was restored by pre-incubation of BLMA with the anti-BLMA monoclonal antibody.

Acetyltransferases↗

PubMed1982

Labeled bleomycin as a tumor localizing agent III. Selectivity of tumor tissue uptake of the different forms of [57Co] bleomycin A2 and B2.

The cell uptake of the different forms (I and II) of [57Co]bleomycin A2 and B2 was studied in a Rhabdomyosarcoma cell culture. The results show that the uptake of form I appears to be significantly higher than the uptake of form II. The evidence presented indicates that form I is formed in vivo as well as in vitro from form II by biotransformation. Transferrin stimulates the uptake of Co-bleomycin B2 form I only. As a result of trypsin treatment, it is suggested that form II binds only on the outer cell membrane and is not able to pass this membrane.

Animals↗

PubMed1990

Botran and bleomycin induce crossing-over, and bleomycin also increases aneuploidy in diploid strains of Aspergillus.

Both bleomycin, an antineoplastic drug, and botran (2,6-dichloro-4-nitro-aniline), a fungicide, are known to inhibit growth and induce genetic segregation in diploid tester strains of Aspergillus nidulans when present in agar media. To identify primary effects, samples of induced apparent crossover types were analysed in detail. For both compounds, coincident and consecutive events of mitotic crossing-over were found to be very frequent and such events showed a random distribution among isolated colour sectors. In the case of botran, a thorough search for imbalanced precursor types was negative and recessive lethals were found only rarely. Such segregants are therefore unlikely the result of terminal deletions. For bleomycin, induction of reciprocal crossing-over was confirmed by treatments of germinating conidia. On plating to normal growth medium, crossover segregants showed up as coloured half- or quarter-colonies, including some "twin spots". Whole coloured colonies were also frequent and these increased with dose levels which caused decreasing survival and increasing frequencies of abnormal colonies. Analysis of large fractions of such "abnormals" identified aneuploids in all cases. While botran, in plate tests, also increased haploid segregants and disomic precursors could be found, tests of germinating conidia "in liquid" were inconclusive, because botran is insoluble in water. Some increases of aneuploids were observed, but only when botran and the solvent DMSO both were present at increased levels.

Aneuploidy↗