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PubMed1980

Chemical properties and tumor affinity of separated isomers of cobalt-bleomycin.

Co-57 bleomycin is a chemically stable and diagnostically useful radiopharmaceutical. Stoichiometric preparation of Co-bleomycin causes two chemically different complexes. Four kinds of chelates (A2- type I, A2-type II, B2-type I and B2-type II) are easily separated by silicagel then-layer chromatography. Circular dicroism study of these chelates indicate that two types of complexes are conformational isomers. This chemical difference is assumed to cause the difference in the biological behavior. The biodistribution study of each type of complex, using tumor-bearing mice, showed higher tumor-to-blood ratios and tumor-to muscle ratios as compared with the clinical grade Co-bleomycin mixture. But the difference between the two types was not as large as expected. The similarity in biologic bahavior suggests that the groups on the bleomycin molecule, which are concerned with chelate formation, do not take part in its binding to DNA.

Animals↗
PubMed1979

The influence of chemotherapy on the distribution of 57Co-bleomycin in chemically induced squamous cell carcinoma of mouse skin.

Organ distribution and tumor uptake of 57Co-bleomycin (BLM) were examined in NMRI mice without tumor and with chemically (DMBA-) induced squamous cell carcinoma. In these tumors high accumulation of 57Co-BLM was recorded shortly after injection of 57Co-BLM and low uptake 24--48 h after application. Two groups of tumor-bearing mice received unlabeled bleomycin as a cytostatic in two different doses. Uptake of 57Co-bleomycin was reduced. The study suggests that in patients currently or previously under chemotherapy, 57Co-bleomycin tumor scintigraphy may lead to false negative results.

Animals↗
PubMed1980

Comparison of 67Ga-citrate, 111In-bleomycin and 99mTc-citrate in the evaluation of pulmonary lesions.

A total of 128 patients were examined using three tumor localizing agents, 99mTc-citrate, 111In-bleomycin and 67Ga-citrate. All these patients had clinical symptoms of pulmonary disease and chest x-rays. Twenty-two patients were excluded from the original number. From the 106 remaining patients, 14 were benign cases and 92 malignant. A scan with a gamma-camera was performed 3 to 4 h following an intravenous injection of 15 mCi of 99mTc-citrate. Upon completion of this examination, the patient was given 2.5 mCi of 67Ga-citrate and 72 h later, scans were obtained using a 5in. rectilinear scanner. Fifteen days later 2.5 mCi of 111In-bleomycin was given and a similar examination to that of gallium was performed. In evaluating benign lesions, 99mTc-citrate gave no false positive results, while 111In-bleomycin gave 5% and 67Ga-citrate 20%. In the case of malignant lesions, 67Ga-citrate gave 79% true positive diagnosis, 111In-bleomycin 65% and 99Tc-citrate (of 57 evaluated patients) 46%.

Adult↗
PubMed1984

Bleomycin-induced chromosomal aberrations and sister chromatid exchanges in Down lymphocyte cultures.

Peripheral blood lymphocytes from three patients with Down syndrome (DS; trisomy 21; aged 5-6 years) and three age-matched control children were studied for the induction of chromosomal aberrations and sister chromatid exchanges (SCEs). Cells in G0 were exposed to bleomycin (20-100 micrograms/ml) for 3 h, and then cultured in medium containing 5-bromodeoxyuridine and phytohemagglutinin for 66 h. By the sister chromatid differential staining method, chromosome analyses were performed on metaphase cells that had divided one, two, or three or more times after treatment. The results indicate that DS cells exposed to bleomycin are hypersensitive to the production of dicentric and ring chromosomes compared to normal cells. Bleomycin also led to a dose-related increase in the frequency of SCEs, but no difference was found between the SCE frequencies in DS or normal lymphocytes exposed to bleomycin.

Bleomycin↗
PubMed1986

Comparison of bleomycin and peplomycin toxicity on clonogenic tumor cells from various human tumors.

The cytotoxic effect of bleomycin and peplomycin was compared using a methylcellulose monolayer assay for the cultivation of human tumor cells. In 3 out of 4 samples from human malignant melanomas peplomycin proved to be more cytotoxic than bleomycin. Peplomycin was more cytotoxic than bleomycin in 1 of 5 myosarcoma samples, whereas 2 samples from squamous cell carcinomas of the lung showed identical dose response curves. In 1 carcinoma of the gall bladder peplomycin was more toxic than bleomycin.

Bleomycin↗
PubMed1976

Vascular lesions following perfusion with bleomycin. Electron-microscopic observations.

