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PubMed1976

Labelling of bleomycin with cobalt-57, indium-111, technetium-99m, mercury-197, lead-203, and copper-67.

The radiochemical purity of the cobalt-57 complex of bleomycin could be enhanced by adjusting the pH of the final product to a value between 5 and 6. This radiopharmaceutical appeared to have better tumor visualizing properties compared to the not neutralized preparation. The clinical use of the cobalt-57 bleomycin complex is however limited by the long physical half-life of the label, causing a risk of radioactive contamination. It appeared to be possible to label bleomycin with radioactive cations (111In3+, 99mTc4+, 197Hg2+ and 67Cu2+) having suitable gamma ray energies and short half-lifes. These bleomycin complexes showed a high radio-chemical purity judged by their behaviour on thin layer chromatography, paper chromatography, and electrophoresis, but their application as tumor visualizing radiopharmaceutical turned out to be disappointing compared with cobalt-57 bleomycin.

Bleomycin↗
PubMed1980

Increase of antitumor effect on bleomycin by reduced nicotinamide adenine dinucleotide phosphate and microsomes in vitro and in vivo.

The DNA chain breakage effect of bleomycin A2 on isolated nuclei was enhanced over 150-fold by the reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent electron transport system of isolated microsomes. The enhancement of bleomycin A2-induced DNA chain breakage by NADPH was also shown at the level of the intact AH66 cells. Furthermore, it was found that the simultaneous administration of bleomycin and NADPH apparently inhibited the growth of Erhlich tumors in mice compared with the administration of bleomycin alone. These results indicate that the action of bleomycin on DNA is stimulated by the microsomal NADPH-dependent electron transport system not only in vitro but also in vivo.

Animals↗
PubMed1980

[Cellular transport mechanisms for 57Co-bleomycin].

The cell-specific absorption mechanism for 57Co bleomycin and the transport behavior was examined under various parameters in an in vitro tumor cell system. The 57Co bleomycin absorption of vital Ehrlich-ascites tumor cells showed a positive time-dose-temperature correlation plus a definite indication of an active intracellular transport mechanism. Because erythrocytes, as compared to Ehrlich-ascites tumor cells, absorb almost no 57Co bleomycin, it could be concluded indirectly that active transport of 57Co bleomycin into the intracellular space is controlled by endocytosis. The additional 57Co bleomycin absorption in membrane structures was also demonstrated in examinations of an Ehrlich-ascites tumor cell membrane preparation.

Animals↗
PubMed1980

Bleomycin-induced pulmonary fibrosis in the rat. Prevention with an inhibitor of collagen synthesis.

Pharmacologic treatment of pulmonary fibrosis has been limited to the use of corticosteroids occasionally combined with other immunosuppressive agents. We tested the ability of a proline analogue that is a potent inhibitor of collagen biosynthesis to prevent the manifestations of bleomycin-induced pulmonary fibrosis in an animal model. Bleomycin sulfate was administered by intratracheal instillation to produce pulmonary fibrosis in male Fischer 344 rats. After 28 days lungs from bleomycin-treated animals had histologic, biochemical, and functional alterations consistent with pulmonary fibrosis. Vital capacity and compliance were reduced to 62% and 41% of their respective control values. Lung prolyl hydroxylase activity doubled during the first week after bleomycin, at a time when total lung collagen content remained unchanged. Thereafter total lung collagen content slowly rose to 72% above control values at 28 days. We administered the proline analogue DHP at a dose that completely inhibited the elevated levels of lung prolyl hydroxylase activity. Pulmonary collagen content of animals treated with DHP was only minimally elevated, and functional abnormalities were reduced. Pulmonary compliance increased significantly from 0.25 to 0.44 ml/cm of H2O, and vital capacity increased from 3.94 to 5.65 ml. These studies suggest that proline analogues offer potential for modifying the manifestations of pulmonary fibrosis that occur as a consequence of acute lung injury. Elevation of lung prolyl hydroxylase activity is an early even that serves as a useful index of the acute lung injury produced by bleomycin.

