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At least 19 recordsLinked to original sources
PubMed1985

Interaction of bleomycin A2 with deoxyribonucleic acid: DNA unwinding and inhibition of bleomycin-induced DNA breakage by cationic thiazole amides related to bleomycin A2.

The association of the antitumor antibiotic bleomycin A2 with DNA has been investigated by employing several 2-substituted thiazole-4-carboxamides, structurally related to the cationic terminus of the drug. With a 5'-32P-labeled DNA restriction fragment from plasmid pBR322 as substrate, these compounds have been shown to inhibit bleomycin-induced DNA breakage. Analogues possessing 2'-aromatic substituents on the bithiazole ring were more potent inhibitors than those carrying 2'-aliphatic groups, e.g., the acetyl dipeptide A2. The degree of inhibition was similar at all scission sites on DNA, and inclusion of the analogues did not induce bleomycin cleavage at new sites. DNA binding of bithiazole derivatives has also been studied by two complementary topological methods. Two-dimensional gel electrophoresis using a population of DNA topoisomers and DNA relaxation experiments involving calf thymus DNA topoisomerase I and pBR322 DNA reveal that bleomycin bithiazole analogues unwind closed circular duplex DNA. The inhibition and unwinding studies together support recent NMR studies suggesting that both bleomycin A2 and synthetic bithiazole derivatives bind to DNA by an intercalative mechanism. The results are discussed in relation to the DNA breakage properties of bleomycin A2.

Animals↗
PubMed1986

Increased lethality of calmodulin antagonists and bleomycin to human bone marrow and bleomycin-resistant malignant cells.

The effect of bleomycin and calmodulin antagonists on human cells was studied using a clonogenic assay. A 1-h exposure to nontoxic concentrations of the calmodulin antagonists melittin (0.5 microM), pimozide (5 microM), and chlorpromazine (20 microM) increased the lethality of bleomycin to human ovarian carcinoma cells (SK-OV). No increase was seen with chlorpromazine sulfoxide, which lacks calmodulin antagonistic activity. Maximum enhancement of bleomycin lethality by calmodulin antagonists was seen when the antagonist was present simultaneously with bleomycin rather than before or after bleomycin. The cytotoxicity of bleomycin to A-253 head and neck squamous carcinoma cells, which were 10-fold more sensitive to bleomycin alone compared to SK-OV cells, was not markedly altered by the presence of 20 microM chlorpromazine. Chlorpromazine, melittin, or pimozide also increased the toxicity of bleomycin to human granulocyte/macrophage and erythroid stem cell colonies. These results demonstrate that calmodulin antagonists can significantly increase the lethality of bleomycin to some but not all human tumor cells and that nonmalignant hematological human cells may also be affected by this combination.

Bleomycin↗
PubMed1987

Enhanced bleomycin-mediated damage of DNA opposite charged nicks. A model for bleomycin-directed double strand scission of DNA.

The anticancer drug, bleomycin, causes both single and double strand scission of duplex DNA in vitro, with double strand scission occurring in excess of that expected from the random accumulation of single strand nicks. The mechanism of the preferential double strand scission of DNA by bleomycin has been investigated through the synthesis of a series of double hairpin and linear oligonucleotides designed to contain a single nick-like structure at a defined site to serve as models of bleomycin-damaged duplex DNA. The 3' and/or 5' hydroxyls flanking the nick have been phosphorylated to model the increased negative charge at a bleomycin-generated nick. The ability of bleomycin to cleave the intact strand opposite the nick was then determined by autoradiography. The results demonstrate that phosphorylation at either the 3' or 5' hydroxyl, and especially when both sites are phosphorylated, strongly enhances selective cleavage by bleomycin of the opposite strand. These experiments indicate that bleomycin-mediated double strand scission is a form of self-potentiation in which the high affinity of bleomycin for the initially generated nicked sites leads to a greatly enhanced probability of scission of the strand opposite those sites.