During intra-arterial perfusion therapy of oral squamous cell carcinomas with bleomycin, circumscribed necrotic areas in the perfused region are observed in a few cases. These are usually located in the acral regions. As the cause, a lesion of the blood vessels with formation of microthrombosis could be demonstrated. Electron-microscopic observations of the blood vessels in five bleomycin-perfused tumor areas demonstrated lesions of the endothelium characterized by swelling of the cells, formation of intracytoplasmatic vacuoles and villous projections into the lumen of the vessel. In arterioles, separation of the endothelium from the underlying tissue, swollen smooth muscle cells and destruction of elastic lamellae were found. These were the pacemakers for the formation of thrombosis. A negative influence of the vascular lesions on the cytostatic effect on the tumor is likely. Vascular lesions also constitute one of the initial factors for the development of the bleomycin-induced lung lesion (bleomycin lung).

Bleomycin↗
PubMed1989

Phase I trial of combined therapy with bleomycin and the calmodulin antagonist, trifluoperazine.

Calmodulin antagonists, such as trifluoperazine, can enhance the cytotoxic effects of bleomycin both in tissue culture and in vivo. Therefore, we evaluated the effects of combination treatment with these drugs in a phase I clinical trial. Patients with objectively measurable or evaluable cancer refractory to conventional treatment who had an acceptable performance status (ECOG 0-2) and acceptable laboratory studies were eligible. All patients gave written informed consent. A cycle of therapy consisted of three weekly treatments with trifluoperazine (days 1-4) and 30 IU bleomycin (day 3). After three patients completed a cycle of therapy without experiencing dose-limiting toxicity, new patients were entered in the study and received a higher dose of trifluoperazine. The dose of bleomycin remained constant. Evaluable patients received at least 2 weeks of treatment and survived for 6 weeks; of 19 patients, 2 were unevaluable. The major toxicities were neurological and pulmonary and included one case of fatal pneumonia with interstitial pulmonary fibrosis. There was no hematologic toxicity. Two patients underwent partial responses (PRs) and two had complete responses (CRs). We conclude that trifluoperazine can safely be given with bleomycin and that further study of the potential efficacy of this treatment is indicated.

Adult↗
PubMed1976

Comparative studies of the incorporation inhibition of radioactive nucleotides and amino acids in vitro under the influence of adriamycin, bleomycin, and sodium arsenate.

The incorporation of 14C-marked nucleotides and amino acids into the nucleic acids and into the cellular protein of PHA-stimulated human lymphocytes was inhibited variably by increasing doses of Adriamycin, Bleomycin and Na2HAsO4. The findings, which were obtained with the aid of the liquid scintillation counter and partly by means of 14C-thymidine-marked autoradiographies shows clearly that Adriamycin causes the strongest incorporation inhibition. In contrast to this, the inhibition caused by Bleomycin and arsenate is considerably less destructive. It was shown by means of cytophoto metrical examinations that Adriamycin is capable of fixing cells in the G2 phase and in the S phase. Cells react similarly to Bleomycin and arsenate. The differential inhibition of nucleic acid and protein metabolism induced by Adriamycin, Bleomycin and arsenate is correlated with a varying responsiveness of lymphocytes to the cytostatically effective substances.

Arsenates↗
PubMed1984

[Bleomycin-induced pulmonary infiltrations in the treatment of testicular cancer].

Under Cisplatinum/Vinblastine/Bleomycin treatment six of 82 patients with nonseminomatous testicular cancer developed a Bleomycin-induced pulmonary toxicity. After a total Bleomycin dose of 300-360 mg all six patients showed multiple nodular densities near the pleura in the basal lung areas on the computed tomographic scanning (CT). Disseminated interstitial infiltrates, mostly in the lower lung fields were spontaneously observed by means of chest X-rays in only one case. In two other cases only minimal changes were found retrospectively. In five cases the diffusion capacity did not decrease significantly. Diffusion capacity, vital capacity and oxygen fell significantly in only one case. The latter was also the only patient showing clinical symptoms. The lung changes were completely reversible in four patients 4-6 months after cessation of Bleomycin. In two patients there were reversible residual changes after a timespan of 20 and 24 months. Two patients received no further antineoplastic treatment, two were under maintenance therapy, two under further induction chemotherapy because of the assumption of lung metastases. None of the six patients show any evidence at present of testis tumor (observation period 17-34 months). It can be difficult to distinguish between Bleomycin-induced lung damage and tumor metastases by radiological means. We were able to differentiate by observing the clinical course of the six patients. In case of doubt a histological examination is strongly recommended.

Adult↗
PubMed1989

Bleomycin-kanamycin resistance as a marker of the presence of transposon Tn5 in clinical strains of Escherichia coli.

The aminoglycoside modifying enzyme aminoglycoside 3'-phosphotransferase II (APH(3')II) is encoded for on transposon Tn5 by the aphA gene, in the same operon as the ble gene determining bleomycin resistance. To document this linkage 82 kanamycin-resistant Escherichia coli strains of clinical origin were studied; all 18 isolates presenting bleomycin-kanamycin resistance were shown by an enzymatic assay to produce APH(3')II, and the presence of Tn5 was demonstrated by gene hybridization. Similarly, bleomycin-kanamycin resistance was shown to be linked to APH(3')II production in Salmonella spp. The epidemiology of strains with Tn5-encoded APH(3')II may thus be studied, at least in Escherichia coli, by a simple diffusion test using bleomycin and kanamycin discs.

