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PubMed1985

Chemical reactivities of bleomycin.

Ferric bleomycin was tested for its ability to catalyze a set of six oxidative reactions characteristic of the heme-containing proteins, cytochrome P-450 and chloroperoxidase. These reactions included peroxyacid decarboxylation and aliphatic hydroxylation as typical cytochrome P-450 chemistries. Peroxyacid-supported oxygen evolution and hydrogen peroxide-mediated chlorination were utilized as characteristic chloroperoxidase reactivities. A typical peroxidative reaction and heteroatom dealkylation, common to both O2 activating enzymes, were also studied. Bleomycin was found to catalyze peroxidation of o-dianisidine. The ferric drug complex was found competent in carrying out N-demethylation of N,N-dimethylaniline when peroxides or peroxyacids or iodosobenzene were used as the oxidants. N-Demethylation was not achieved when N,N-dimethylaniline-N-oxide was substituted as the oxidant under similar conditions. Hydroxylation of cumene and decarboxylation of phenylperacetic acid were not found to be catalyzed by bleomycin. Oxygen evolution from m-chloroperbenzoic acid and chlorination of monochlorodimedone from chloride ion and hydrogen peroxide were found to be catalyzed by bleomycin. Cytochrome P-450cam was also evaluated for O2 evolution, and halogenation activity and was found not to demonstrate such reactivities. The results of this initial survey, along with those of previous studies, appear to indicate that the chemical reactivity of bleomycin can be more closely aligned with the reactivities demonstrated by chloroperoxidase than those of cytochrome P-450.

Aniline Compounds↗
PubMed1985

Bleomycin lung injury in children. Pathophysiology and guidelines for management.

The development of pulmonary side effects, especially pulmonary fibrosis, during treatment with bleomycin is well documented in adult oncology patients, but not in children. A report of fatal pulmonary fibrosis which developed after exposure to oxygen while under anesthesia in a 3-year-old boy treated with bleomycin exemplifies the problem. The prevention of long-term complications associated with bleomycin is especially important in children, since a child cured of a malignant neoplasm may enjoy many years of productive life. Given the present limitations, guidelines for management of pediatric patients given bleomycin include: discontinuation of bleomycin therapy with the onset of symptoms; serial pulmonary function testing during the course of treatment; and early treatment with high-dose corticosteroids (prednisone 2 mg/kg/day) if symptoms occur.

Bleomycin↗
PubMed1985

Deferoxamine injection does not affect bleomycin-induced lung fibrosis in rats.

Bleomycin is an antineoplastic agent that causes a dose-related lung fibrosis that limits its therapeutic effectiveness. It has been proposed that the cellular toxicity and antitumor effects of bleomycin occur by formation of O2-Fe(II)-bleomycin complexes that degrade DNA and release O2- and OH radicals that attack other cellular components. Twice daily injections of the iron chelator deferoxamine were utilized in an attempt to ameliorate bleomycin-induced lung fibrosis. They failed to diminish bleomycin-induced lung inflammation and fibrosis in rats.

Animals↗
PubMed1986

Promotion of pulmonary metastasis in mice by bleomycin-induced endothelial injury.

The passage of circulating tumor cells across the vascular wall is an important step in the evolution of cancer metastases. Since tumor cells attach preferentially to subendothelial matrix at sites of endothelial injury and retraction in vitro, we have used an established in vivo model of pulmonary endothelial damage to examine the effects of endothelial injury on the localization and metastasis of circulating tumor cells in vivo. C57BL/6 mice were given a single i.v. dose of bleomycin (120 mg/kg) or multiple i.p. injections (10 mg/kg, twice weekly for 6 wk). Five days after the single injection or 4 days after the last i.p. injection, 2 X 10(5) [131I] iododeoxyuridine-labeled fibrosarcoma cells or unlabeled cells were injected i.v. Two to 8 times as many labeled cells were found in the lungs of bleomycin-treated animals after 24 h. Two and 3 wk after injecting unlabeled fibrosarcoma cells, 1.4 to 5 times more metastatic lung colonies were counted in bleomycin-treated animals than in controls. Morphometric analysis of histological sections demonstrated that the percentage of lung area occupied by tumor in bleomycin-treated animals was between 4 and 16 times that of controls. Analysis of bronchoalveolar lavage fluids demonstrated 5-fold increases of total protein content and leakage of previously injected 125l-labeled albumin, indicating increased endothelial permeability. Electron microscopic examination of lungs of bleomycin-treated mice demonstrated endothelial retraction with exposure of the underlying basement membrane. Electron microscopy of [3H]thymidine-labeled tumor cells, located by autoradiography, demonstrated their attachment to exposed basal lamina. Data from these experiments in vivo support the hypothesis that endothelial damage can facilitate the metastasis of circulating tumor cells.