Base Sequence↗
PubMed1975

Binding of bleomycin to DNA in bleomycin-sensitive and -resistant rat ascites hepatoma cells.

The 14C activity of [14C]bleomycin bound to DNA in bleomycin-sensitive rat ascites hepatoma cells (AH-66) was 8.7 times higher than in resistant cells (AH-66F) when the cells were incubated with [14C]bleomycin. The difference in permeability to bleomycin was not significant; uptake of [14C]bleomycin by the sensitive cells was only 1.2 times larger than that by the resistant cells, and the radioactivity incorporated into the nuclei of sensitive cells was only 1.3-fold greater. The bleomycin-inactivating enzyme level in the resistant cells was 3.5 times higher than in the sensitive cells, indicating that the antibiotic incorporated into the resistent cells was reduced in DNA-binding activity to a large extent. The level of protein-free thiol compound in the sensitive cells was 1.8-fold higher than in the resistant cells, suggesting a possible enhancement of bleomycin action by intracellular thiol compound as is found in vitro. These factors probably affect the DNA strand scission and the sensitivity of cells to this antibiotic. Binding of [14C]bleomycin to DNA in vitro was studied in the presence and the absence of dithiothreitol. A large portion of the radioactivity bound in the presence of dithiothreitol was unstable to acid, but the acid-resistant binding was also enhanced by this thiol compound.

Animals↗
PubMed1977

Comparison of oncophilic radiopharmaceuticals, *I-fibrinogen, 67Ga-citrate, 111In-bleomycin, and *I-bleomycin in tumor-bearing mice.

The pharmacokinetics of 67Ga-citrate, 111In-bleomycin, *I-bleomycin, and *I-fibrinogen were compared in a murine KHJJ tumor model in order to assess their relative potential as agents for in vivo detection of cancer. Although all four agents have been reported to be clinically efficacious, in this tumor model, *I-fibrinogen and 67Ga-citrate had the greatest tumor accumulation with maximum concentrations of 11.7% and 10.5% respectively. However, both these radiopharmaceuticals cleared slowly from the blood and animal. The maximum tumor concentrations of 111In-bleomycin and *I-bleomycin were 2.9% and 2.6% respectively, but *I-bleomycin had the advantage of rapid clearance from the blood and animal. 67Ga-citrate did not achieve its maximum tumor concentration until 24 hours after administration, whereas the other radiopharmaceuticals achieved maximum tumor concentration within several hours of administration. From these observations 123I-bleomycin seems to deserve clinical trials in patients. 123I-fibrinogen appears to have significant oncophilic potential if its clearance from the animal can be accelerated without altering its accumulation in the tumor.

Animals↗
PubMed1980

Metal binding to modified bleomycins. Zinc and ferrous complexes with an acetylated bleomycin.

We have studied the DNA- and metal-binding properties of a bleomycin A2 derivative in which the alpha-amino group of the beta-aminoalanine moiety has been N-acetylated. The modified antibiotic has been shown to be without activity in mediating the in vitro release of [3H]thymine from Pm-2 DNA. Fluorescence experiments indicate that the degree of quenching by DNA of the bithiazole fluorescence is unaffected by N-acetylation of bleomycin. Furthermore, 1H NMR experiments demonstrate that N-acetylation does not alter the stoichiometry of metal binding. The Fe(II)--Ac-bleomycin A2 complex, however, has been found to be stable in the presence of both O2 and CO, and thus inactivation appears to be accounted for by the loss of the ability to bind and/or reduce O2. Comparison of the 1H NMR spectra of the Fe(II)--bleomycin and Fe(II)--Ac-bleomycin A2 complexes indicates that either a drastic reorganization of the ligands with respect to the central iron atom has occurred or that an altered spin state is stabilized. These experiments establish that the ability of bleomycin to cause DNA damage is sensitive to even minor structural alterations within the antibiotic.

Animals↗
PubMed1979

Structural studies of of "active complex" of bleomycin: assignment of ligands to the ferrous ion in a ferrous-bleomycin-carbon monoxide complex.