Animals↗
PubMedDate not supplied

Pulmonary toxicity studies of bleomycin and talisomycin.

The comparative pulmonary toxicity induced by bleomycin and talisomycin (former trivial name: tallysomycin A) was evaluated by measuring lung hydroxyproline content. Based on published subacute toxicity data, in which talisomycin was found to be four times as toxic as bleomycin, the following doses of each drug were given sc to BDF1 male mice twice weekly for 4 weeks: 2.5, 5, and 10 mg/kg of bleomycin and 0.625, 1.25, 2.5, and 3.75 mg/kg of talisomycin. Equivalent dose-related effects in body weight were produced by bleomycin and talisomycin at a respective dose ratio of 4:1. Similarly, equivalent dose-dependent increases in lung hydroxyproline content, an index of collagen, were produced by bleomycin and talisomycin. Neither drug caused deaths at the doses used.

Animals↗
PubMedDate not supplied

Prospective study of the pulmonary toxicity of continuously infused bleomycin.

Bleomycin is an effective antitumor drug but must be used cautiously because of its pulmonary toxicity. We performed a prospective study of the effects on pulmonary function when bleomycin was given as a continuous iv infusion over a 7-day period. Bleomycin was administered at a dose of 15 units/m2 as an iv push followed by 15 units /m2/day as a continuous iv drip. Thirteen previously untreated patients completed the study after receiving a mean total dose of 228 units. Pulmonary function tests were performed before bleomycin treatment and periodically during the subsequent 6 months. There was a small mean increase in both vital and diffusing capacities after 6 months, which was not statistically significant. No patient had a serious loss in pulmonary function. We conclude that the risk of bleomycin toxicity is low when the drug is given at this dose by continuous infusion. The risk may be less than the risk of toxicity from bolus injection in this dose range.

Aged↗
PubMed1981

Bleomycin and radiotherapy in nonresectable thoracic oesophageal carcinoma.

The survival rates of nonresectable thoracic oesophageal carcinoma patients were studied in 50 patients treated by radiotherapy and by a combination of radiotherapy and bleomycin. The patients of two series were very similar. The one-year survival rates were 21 and 10 per cent, in radiotherapy and in radiotherapy with bleomycin group, respectively. In the literature, there were only few reports from survival figures of patients with oesophageal carcinoma treated with bleomycin in combination with radiotherapy. The authors concluded that the combination of bleomycin and radiotherapy has very limited effect on advanced oesophageal carcinoma. The survival rate after this combination therapy is not better with radiotherapy alone, if bleomycin and radiotherapy are used with reduced doses and without severe complications.

Aged↗
PubMed1981

Activated bleomycin. A transient complex of drug, iron, and oxygen that degrades DNA.

"Activated bleomycin" is an oxygenated iron drug complex which embodies the drug's DNA-cleaving activity. This activity is exercised on DNA, if present, but if DNA is absent, the drug itself is inactivated. Hyperfine interactions in the EPR spectra of activated bleomycin prepared with 57Fe(II) and 17O2 demonstrate the presence of iron as Fe(III) and of bound oxygen originating in dioxygen. Bleomycin can also be activated with Fe(III) and either H2O2 or ethyl hydroperoxide. These latter reactions do not produce a ferrous intermediate nor do they require O2. But O2 is required for the reaction of activated bleomycin with DNA to yield the malondialdehyde-like chromogens used to monitor DNA degradation. The attack on DNA is quantitatively concurrent with the decay of activated bleomycin, however generated.

Aerobiosis↗
PubMed1981

Collagen lysyl oxidase activity in the lung increases during bleomycin-induced lung fibrosis.

