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Chemico-biological Interactions 1990Belomycin is a glycopeptide antibiotic routinely used to treat human cancer. It is commonly thought to exert its biological effects as a metallodrug, which oxidatively... (Review)
Review
Belomycin is a glycopeptide antibiotic routinely used to treat human cancer. It is commonly thought to exert its biological effects as a metallodrug, which oxidatively damages DNA. This review systematically examines the properties of bleomycin which contribute to its reaction with DNA in vitro and may be important in the breakage of DNA in cells. Because strand cleavage results from the reductive activation of dioxygen by metallobleomycins, the mechanism of this process is given primary attention. Current understanding of the structures of the coordination sites of various metallobleomycins, their thermodynamic stabilities, their propensity to form adduct species, and their properties in ligand substitution reactions provide a foundation for consideration of the chemistry of dioxygen activation as well as a basis for thinking about the metal-speciation of bleomycin in biological systems. Oxidation-reduction pathways of iron-bleomycin, copper-bleomycin, and other metal-bleomycin species with O2 are then examined, including information on photochemical activation. With this background, structural and thermodynamic features of the binding interactions of DNA with bleomycin, its metal complexes, and adducts of metallobleomycins are reviewed. Then, the DNA cleavage reaction involving iron-bleomycin is scrutinized on the basis of the preceding discussion. Particular emphasis is placed on the constraints which the presence of DNA places on the mechanism of dioxygen activation. Similarly, the reactions of other metalloforms of bleomycin with DNA are reviewed. The last topic is an analysis of current understanding of the relationship of bleomycin-induced cellular DNA damage to the model developed above, which has evolved on the basis of chemical experimentation. Consideration is given to the question of the importance of DNA strand breakage caused by bleomycin for the mechanism of cytotoxic activity of the drug.
Topics: Animals; Bleomycin; Chemical Phenomena; Chemistry; DNA; DNA Damage; Humans; Metals; Molecular Structure; Oxidation-Reduction; Structure-Activity Relationship
PubMed: 1690086
DOI: 10.1016/0009-2797(90)90001-4 -
Gan To Kagaku Ryoho. Cancer &... Nov 1987Bleomycin, with was discovered by H. Umezawa et al., is being used throughout the world of its clinically proved effect on tumors such as squamous epithelical carcinoma,...
Bleomycin, with was discovered by H. Umezawa et al., is being used throughout the world of its clinically proved effect on tumors such as squamous epithelical carcinoma, malignant lymphoma etc. Elucidation on the mechanism of its effect has advanced to a molecular level, and it is believed that the agent cuts a DNA chain via a ferrum chelate [active type of BLM-Fe(III) chelate]. The heterologous dosage forms (oleosu, ointment) were developed for exerting a long-lasting at local tumor sites. And moreover, the assessment of derivatives to obtain increase the antitumor effect and reduce side effects provided clues leading to the development of Peplomycin. The essential clinical applications of this agent involve its combined with other carcinostatics and combination therapy with surgery and radiation. Many regimens have been studied in order to increase its anti-tumor effect in each field of application. There is the characteristic feature of side effects on bleomycin, which has no myelotoxicity but has fibroid lung as dose limiting toxicity. So it is necessary for the agent to be used carefully in order to reduce this pulmonary toxicity. Selection of cases, method of administration, method of early diagnosis and treatment of side effects should also be taken into consideration.
Topics: Bleomycin; DNA; Humans; Neoplasms
PubMed: 2445296
DOI: No ID Found -
Seminars in Oncology Apr 1992Bleomycin is a polypeptide antibiotic that has been used in clinical cancer chemotherapy for over 20 years. Risk factors associated with bleomycin include total dose of... (Review)
Review
Bleomycin is a polypeptide antibiotic that has been used in clinical cancer chemotherapy for over 20 years. Risk factors associated with bleomycin include total dose of drug, age of patient, high-dose oxygen therapy during surgery, and prior and concomitant radiation therapy. Attempts at developing predictive and precise monitoring systems have not been completely successful; however, the combined use of clinical and laboratory tests, such as the DLCO test, can be used to permit safe administration of the drug. Recent work has emphasized the development of new analogues, such as liblomycin, that appear to possess less pulmonary toxicity than does bleomycin, and has focused on understanding the pathogenesis of pulmonary toxicity, particularly as it relates to the immune system.
Topics: Bleomycin; Humans; Lung; Lung Diseases; Risk Factors
PubMed: 1384147
DOI: No ID Found -
Current Opinion in Drug Discovery &... Nov 2003The bleomycins are a group of structurally related glycopeptide antibiotics originally isolated from Streptomyces verticillus in the 1960s. They are used for the... (Review)
Review
The bleomycins are a group of structurally related glycopeptide antibiotics originally isolated from Streptomyces verticillus in the 1960s. They are used for the treatment of cancers including Hodgkin's lymphomas, carcinomas of the skin, head and neck, and testicular tumors. Whereas analogs of bleomycin have been synthesized to facilitate an understanding of its biochemical properties, the complexity of the molecule has severely limited the total number of analogs synthesized. The solid-phase synthesis of fully functional and active deglycobleomycin and bleomycin analogs is described. This approach has resulted in the synthesis of over 160 unique deglycobleomycin and bleomycin analogs in the past two years, an accomplishment that would not have been possible without the solid-phase methodology.
