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PubMed1985

Isolation and characterization of Chinese hamster ovary cell lines sensitive to mitomycin C and bleomycin.

Seven Chinese hamster ovary K1 cell lines exhibiting sensitivity to anticancer drugs have been isolated by a replica-plating technique. Five of the mutants are hypersensitive (approximately 7-fold, as judged by D37 values) to the DNA cross-linking agent mitomycin C. Of these, one is also appreciably sensitive to UV light. Significant variations in their cross-sensitivity to cis-platinum(II) diammine dichloride, chlorambucil, and Adriamycin have also been observed. Two additional mutants have been isolated on the basis of sensitivity to the radiomimetic agent bleomycin. One of these shows greater than 6-fold sensitivity to bleomycin, while the other is approximately 14 times more sensitive than the parental strain to bleomycin and is also hypersensitive to a number of other DNA-damaging agents, including cis-platinum(II) diammine dichloride, chlorambucil, X-rays, and UV light. Both bleomycin-sensitive mutants also exhibit some degree of sensitivity to Adriamycin. In all cases, the cell lines have been grown in continuous culture for 3 months without evidence of reversion and should act as suitable recipients in DNA transfection experiments aimed at identifying human DNA repair genes.

Animals↗
PubMed1985

Bleomycin cleaves DNA depending on DNA primary, secondary, and tertiary structures.

The cleavage by bleomycin-Fe(II) complex in the presence of dithiothreitol was investigated by using 3'- or 5'-end-labeled DNA containing the region of the bacteriophage G4 origin of complementary strand synthesis as substrates. Bleomycin cleaved single-stranded DNA substrates preferentially at inverted repeat sequences, which potentially form stem-and-loop structures, in addition to the primary sequence specificity previously reported. DNA sequences preferentially cleaved in the double-stranded substrate were resistant when they lay outside the stem regions. These results suggest the formation of three predicted stem-and-loop structures and other possible secondary structures near the replication origin. Changes of the degree of bleomycin-induced DNA cleavage in a NaCl concentration between 0 and 50 mM suggest that a subtle change of ionic conditions within the double helix, or of DNA conformation, or of both, may occur at 0-50 mM NaCl. Bleomycin appears to be a useful reagent for analyzing secondary and tertiary structures of DNA.

Base Sequence↗
PubMed1986

[Experimental research following intratumor bleomycin use in the nude mouse model of oral mucosa cancer and the clinical pilot study].

Experiments concerning the kinetics and bio-distribution of 57Co-Bleomycin in three different lines of the squamous cell carcinoma of the oral cavity in a nude-mouse model yielded a more than tenfold higher concentration after a single intratumoral (i.t.) application of an aqueous solution of 57Co-labelled Bleomycin in spite of a remarkable radioactivity-wash in the tumor up to 48 hours post applicationem, compared to the intravenous (i.v.) injection. For the investigation of the radiopharmacon within the tumor we used the macro-autoradiographic method. The xenografts have been removed and cut (5 micrograms) 1;5; 24, and 48 hours after the Bleomycin administration, respectively. These preparations have been covered with an autoradiographic film and exposed for about three weeks. After this an inhomogenous distribution of the radioactive nuclide was produced within the tumor, and a particularly high activity-concentration could be demonstrated in the necrotic tumor areas. The results obtained from the animal experiments have been corroborated by a pilot-study consisting of i.t. Bleomycin application in nine patients with a carcinoma of the oral mucosa.

Animals↗
PubMed1986

Bleomycin increases superoxide anion generation by pig peripheral alveolar macrophages.

Pulmonary fibrosis is the major toxic effect of bleomycin chemotherapy; however, the molecular mechanisms of the pathological process are unknown. Since alveolar macrophages produce toxic oxygen metabolites and these can damage lung cells, the effect of bleomycin on superoxide anion production was investigated in subpopulations of pig alveolar macrophages. Cells were lavaged from the lung and separated into three subpopulations according to their density. Their capacity to generate superoxide anions increased the more distally they were located. Bleomycin (5.0 milliunits/ml) increased the rate of superoxide production by 75 +/- 24% in dense alveolar macrophages located in the lung periphery. Hydrocortisone (10.0 micrograms/ml) inhibited this superoxide production by 33 +/- 10%. Results from this study suggest that an excess production of superoxide anions by alveolar macrophages may be the underlying cause of bleomycin pulmonary toxicity.