Intratracheal administration of bleomycin caused pulmonary fibrosis in rats. Bleomycin sulfate (640 micro grams/165 g b.wt. in 0.5 ml of sterile saline) was instilled Intratracheally into male Fisher 344 rats (169 +/- 5 g), whereas control animals received 0.5 ml of sterile saline by the same route. One, 3, 7, 14, 28 and 322 days after instillation, the animals were killed, the lungs were homogenized in 6 M urea, 0.01 M NaCl, 0.001 M potassium phosphate (pH 8.3) and the homogenates were subjected to ultracentrifugation. The 106,000 x g supernate was assayed for lysyl oxidase activity. Total lung hydroxyproline and desmosine content was determined at each time point. Lysyl oxidase specific activity in the lung was elevated significantly 3 days after bleomycin treatment, peaked 14 days after bleomycin treatment at 230% above the control value and was returned toward normal 28 days after treatment. The increase of lysyl oxidase activity preceded the maximal increase of total lung hydroxyproline and desmosine which occurred 28 days after bleomycin instillation.

Amino Acid Oxidoreductases↗
PubMed1982

Potentiation of bleomycin toxicity by oxygen.

The clinical usefulness of bleomycin is limited by pulmonary toxicity. Recent clinical observations indicate that the pulmonary toxicity is potentiated in patients who are exposed to elevated but nontoxic concentrations of O2. We studied the interactions of O2 and bleomycin using a murine model. Mice were divided into two groups. One group was continuously exposed to 40% O2 at 1 atmosphere while the other group breathed compressed room air. The elevated O2 concentration alone was not toxic to animals. Mice in each group received either 40 mg/kg of bleomycin or normal saline twice a week sc. Median survival of mice receiving bleomycin was shortened from 8.24 to 4.35 weeks when the animals were maintained on 40% O2 (P = 0.0001). We conclude that exposure to a nontoxic but elevated O2 concentration can potentiate the toxic effects of bleomycin.

Animals↗
PubMed1982

[Mutagenesis in Streptomycete cultures exposed to bleomycin].

Mutagenic properties of bleomycin, an antitumor antibiotic were studied with respect to 2 species of streptomycetes producing practically important antibiotics. A multifold increase in the frequency of prototrophic revertants among the survivors of strains His- and Met- of Actinomadura carminata exposed to bleomycin was observed. Bleomycin was effective in induction of various morphological mutants, and auxotrophs at a high survival rate of the spores of Str. cremeus var. tobramycini, a tobramycin-producing organism. It was shown with the method of subsequent mutagenesis that the efficacy of induction of morphological and auxotrophic mutants in germinating spores of Actinomadura carminata, a carminomycin-producing organism by bleomycin in a concentration of 100 micrograms/ml and an exposure time of 5 minutes was much higher that in the latent spores. The mutagenic effect of bleomycin is comparable with that of ionizing radiation.

Actinomycetales↗
PubMed1982

Bleomycin-induced increase of collagen turnover in IMR-90 fibroblasts: an in vitro model of connective tissue restructuring during lung fibrosis.

Late-log-phase IMR-90 human fetal lung fibroblasts were incubated with bleomycin sulfate for 48 hr. The culture medium was removed and replaced with serum-free medium and [5-3H]proline. The cells were then incubated for increasing time intervals. The cells and culture medium were collected, and radioactive proline incorporated into collagen and noncollagen protein was determined. Intracellular collagen synthesis was selectively increased. Furthermore, polysomes isolated from bleomycin-treated cells synthesized significantly more collagen in the wheat germ lysate than did control polysomes. Prolyl hydroxylase activity was also increased significantly in the bleomycin-treated cells. Free and peptide-bound radioactive hydroxyproline in the cells and medium was greatly increased in bleomycin-treated cells, which indicates increased collagen degradation. The results demonstrate that, although collagen synthesis in lung fibroblasts is increased by bleomycin, the newly synthesized collagen is rapidly degraded in both the cell layer and the medium. This increased collagen degradation may be responsible for the remodeling which takes place during lung fibrosis.

Bleomycin↗
PubMedDate not supplied

Influence of bleomycin on the crosslinking of dermal collagen in rat.

The effect of bleomycin on dermal collagen crosslinking was studied in male albino rats. The skin samples were taken on the 28th day in both groups. Results showed that the percent reversibilities of neutral salt soluble collagen gels and the solubility of insoluble collagen in KCNS, urea or pronase were decreased in bleomycin treated animals whereas the aldehyde content was significantly increased in bleomycin treated animals compared to controls. The electrophoretic pattern of neutral salt soluble collagen on SDS-polyacrylamide gels revealed a marked decrease of alpha/beta ratio in bleomycin treated group. These results indicated that both the intra and inter molecular crosslinks of collagen were increased in the bleomycin treated group.