Proton NMR studies at 360 MHz establish the binary Fe(II)-bleomycin complex to be paramagnetic with a spectrum covering 70 ppm. Addition of carbon monoxide generates a stable, diamagnetic Fe(II)-bleomycin-CO complex that is a putative structural analog of the "active" Fe(II)-bleomycin-O2 complex. The following six groups have been determined to be coordinated to the Fe(II) ion from analysis of the highly resolved 1H NMR spectra of this complex: CO, the primary and secondary amine nitrogens of the beta-aminoalanine moiety, the carbamoyl moiety on the 3-position of mannose, the pyrimidine N-1, and the imidazole N-1. The Fe(II)-bleomycin-CO complex binds to DNA, as shown by fluorescence quenching experiments, but Fe(II)-bleomycin-CO does not mediate thymine release. These results necessitate a major revision in the current model for metal coordination to bleomycin.

Bleomycin↗
PubMed1979

Oxygenated iron bleomycin. A short-lived intermediate in the reaction of ferrous bleomycin with O2.

The reaction of Fe(II) . bleomycin with O2 to yield Fe(III) . bleomycin has been resolved into two kinetic events by stopped-flow spectrophotometry. The first event is first order with respect to both bleomycin and O2 and may be regarded as a second order reaction (k = 6.1 x 10(3) M-1s-1 at 2 degrees C). The first product has no EPR spectrum. The optical spectrum resembles those of Fe(II) . bleomycin complexes with CO, NO, and ethyl isocyanide. We propose that the first product is an Fe(II) . bleomycin . O2 complex. The second kinetic event is first order with respect to the first accumulated product (k = 0.11 s-1 at 2 degrees C) and independent of oxygen concentration. The product of this reaction is indistinguishable from Fe(III) . bleomycin by optical and EPR spectroscopy.

Bleomycin↗
PubMed1987

Mechanism of reduction of bleomycin-Cu(II) by CO2- and oxidation of bleomycin-Cu(I) by H2O2 in the absence and presence of DNA.

The reduction reaction of bleomycin-Cu(II) by CO2- has been studied by gamma and pulse radiolysis at pH7. The CO2- radical reduces bleomycin-Cu(II) at a rate of (6.7 +/- 0.7) X 10(8) dm3 mol-1 s-1. In the presence of calf thymus DNA the rate of the reduction decreased as the concentration of DNA increased, indicating that the reduction reaction proceeds through free bleomycin-Cu(II). The stoichiometry and the kinetics of the oxidation of bleomycin-Cu(I) by H2O2 in the presence and absence of DNA have been studied. Our observations suggest that the OH. radical is not produced during this reaction and the degradation of the drug occurs in the absence and presence of DNA. We assume that bleomycin-Cu(II) in the presence of a reducing agent and molecular oxygen or H2O2 does not cleave DNA since the oxidizing species, which are formed during the oxidation reaction by H2O2, attack the drug even in the presence of DNA.

Bleomycin↗
PubMedDate not supplied

Therapy of advanced esophageal cancer with bleomycin, irradiation and combination of bleomycin with irradiation.

Results from treating 51 patients with advanced esophageal cancer are presented. Fifteen patients were treated with Bleomycin, 12 with radiotherapy, and 24 with a combination of bleomycin and radiotherapy. The best results were achieved in the group of patients treated with combined therapy showing 62% objective remissions (15/24) which was statistically significant (P less than 0.001) in comparison to the other groups. In the Bleomycin therapy group, there were 26% objective remissions (4/15), and in the group treated only with radiotherapy 33% (4/12)- The median duration of remission was 9 months in the combined therapy group, 6.3 months in the group treated with radiotherapy, and 2.6 months in the Bleomycin treated group. The authors concluded that the combination of Bleomycin and radiotherapy seems to be a further step in palliative treatment of advanced esophageal cancer.

Adult↗