Animals↗
PubMed1986

[The role of bleomycin combination in radiation therapy of squamous cell carcinoma of the oral cavity].

In an effort to improve tumor control by radiation therapy, a treatment regimen consisting of concurrent combination of bleomycin (90 mg/3 weeks) and radiation (30 Gy/3 weeks) was applied. Between 1972 and 1981, 287 patients with squamous cell carcinoma in the oral cavity were subjected to this bleomycin-radiation combination regimen. All except 4 patients experienced marked response after treatment using the bleomycin-radiation combination alone. One hundred thirty-four patients (47%) obtained CR and 149 (53%) PR. Higher CR rates were obtained in patients with carcinoma of the lower gum (62%), of the upper gum (68%), and of the cheek mucosa (43%), compared to patients with carcinoma of the floor of the mouth (21%), and of the tongue (15%). In each of the tumor sites, small lesions (T1, T2) obtained higher CR rates, compared with large lesions (T3, T4). Of the 134 patients who experienced CR, 83 were observed without any further treatment after bleomycin-radiation combination alone. Local recurrence-free rates of these patients were 72% for T1, T2 lesions and 48% for T3, T4 lesions. Local control rates were increased to 85% and 78%, respectively, with successful salvage treatment involving surgery or interstitial radiotherapy for post-irradiation failures.

Bleomycin↗
PubMed1986

Destruction of VX2 tumor in rabbits by hyperthermia plus bleomycin suspended in sesame oil.

The combined antitumor effects of local hyperthermia and a simultaneous injection of bleomycin suspended in sesame oil (BLM-sesame oil) into the proper hepatic artery were studied in a model of liver cancer in rabbits. Fourteen days after inoculation of VX2 carcinoma into the left anterior lobe, 107 rabbits were used for the experiments. Local hyperthermia of 43-47 degrees C for 20 minutes was administered directly to the liver tumor via a 915 MHz microwave. In a preliminary study, administration of sesame oil alone into the proper hepatic artery led to a peripheral hepatic artery embolization, as evidenced by microangiography, and to the inhibition of tumor growth. The tumor-bearing rabbits were placed into groups of six. The first group was treated with hyperthermia, the second with a saline solution of bleomycin given intra-arterially, the third with a combination of hyperthermia and a saline solution of bleomycin given intra-arterially, the fourth with BLM-sesame oil given intra-arterially, the fifth with a combination of hyperthermia and sesame oil given intra-arterially, and the sixth with a combination of hyperthermia and BLM-sesame oil given intra-arterially. Consequently, the concomitant application of hyperthermia and intra-arterial injection of sesame oil led to a prominent inhibition of tumor growth, as compared with each modality alone (P less than 0.001). The most significant effect was obtained in the case of a combination of hyperthermia and BLM-sesame oil, as compared with a combination of hyperthermia and sesame oil (P less than 0.001). Local hyperthermia concurrent with the blockage of blood flow supplying the tumor led to a prominent inhibition of tumor growth, and addition of bleomycin to this regimen had an even greater antitumor effect. Thus, a combination of hyperthermia and chemoembolization with BLM-sesame oil is an effective treatment for liver cancer, at least in rabbits.

Angiography↗
PubMed1986

Modification of the balance between damage and repair of bleomycin-induced DNA-strand breakage by hyperthermia.