Animals↗
PubMed1986

Cytotoxicity of hyperthermia combined with bleomycin or cis-platinum in cultured RIF cells: modification by thermotolerance and by polyhydroxy compounds.

The effect of thermotolerance and of polyhydroxy compounds on the cytotoxicity of bleomycin and cis-platinum was studied in cultured RIF tumor cells. Cell survival in response to drug-heat treatments was compared in cells not previously exposed to hyperthermia and in preheated cells that had developed thermotolerance. Since cellular accumulation of polyhydroxy compounds is a potential mechanistic basis of thermotolerance, we also compared cell survival of thermotolerant cells and chemically heat-protected cells. The cytotoxicity of bleomycin and cis-platinum in control cells treated with drug plus heat (43 degrees C, 1 h) was increased synergistically over the cytotoxicity of drug and heat alone. In thermotolerant cells, the synergistic interaction was largely reversed with the bleomycin-heat combination but retained with cis-platinum at 43 degrees C. In the absence of heat, bleomycin and cis-platinum showed similar cytotoxicity in control and thermotolerant cells. The addition of heat protectors (erythritol or galactose) modified the drug-heat cytotoxicity similar to thermotolerance. The synergistic interaction of bleomycin-43 degrees C, but not cis-platinum-43 degrees C, was reversed by the polyhydroxy compounds.

Bleomycin↗
PubMedDate not supplied

Response of mammary tumors of C3H/He mice to hyperthermia and bleomycin in vivo.

The cytotoxicity of bleomycin in vitro has previously been shown to be enhanced by hyperthermia. This study demonstrates in vivo a synergistic interaction between local hyperthermia (43 degrees C, 45 min) and bleomycin (15 mg/kg) against implanted mammary tumors of C3H/He mice. Hyperthermia was given by water bath heating. When combined treatments of heat and bleomycin were administered within 30 min of each other, a synergistic effect was observed. In contrast, when the interval between heat and bleomycin injection was longer than 30 min, only an additive effect was obtained. Timing is therefore considered to be a critical factor for the optimal combination of hyperthermia and bleomycin.

Animals↗
PubMed1986

Hydroxyurea-induced conversion of mammalian ribonucleotide reductase to a form hypersensitive to bleomycin.

Bleomycin is a commonly used chemotherapeutic agent known to cause extensive DNA damage. In this paper we show that bleomycin inhibits ribonucleotide reductase activity in mouse L-cells. The effectiveness of the drug is a result of its metal-chelating properties which enable it to inactivate the iron containing M2 subunit of the enzyme. A hydroxyurea-resistant mouse L-cell line was used to show that the degree of inhibition caused by bleomycin can be greatly enhanced if ribonucleotide reductase has been previously exposed in vivo or in vitro to agents, such as hydroxyurea, which destroy the tyrosine free radical of subunit M2. The increased effectiveness of bleomycin appears to result from a decrease in the stability of the iron center of protein M2 following exposure to hydroxyurea. These findings have important implications in terms of the use of bleomycin as an anticancer agent, especially in combination chemotherapy where it can be used with other drugs that act at ribonucleotide reductase.

Adenosine Diphosphate↗
PubMed1986

Measurement of bleomycin, neocarzinostatin, and auromomycin cleavage of cell-free and intracellular simian virus 40 DNA and chromatin.