Aldehydes↗
PubMed1983

Cisplatin-induced changes in bleomycin elimination.

Bleomycin disposition was studied in two children who received at least six courses of vinblastine, bleomycin, and cisplatin. Total plasma clearance of bleomycin decreased from 39 to 18 ml/min/m2, while the terminal-phase half-life increased from 4.4 to 6.0 hrs since the cumulative cisplatin dose was greater than 300 mg/m2. In one patient, renal clearance of bleomycin decreased from 30 to 8.2 ml/min/m2. Changes in serum creatinine or BUN were not predictive of changes in bleomycin elimination.

Adolescent↗
PubMed1982

[Lethal effect of bleomycin on Burkitt lymphoma cells at stationary phase].

Effects of bleomycin on cultured Burkitt lymphoma cells (P3HR-1) at the stationary phase were studied. They showed a marked less sensitivity to bleomycin than the cells at the exponential phase. The cell kinetic analysis revealed that the stationary phase was occupied by G1 cells, which were different from exponential G1 cells at various points of metabolic and nutritive state except for DNA content. Then, by synchronizing the exponential cells with hydroxyurea, the response of G1 cells to bleomycin was obtained. As a result, their sensitivity to the drug was found to almost coincide with that of the stationary cells. Therefore, the less sensitivity of the stationary cells to bleomycin was due to the total occupation of the stationary phase by G1 cells showing originally resistance to bleomycin.

Bleomycin↗
PubMed1983

Pimaricin potentiation of bleomycin activity against murine tumors.

Antitumor activity of bleomycin against Ehrlich ascites carcinoma in mice was examined in the presence and absence of a polyene antibiotic, pimaricin. A single intraperitoneal (ip) injection of bleomycin and pimaricin in combination into tumor-bearing mice on day 1 produced a synergistic life-prolongation effect as compared with that of each agent alone. Accumulation of abdominal ascites was almost completely blocked by bleomycin in combination with the tetraene antibiotic. Frequent ip injection of small doses of bleomycin and pimaricin on day 1 produced a much greater increase in life span than the single ip injection. To obtain effective synergism under these treatment schedules, it appeared that the dose of bleomycin should be reciprocally proportional to the dose of pimaricin.

Animals↗
PubMed1983

[Bleomycin in the treatment of squamous cell carcinoma of the penis and bladder].

Bleomycin is an antineoplastic antibiotic with special effects on squamous cell carcinomas. Penile carcinomas in early stages may be treated with good early results by Bleomycin alone. In contrast to the normal course of penile carcinomas late recurrences and metastases may develop even after an interval of more than seven years. Therefore the monotherapy with Bleomycin is no longer recommended. The effects of Bleomycin on squamous cell carcinomas of the bladder are disappointing. The new therapeutic approach with Bleomycin and hyperthermia of the bladder may give better results.

Antineoplastic Agents↗
PubMed1983

The place of 57Co-bleomycin in the evaluation of tumours.

162 patients were investigated by 57Co-bleomycin scintigraphy. 62 of these patients were also studied with 67Ga. 142 were suspected for malignant neoplastic disease, 20 for a focal inflammatory process. Good visualization with 57Co-bleomycin was obtained in 75% of malignant tumours and in 66% with 67Ga. Most of the patients were studied for abdominal disease and in this region 57Co-bleomycin was found to be qualitatively superior to 67Ga. The principal advantage of 57Co-bleomycin is a very low tissue background specially concerning the bowel. Neither 57Co-bleomycin nor 67Ga are tumour-specific. Both radiopharmaceuticals are taken up by inflammatory processes. This is a disadvantage in tumour diagnostics but the radionuclides can be useful for localizing inflammatory foci. The possibilities of studying the localisation of radionuclides at the cellular level will be discussed.

Animals↗