It is well recognized that hyperthermia can greatly enhance the cytotoxic effect of bleomycin. It has been suggested that the mechanism of hyperthermic potentiation of bleomycin toxicity involves the inhibition of DNA repair function. We have investigated how hyperthermia can modify the repair capacity of bleomycin treated cells by monitoring the induction of DNA damage and repair, using two essentially different techniques (DNA unwinding assay and nucleoid sedimentation assay). We have also investigated whether the enhancement of DNA-damaging potential of bleomycin was related to the availability of new sites within chromatin for drug attack. We have found that heat treatment (even for non-toxic exposures of 30 min at 44 degrees C) restricts the access of active drug to DNA, probably by the increase in nuclear protein content. The results obtained show that the increase in drug-induced DNA damage in heat-treated cells probably represents an underestimation of the predominant effect of hyperthermia on reducing cellular DNA repair capacity.

Animals↗
PubMed1987

Potentiation of sensitivity to bleomycin and the drug-induced DNA damage in EMT6 cells by the calmodulin inhibitor trifluoperazine.

It has been shown that inhibitors of calmodulin can increase the sensitivity of rodent cells to Bleomycin by interfering with DNA repair functions. As a result of this study we have found that treatment of plateau-phase EMT6 cells with Bleomycin causes a decrease in cell survival due to DNA damage. This toxic effect can be potentiated by the addition of a nonlethal dose of the calmodulin inhibitor Trifluoperazine. Furthermore, it was found that Trifluoperazine greatly potentiated Bleomycin-induced DNA breakage. Considering the results obtained by alkaline-denaturation assay (detects single-strand breaks, including these arising from alkali-labile lesions) and nucleoid sedimentation (in neutral sucrose gradients) assay (detects only frank breaks), a difference, presumably due to the Trifluoperazine-produced discrete block in the repair of Bleomycin-induced DNA alkali-labile lesions was found. These data suggest a role for calmodulin in the DNA repair pathway and provide a rational basis for the use of calmodulin inhibitors in cancer chemotherapy.

Animals↗
PubMed1988

Effect of bleomycin on murine tumor cells at elevated temperatures and two different pH values.

The cytotoxic effect of bleomycin, an antibiotic chemotherapeutic agent, at elevated temperatures was investigated. Single cell suspensions of FSa-II tumor cells were treated at elevated temperatures with or without bleomycin either at pH 7.4 or 6.7. Immediately after treatment, cells were cooled and diluted for lung colony assay. Cyclophosphamide of 200 mg/kg was injected i.p. into the recipient mice 48 h before i.v. injection of tumor cells. Lungs were removed 13 days thereafter and fixed in Bouin's solution. Colonies formed on the surface of each lobe were counted, and the surviving fractions were calculated. Cell survival was determined as a function of treatment time at various temperatures. Survival curves following bleomycin treatment at various temperatures were biphasic. Initial steep portion was followed by a resistant tail. The surviving fractions were reduced to 0.1 within 20 min of treatment at pH 7.4 in the temperature range from 39.0 degrees-43.5 degrees C, and 10 min at pH 6.7. The slope of the resistant tail becomes steeper with increasing temperature, indicating that the cytotoxic effect of bleomycin was enhanced at elevated temperatures. The reciprocal of D0 (treatment time to reduce surviving fraction from 1.0 to 0.37 on the exponential portion of survival curve) of the resistant tail was plotted as a function of the treatment temperature, and activation energy was calculated. This analysis indicates that the enhancement of the cytotoxic effect increases with increasing temperature. However, above 42.5 degrees C, this enhancement appears to be dominated by lethal thermal damage.

Animals↗
PubMed1988

The sequence specificity of bleomycin damage in three cloned DNA sequences that differ by a small number of base substitutions.

The DNA sequence specificity of the cancer chemotherapeutic agent, bleomycin, has been investigated in three clones of human alpha RI-DNA. The three 340-base pair alpha RI-DNA sequences were almost identical in their nucleotide sequence enabling the study of subtle effects of base substitutions on bleomycin cleavage. By utilizing densitometer scanning and statistical analysis of the degree of bleomycin DNA cleavage, we found 17 significant differences between the three DNA sequences. Eleven of these differences could be attributed to base substitutions close to the dinucleotide cleavage site. However, six of the differences were at positions two or more base pairs from the base substitution sites. The significant differences were up to 12 base pairs from base substitutions. It is proposed that these long range effects are due to base substitutions causing microvariation in the DNA structure to which bleomycin cleavage is sensitive.