Simian virus 40 (SV40) was used as a model for eukaryotic chromatin to allow analysis of strand scission drug action on DNA of the same nucleotide sequence in different environments. Cleavage of purified DNA, cell-free chromatin, and intracellular chromatin by the antitumor drugs bleomycin, neocarzinostatin, and auromomycin was assayed. Comparison of total (single-and double-stranded) drug-induced cutting of purified SV40 DNA and isolated viral minichromosomes, as measured by the conversion of supercoiled DNA to the nicked circular form, revealed that a 2-3-fold higher concentration of all three drugs is required to cut minichromosomes as extensively as naked DNA. In addition, differences in drug activity on cell-free nuclear viral chromatin and intracellular SV40 chromatin were measured. Three times more auromomycin was needed to cut intracellular SV40 DNA as extensively as the viral DNA in isolated nuclei, whereas, surprisingly, the increases in bleomycin and neocarzinostatin concentrations were 200-fold and 1000-fold respectively. When the drugs were used to treat SV40-infected cells, no repair of strand scissions was detected. Formation of double-stranded breaks by bleomycin, neocarzinostatin, and automomycin, measured at equivalent levels of total cleavage, was also examined to provide information on the distribution of strand scissions in different environments. Nucleoproteins were found to cause a 3-fold higher level of neocarzinostatin-induced double-stranded breaks to be made on isolated minichromosomes than on purified DNA, but they had no effect on double-stranded break formation by either bleomycin or auromomycin. In contrast, auromomycin made twice as many double-stranded breaks on intracellular SV40 DNA as on minichromosomes in isolated nuclei. However, neither bleomycin- nor neocarzinostatin-induced double-stranded breaks on intracellular SV40 DNA were significantly different from those made on SV40 in isolated nuclei.

Animals↗
PubMed1987

Treatment of favorable-prognosis nonseminomatous testicular germ cell tumors with etoposide, cisplatin, and reduced dose of bleomycin.

We have explored a dose reduction of bleomycin in combination with etoposide and cisplatin in the treatment of a good-prognosis subgroup of patients with nonseminomatous germ cell tumors. Twenty-two patients were treated with etoposide, cisplatin, and low-dose bleomycin. All patients achieved complete remission, but four relapsed. Three patients achieved long-term remission after salvage therapy. The disease-free survival rate of 82% (18 of 22 patients) at a median follow-up of 24 months (range, 17-33) was significantly worse compared to the 99% disease-free survival rate in 91 patients receiving full-dose bleomycin, etoposide, and cisplatin. These results are similar to a previously reported 82% disease-free survival rate of 17 patients treated with etoposide and cisplatin alone. The combined results of the 82% disease-free survival rate in the total group of 39 patients treated with etoposide and cisplatin and etoposide, cisplatin, and low-dose bleomycin suggest that the reduced bleomycin regimens in their present schedule constitute inadequate therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Radiation doses from 51Cr-bleomycin.

Extensive studies were made of long-term whole-body retention, plasma concentration, urinary excretion and organ retention of 51Cr in rats after intravenous injection of 51Cr-bleomycin. A similar but less extensive investigation was performed on rabbits, and whole-body retention, plasma concentration and urinary excretion was also followed in patients given 51Cr-bleomycin for diagnostic purposes. From an analysis of the collected information it followed that integrated whole-body and organ retention, corrected for radioactive decay, is similar in man and rabbit, and higher by a factor of about 2 in the rat. Doses to organs and whole body in man were calculated using the MIRD methodology and assuming conservatively that the kinetic data derived in rats are applicable to man. The organ and whole-body MIRD doses after 51Cr-bleomycin administration are comparable to those after 67Ga-citrate and the effective dose equivalent from a diagnostic amount of 740 MBq of the 51Cr complex amounts to about 6 mSv. However, the subcellular distribution in the liver of 51Cr, administered in the form of 51Cr-bleomycin, indicated a significant enrichment of 51Cr in the nuclei and in the DNA over mean concentrations in the liver cells. Also, the quality factor for Auger electrons, emitted by 51Cr, when assessed on the basis of the Q vs. LET relationship, as proposed by ICRP, was substantially higher than unity. Doses calculated for cell nuclei and the DNA in the liver cells were higher than the cell-averaged values by a factor 2.5 and 5, respectively, and the corresponding dose equivalents by a factor of 9 and 24. The effective dose equivalent, estimated on the basis of dose equivalents to cell nuclei and the DNA, amounted to 33 and 83 mSv per examination (740 MBq of 51Cr-bleomycin), respectively.