Topics: Anti-Bacterial Agents; Bleomycin; Combinatorial Chemistry Techniques; Heterocyclic Compounds; Humans
PubMed: 14758754
DOI: No ID Found -
Environmental and Molecular Mutagenesis 1995The sensitivity to micronucleus (MN) induction of human, mouse, and rat peripheral blood lymphocytes (PBLs) exposed to bleomycin sulfate (BLM) in vitro was compared in...
The sensitivity to micronucleus (MN) induction of human, mouse, and rat peripheral blood lymphocytes (PBLs) exposed to bleomycin sulfate (BLM) in vitro was compared in cytochalasin B-induced binucleated (BN) cells. For the PBLs of each species, either 0, 5, 10, 20, 40, 60, 80, or 160 micrograms/ml BLM was added to 5 ml aliquots of whole blood for 4 hr at 37 degrees C in a 5% CO2 atmosphere. Leukocytes were isolated on a density gradient and cultured in the presence of phytohemagglutinin to stimulate blastogenesis, and cytochalasin B was added to each culture at 21 hr postinitiation to prevent cytokinesis. A total of 4,000 BNs/concentration/species was analyzed for MN in two independent experiments. In addition, multiple-MN-BNs were quantitated, and the nucleation index was determined. Significant increases both in total MN-BNs and multiple-MN-BNs were observed at all concentrations in all species. All three species' concentration-response curves gave good fits (r2 values from 0.87 to 0.95) to either a linear or a square root model (y = mx + b or y = m[x]0.5 + b, respectively; where y = the percentage of MN-BN, m is the slope, and b is the y-intercept). The MN induction in the human and rat PBLs was not statistically different, but both were significantly less sensitive than the response shown by the BLM-exposed mouse PBLs. This difference in MN susceptibility was observed only at BLM test concentrations > or = 20 micrograms/ml. The nucleation index was significantly decreased in all species at either 80 or 160 micrograms/ml.
Topics: Animals; Bleomycin; Cell Cycle; Cells, Cultured; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Micronucleus Tests; Mutagens; Rats
PubMed: 7533077
DOI: 10.1002/em.2850250106 -
The Journal of Foot and Ankle Surgery :... 1996In this report, the authors will supplement research performed in 1989 by Sollitto, Napoli, and Gazivoda on the use of intralesional bleomycin for the treatment of...
In this report, the authors will supplement research performed in 1989 by Sollitto, Napoli, and Gazivoda on the use of intralesional bleomycin for the treatment of verrucae. With various alterations of technique, their original success rate of 32.2% was improved to 65.4%. Thus, bleomycin is a very effective first line treatment for multiple verrucae, particularly of the mosaic variety. An association is also made between patients with pedal hyperhidrosis and the occurrence of multiple verrucae, notably lesions that prove recalcitrant to initial therapy.
Topics: Adolescent; Adult; Bleomycin; Child; Female; Follow-Up Studies; Foot Diseases; Humans; Hyperhidrosis; Injections, Intralesional; Male; Middle Aged; Papillomaviridae; Warts
PubMed: 8722887
DOI: 10.1016/s1067-2516(96)80036-6 -
European Journal of Pharmacology Jan 2014Seroma formation is one of the most common complications following breast cancer surgery. It may lead to delay of adjuvant therapies and increasement of therapy costs....
Seroma formation is one of the most common complications following breast cancer surgery. It may lead to delay of adjuvant therapies and increasement of therapy costs. Bleomycin sulfate is a sclerosing antibiotic with antineoplastic efficacy. It is locally used in the treatment of pleural effusion. The present study aimed to investigate seroma-reducing effect of local bleomycin application after mastectomy. Sixteen female Wistar Albino rats were used in this study. The rats were divided into two equal groups. Under general anesthesia all rats underwent unilateral mastectomy as definition by Harada. Serum physiologic was applied to animals in Group 1 (control group) and bleomycin to Group 2. Mastectomized localization was explored on the 10th day postoperatively. Seroma and tissue samples were obtained from axilla and thoracic wall for histopathological examination. The amount of seroma was significantly lower in the bleomycin group as compared to the control group (P=0.002). Fibrosis, PNL infiltration and the number of fibroblasts were significantly higher in the bleomycin group. No difference was identified between the groups in terms of angiogenesis, edema, congestion, and monocyte, lymphocyte and macrophage infiltration. Local bleomycin sulfate application might be a therapeutic option in patients with seroma formation, as well as in the patients with malignant pleural effusion. Nonetheless, further studies that compare the efficacy and adverse effects (benefit-to-harm ratio) of bleomycin sulfate are needed.