Base Sequence↗
PubMed1988

Dietary vitamin E supplement does not inhibit changes in lung pressure-volume characteristics produced by bleomycin in hamsters.

We tested the hypothesis that a dietary supplement of vitamin E (VE) may lessen changes in pulmonary pressure-volume characteristics induced by intratracheal instillation of bleomycin. Ninety-nine male hamsters were separated into a control group (C), a VE supplement group (E), a control plus bleomycin group (CB) and a VE supplement plus bleomycin group (EB). Animals were killed at 30, 40, 55, 70 and 90 days and the pressure-volume curves of their lungs, both air-filled and saline-filled, were determined. Bleomycin was instilled on the thirtieth day. Lung volumes, compliance and curve-fitting data were compared. The mean serum VE concentration was 17.5 micrograms.ml-1 in groups E and EB as compared to 5.7 micrograms.ml-1 in groups C and CB. Despite the remarkably high VE content, no significant difference was found between groups CB and EB for the parameters compared.

Animals↗
PubMedDate not supplied

Developing guidelines for bleomycin test dosing.

Anaphylactoid systemic reactions to bleomycin are potentially lethal. Test dosing is recommended to prevent or quickly detect immediate hypersensitivity reactions in patients receiving bleomycin for the first time. Specific test dosage recommendations vary but general considerations include the patient's age, body size, and previous allergy history, and the care setting. Facilities administering bleomycin should implement guidelines that address bleomycin test dosing since the prevention and recognition of anaphylactoid reactions is a primary responsibility of the nurse administering chemotherapy.

Bleomycin↗
PubMed1989

Bleomycin-induced potentially lethal damage and its repair.

The dependence of the survival of V79 Chinese hamster cells which were treated with bleomycin on a post-treatment with anisotonic phosphate-buffered saline and/or conditioned medium was examined. In qualitative similarity to the effects of these post-treatments on survival following exposure to X rays, it was found that: anisotonic saline, both hypo- and hypertonic, significantly enhanced cell killing; the degree of enhancement increased with time and temperature; and incubation in conditioned medium resulted in the rescue of cells whether or not they were challenged with hypertonic saline after treatment with bleomycin. Based upon the qualitative similarity of these findings to those which we have observed following X irradiation, and observations of others on the site of action of bleomycin in cells and the ability that it has to break DNA, we propose that both bleomycin and radiation (X rays and fast neutrons) act on similar sensitive sites which are probably contained in or close to the envelope and/or the protein matrix of the nucleus.

Animals↗
PubMed1989

[Preclinical pharmacologic evaluation of bleomycin A6].

Bleomycin A6 is an antineoplastic antibiotic. Toxicologic study showed that the LD50 values of bleomycin A6 in mice were 92 +/- 7.4 mg/kg (IV), 72 +/- 5.6 mg/kg (IM), 82 +/- 4.5 mg/kg (SC), 102 +/- 0.6 mg/kg (IP) and 520 +/- 0.1 mg/kg (PO), respectively. Wistar rats were divided into 6 groups. Doses of 20, 10, 5, 2 and 0.5 mg/kg/day were given intraperitoneally every other day for 60 days. Renal damage to various degrees was found in rats with doses higher than 2 mg/kg. However, no pathologic changes were observed in the liver, heart, lungs, spleen, stomach, intestines, pancreas or brain. Three groups of dogs (3 in each group) were injected i.v. every other day for 60 days with a dose of 1.0, 0.5 and 0.1 mg/kg, respectively. The three dogs receiving 1.0 mg/kg died between the 4th and 7th week. Dogs treated with 1.0 and 0.5 mg/kg had renal damage and skin ulceration. With a dose of 0.1 mg/kg, dogs showed good tolerance and no renal damage was found. Multiple doses of bleomycin A6 injected into rabbit muscles caused no obvious local changes. After IV injection into rabbits, the maximal serum concentration of bleomycin A6 was 18.5 micrograms/ml, having a half life of 2.8 hours and 7.7% of the drug were excreted in the urine within 12 hours.