Animals↗
PubMedDate not supplied

Enhancement of bleomycin activity by 3-aminobenzamide, a poly (ADP-ribose) synthesis inhibitor, in vitro and in vivo.

A series of poly (ADP-ribose) synthesis inhibitors was evaluated for their ability to potentiate the cytotoxicity of bleomycin compared with their inhibition of poly(ADP-ribose) synthesis in L1210 cultured cells. Theophylline, nicotinamide, 3-aminobenzamide and thymidine inhibited 70 to 80% of poly(ADP-ribose) synthesis in L1210 cells. The degree of inhibition of poly(ADP-ribose) synthesis by these inhibitors corresponded in general with their potentiating ability of bleomycin cytotoxicity. Among these inhibitors, 3-aminobenzamide significantly potentiated the cytotoxic activity of bleomycin (3.6 fold), but it could not potentiate the cytotoxic activity of other antitumor agents, including nitrosourea and Cis-DDP, in L1210 cells in vitro. Treatment of Ehrlich ascites tumor bearing mice with bleomycin and 3-aminobenzamide produced a synergistic effect. 6-Aminonicotinamide also potentiated the antitumor activity of bleomycin against Ehrlich ascites tumor.

Animals↗
PubMed1988

Bleomycin-stimulated hamster alveolar macrophages release interleukin-1.

The capacity of alveolar macrophages (AM) of bleomycin-instilled hamsters to proliferate mouse thymocytes (interleukin-1 activity) and hamster fibroblasts (fibroblast proliferation (FP) activity was studied. Using bleomycin-instilled hamsters, the FP activity of AM culture supernatants was increased significantly on days 1, 5, and 10 after instillation of bleomycin. The interleukin-1 (IL-1) activity, however, was increased significantly on day 1 only as compared with saline-treated hamsters. Next, normal AM were stimulated in vitro by bleomycin. After being fractionated by chromatography, their culture supernatant showed IL-1 activity, which also indicated FP activity. These results suggest that bleomycin directly stimulates AM to release IL-1 in the fibrogenic responses.

Animals↗
PubMed1988

[Clinical usefulness of bleomycin combined with preoperative irradiation in cancer of the esophagus].

The clinical usefulness of bleomycin combined with irradiation was evaluated using 154 preoperatively treated cases with cancer of the esophagus. With the appearance rate Ef-3 (highly effective: no viable tumor cell in the esophageal specimen resected after preoperative treatment) the radiation effect was observed, in comparison with those three groups (30 Gy alone, 40 Gy alone and 30 Gy + 67.5 mg of bleomycin). Dose modifying actor (DMF) of bleomycin for the preoperatively irradiated esophageal cancer was 1.2-1.3. As a serious interstitial pneumonitis was sometimes caused by the administration of bleomycin, it was concluded that the usage of bleomycin combined with preoperative irradiation for cancer of the esophagus, is less useful than that for cancer of the uterine cervix and the head and neck region.

Bleomycin↗
PubMed1985

[Long-term prognosis of oral squamous cell carcinoma histologically judged to have been eliminated by the treatment with bleomycin alone].

This study was intended to reveal the long-term prognosis in 21 patients with oral squamous cell carcinoma evaluated histologically as having disappeared by bleomycin treatment. Of 16 cases treated with bleomycin alone, recurrence was observed in 4, and cervical metastases in 2, with survival achieved for 5 years or more in 7 (more than 10 years in 3). No recurrence was observed in 5 patients in whom surgery was additionally performed after the bleomycin treatment, but cervical metastasis was found in one of them. In the cases with epithelial dysplasia after bleomycin therapy, recurrence and metastasis were frequent compared to those with normal epithelium, and this discrepancy was of statistical significance. It has been proved that there are long-term survivors among patients with oral carcinoma treated with bleomycin alone.