Topics: Animals; Antibiotics, Antineoplastic; Axilla; Bleomycin; Female; Lymph Node Excision; Lymph Nodes; Mastectomy; Rats; Rats, Wistar; Seroma; Thorax
PubMed: 24231620
DOI: 10.1016/j.ejphar.2013.10.067 -
Seminars in Oncology Apr 1992Bleomycin is a glycopeptide antibiotic with a unique mechanism of antitumor activity. The drug binds to guanosine-cytosine-rich portions of DNA via association of the... (Review)
Review
Bleomycin is a glycopeptide antibiotic with a unique mechanism of antitumor activity. The drug binds to guanosine-cytosine-rich portions of DNA via association of the "S" tripeptide and by partial intercalation of the bithiazole rings. A group of five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals including iron, the active ligand, and copper, an inactive ligand. Molecular oxygen, bound by the iron, can produce highly reactive free radicals and Fe(III). The free radicals produce DNA single-strand breaks at 3'-4' bonds in deoxyribose. This yields free base propenals, especially of thymine: cytotoxicity is cell-cycle-phase specific for G2 phase. In humans, bleomycin is rapidly eliminated primarily by renal excretion. This accounts for approximately half of a dose. In patients with renal compromise or extensive prior cisplatin therapy, the drug half-life can extend from 2 to 4 hours up to 21 hours. Thus, dose adjustments are needed when creatinine clearance is less than or equal to 3N mL/min. Finally, resistance to bleomycin in normal tissues can be correlated with the presence of a bleomycin hydrolase enzyme, which is in the cysteine proteinase family. The enzyme replaces a terminal amine with a hydroxyl, thereby inhibiting iron binding and cytotoxic activity. The low concentration of enzyme in the skin and lung may explain the unique sensitivity of these tissues to bleomycin toxicity. However, correlation of hydrolase levels with tumor cell sensitivity has thus far been negative.
Topics: Bleomycin; Cysteine Endopeptidases; Glycoside Hydrolases; Humans
PubMed: 1384141
DOI: No ID Found -
Nano-designed CO donor ameliorates bleomycin-induced pulmonary fibrosis via macrophage manipulation.Journal of Controlled Release :... Jan 2022Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease due to chronic inflammatory responses. The prognosis of IPF is very...
Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible interstitial pulmonary disease due to chronic inflammatory responses. The prognosis of IPF is very poor, however, the therapeutic options are very limited. Previously we developed a polymeric micellar drug delivery system of carbon monoxide (CO) that is a pivotal anti-inflammatory gaseous molecule, i.e., SMA/CORM2, which exhibited therapeutic potentials against dextran sulfate sodium (DSS)-induced mouse colitis and acetaminophen (APAP) induced liver injury. Along this line, here we investigate the applicability of SMA/CORM2 on IPF using a bleomycin (BLM)-induced pulmonary fibrosis model. Severe inflammation and the consequent pulmonary fibrosis were triggered by BLM, whereas SMA/CORM2 treatment remarkably suppressed the inflammation progression and ameliorated the formation of fibrosis. CO is the effector molecule of SMA/CORM2, which exerted the therapeutic/protective effect mostly through suppressing the reprogramming of anti-inflammatory macrophages as revealed by the decreased expressions of CD206 and arginase-1 that were remarkably upregulated by BLM exposure. The suppression of macrophage polarization accompanied the downregulated hypoxia-inducible factor-1α (HIF-1α) and its target molecule heme oxygenase-1 (HO-1), suggesting a HIF-1α/HO-1 pathway for modulating macrophage reprogramming. As the downstream event of anti-inflammatory macrophage polarization, the alveolar epithelial to mesenchymal transition that is the major source of myofibroblast, the hallmark of IPF, was significantly suppressed by SMA/CORM2 via a TGF-β/Smad2/3 pathway. Compared to native CORM2 of equivalent dose, SMA/CROM2 exhibited a much better protective effect indicating its superior bioavailability as an enhanced permeability and retention (EPR) effect-based nanomedicine. We thus anticipate the application of SMA/CORM2 as a therapeutic candidate for IPF as well as other inflammatory diseases and disorders.
Topics: Animals; Bleomycin; Colitis; Epithelial-Mesenchymal Transition; Idiopathic Pulmonary Fibrosis; Macrophages; Mice
PubMed: 34864115
DOI: 10.1016/j.jconrel.2021.11.047 -
Clinics in Dermatology 1985
Topics: Administration, Topical; Bleomycin; Humans; Injections; Skin Neoplasms; Warts
PubMed: 2463863
DOI: 10.1016/0738-081x(85)90065-3