Animals↗
PubMed1989

[Local injection of bleomycin A5 in lymphangioma in children. Analysis of 100 cases].

From Jan. 1985 to Dec. 1988, 100 newborn and small infants suffering from lymphangioma were treated with bleomycin A5 injecting into lymphangioma. The cases were divided into three types: (1) Bleomycin A5 local injection into the lymphangioma were practiced on 70 cases; (2) Surgical partial resection of lymphangioma plus local injection on 26 cases; (3) A previous excision but recurred postoperatively were 4 cases. The dosage of bleomycin A5 was 10 mg per time. The therapeutic course was not more than 5 times. The efficacy of bleomycin A5 were satisfactory in all cases except only one case with a large lymphangioma of previous palliative excision but recurred. There was not a recurrent patient at following-up from 3 months to 4 years.

Antibiotics, Antineoplastic↗
PubMed1985

Potentiation of cell killing by inhibitors of poly(adenosine diphosphate-ribose) synthesis in bleomycin-treated Chinese hamster ovary cells.

Bleomycin-treated Chinese hamster ovary cells synthesize poly(adenosine diphosphate-ribose) in a reaction which is dose and time dependent. Treatment with two poly(adenosine diphosphate-ribose) synthesis inhibitors (3-aminobenzamide and 3-methoxybenzamide) slows down the restoration of DNA structure in bleomycin-treated cells, as shown by nucleoid sedimentation. When added in the culture medium, these inhibitors increase the cell sensitivity towards bleomycin, in the case of both exponentially growing and stationary cells. In control experiments, plateau-phase cells treated with bleomycin can recover by repairing efficiently the potentially lethal damage; this type of repair is mostly suppressed in the presence of the poly(adenosine diphosphate-ribose) synthesis inhibitors.

Animals↗
PubMed1985

Cleavage of stem-and-loop structure DNA by bleomycin. Reaction on the bacteriophage G4 origin of complementary strand synthesis.

The cleavage by bleomycin-Fe(II) complex in the presence of dithiothreitol of 3'-or 5'-end-labeled DNA from the region of the bacteriophage G4 origin of complementary strand synthesis was investigated by using the DNA-sequencing technique. Bleomycin cleaved a single-stranded DNA substrate preferentially at inverted repeat sequences, which potentially form stem-and-loop structures, while it cleaved double-stranded DNA substrates with different specificity. The results support the formation of three adjoining stem-and-loop structures in the region of the phage G4 origin of complementary strand synthesis under the low-salt conditions used and suggest a difference in the form of the double helix between the stem and the double-stranded DNA fragment. Bleomycin appears to be a useful reagent for searching stem-and-loop structures. The results may also contribute to the understanding of the mode of action of bleomycin as an antitumor antibiotic.

Bacteriophages↗
PubMed1975

Ultrastructural study of the effect of bleomycin A2 on the nucleolus and its possibly related cytoplasmic constituents in Novikoff hepatoma cells.

Treatment of Novikoff hepatoma ascites cells with bleomycin A2, in vivo as well as in vitro, in varying doses produced marked alterations in nucleolar and cytoplasmic ultrastructural organization. A series of changes occur including formation of fibrillar centers, fragmentation of fibrillar nucleolar elements, appearance of microspherules, and the loss of fibrillar elements from these nucleoli. A bleomycin concentration of 10 mug/ml in vitro produced an increased number of fibrillar centers with well-defined nucleolonemas. At a concentration of 50 mug/ml, there was an increase in number and fragmentation of these fibrillar centers and many microspherules were found throughout the nucleolus. Approximately one-fourth of the cells contained cytoplasmic fibrillar bodies and amorphous fibrous tufts around the nuclear envelope. At a bleomycin concentration of 100 mug/ml, the nucleoli contained more granular elements and numerous microspherules. Almost 90% of the cells contained cytoplasmic fibrillar bodies. The effects of bleomycin in vivo (10 mg/kg) closely resemble those found in vitro with concentrations of 50 and 100 mug/ml.

Animals↗