Adult↗
PubMed1975

Bleomycin as carrier substance for 99m-Technetium in tumour diagnosis (author's transl).

99m-Tc-Bleomycin is a promising tool for scintigraphic imaging of some types of malignant tumours. The rapid decay of 99m-Tc, together with a high affinity of bleomycin for certain histologically-defined tumours recommends its use in humans. Moreover, by using high specific activities of bleomycin, no toxic effects are to be expected. At 00-C, the chelate of 99m-Tc and bleomycin is stable and its storage or transport are recommended at this temperature. Following the i.v. injection of rats with 99m-Tc-bleomycin, a high specific activity is found in the liver, spleen, lungs and skin. In view of its excretion by the kidneys an extremely high activity is found in the urogenital system. Scintigraphic imaging of lymph nodes in a case of Hodgkin's disease, of a embryonal carcinoma, of a thyroid carcinoma, of an astrocytoma and of a solid carcinoma was obtained in patients investigated by this method.

Adult↗
PubMed1975

[Comparative effectiveness of pulmonary scintigraphy and radiography in detecting toxic side-effects of Bleomycin treatment (author's transl)].

Pulmonary toxic effects subsequent to intravenous injections of bleomycin in cancer therapy have well been demonstrated. In order to prevent the acute pathological pulmonary manifestations of the treatment, it is necessary that the patient be submitted to repeated controls of the lungs. As yet, the efficiency of the current diagnostic procedures for detecting the lesions dues to bleomycin injections is not clearly demonstrated. The authors present the results of a comparative study on the effectiveness of radiological and scintigraphic examination of the lung in detecting toxic side-effects of bleomycin. Both procedures were used repeatedly on rabbits, before, during and after the bleomycin treatment. The findings are discussed on the basis of the macroscopic and histological examination of the lungs. The results demonstrate that pulmonary scintigraphy with radioactive macroaggregates is more sensitive than radiography in detecting the early lesions of the lungs after bleomycin treatment.

Animals↗
PubMed1975

Preparation and chemical characterization of radioiodinated bleomycin.

None of the radionuclides with which bleomycin has been labeled have chemical and nuclear properties that are entirely satisfactory for in vivo tumor localization. Bleomycin has been radioiodinated by the iodine monochloride, chloramine-T, and lactoperoxidase methods. Iodine monochloride proved to be the preferred method and conditions were developed whereby 80% of radioiodide was covalently bound to bleomycin. Bleomycin (140 mug) was added to 200 mul of saline/citrate buffer (pH 7.0) followed by radioiodide and iodine monochloride. This reaction mixture was incubated for 1 hr and purified by Sephadex G-10 chromatography. The iodine monochloride reaction product underwent hydrolytic deiodination in vitro at a rate of about 1.2%/day (0.15 M NaCl, 37 degrees C). Bleomycin A and B components were radioiodinated with equal efficiency on a mole fraction basis.

Bleomycin↗
PubMed1975

[Induction of prophage gamma by means of bleomycin treatment].

The kinetics of induction of lambda prophage with bleomycin A2-CP3, mitomycin C and a combination of these two antibiotics have been studied. Bleomycin has been found to cause a rapid induction of prophage in exponentially growing cultures of E. coli K12 (lambda), and the maximal values of including activity are obtained after treatment for 16 minutes with a concentration of 10 mug/ml. The per cent of induction, calculated from the total number of surviving cells, including the phage producing cells, better expresses the dynamics of the phenomenon. The number of inducing events in the population of exposed cells is proportional to the length of bleomycin treatment. These values are greater than those observed after treatment with mitomycin, at the same concentration. Inducing activity is enhanced by combination of the two antibiotics and this effect is not additive, but synergic. After the 16 minutes of treatment with bleomycin the burst sizes are lower than those which are obtained with mitomycin or with the combination of the two antibiotics. The results are interpreted as a consequence and a confirmation of the different mechanisms of action that distinguishes bleomycin from mitomycin.

Bleomycin↗