Bleomycin↗
PubMed1986

Intravesical bleomycin in bladder tumour prophylaxis.

The authors have evaluated the efficacy, tolerability and systemic absorption of bleomycin administered by intravesical route in the prophylaxis of recurrences of superficial vesical tumours after endoscopic resection (TUR). Thirty mg of bleomycin dissolved in 30 ml of saline solution were instilled in the bladder once a week for the first month and then once a month for 12 months. The instilled fluid was held in the bladder for 1 hour. The systemic absorption of the drug was evaluated by a microbiological assay of bleomycin in plasma and in the perfusion liquid recovered from the bladder. Fifteen patients were treated; most had a long history of multiple recurrent tumours despite previous intravesical treatments. Thirteen patients presented tumour recurrences during the treatment; 4 of them were given a second course of instillations following a second TUR and 3 of these presented further recurrences. The authors conclude that the drug, administered intravesically to high-risk patients with the modalities employed in the present study, was not effective in preventing recurrences. It was well tolerated locally and was free from systemic toxicity. The amount of bleomycin that was not recovered from the bladder after a contact time of one hour was relatively high but the drug did not reach measurable levels in the peripheral blood.

Aged↗
PubMed1979

Fatal interstitial pneumonitis induced by low dosage of bleomycin in an esophageal cancer patient.

One-shot intratumor injection of 60 mg oil-bleomycin prior to subtotal esophagectomy induced fatal, acute interstitial pneumonitis in a 53 year-old esophageal circinoma patient. The progression of bleomycin-induced pneumonitis was rapid and the patient succumbed to respiratory insufficiency 41 days after surgery (58 days after bleomycin administration). Autopsy revealed bilaterally increased lung weight and the organ was of rubbery consistency and anthracotic. Histology showed advanced interstitial fibrosis, numerous lymphocytes in alveolar septi and fibrinous exudate, macrophages and desquamative cells within the alveolar spaces. In the present case, pneumonitis was due not to patient age or dosage level of bleomycin, but rather to the administration method.

Bleomycin↗
PubMed1998

[Bleomycin-induced PSS-like pseudoscleroderma. Case report and review of the literature].

Although the association between administration of the antitumor agent bleomycin and the development of cutaneous fibrosis is established, there are only a small number of cases of bleomycin-induced scleroderma described in the literature. We report the development of generalised scleroderma with wide spread hyperpigmentation in a 52-year-old male patient, who received a total dose of 360 mg bleomycin in combination with cisplatin and etoposid for therapy of a malignant testicular seminoma. The clinical cutaneous alterations as well as the histological findings were indistinguishable from those encountered in progressive systemic sclerosis (PSS). In contrast to PSS however, Raynaud's phenomenon, cutaneous calcinosis, teleangiectasia, arthritis and involvement of additional organs were all absent. PSS-typical auto-antibodies were negative. Even 18 months after discontinuation of the drug and treatment with UVA1 phototherapy (3-4 times per week with 20 J/cm2) as well as physiotherapy, the skin changes had still not resolved. Based on our case and a detailed review of the literature, we discuss characteristics of bleomycin-induced scleroderma including pathogenesis, treatment modalities and course.

Antibiotics, Antineoplastic↗
PubMed1997

Is bleomycin-detectable iron present in the plasma of patients with septic shock?

OBJECTIVE: To assess plasma iron status in critically ill patients with septic shock. DESIGN: Observational, prospective study. SETTING: Adult intensive care units in teaching and tertiary referral hospitals. PATIENTS AND PARTICIPANTS: Fifteen adult patients with established septic shock. Normal control subjects (n = 10) were also investigated. Data from patients and controls were compared with previously published iron values in critical care patients. MEASUREMENTS AND RESULTS: The indices investigated and correlated with clinical scores of illness severity included bleomycin-detectable iron, non-haem iron; transferrin and its percentage iron saturation, and the iron binding (anti-oxidant) activity of transferrin. Bleomycin-detectable iron was not present in the plasma of patients with septic shock whilst the plasma transferrin remained unsaturated with iron. One patient in multi-organ failure displayed bleomycin-detectable iron in plasma (1.16 mumol/l) and had 100% iron-saturation of transferrin. The plasma non-haem iron levels (7.84 +/- 1.82 mumol/l) were the lowest of all critical care patient groups studied by us. The plasma transferrin levels were also low but resulted in a near normal percentage saturation of transferrin with iron (34.6 +/- 6.5%). The scores of clinical severity correlated with changes in plasma iron chemistry. CONCLUSIONS: Patients with septic shock rarely have iron saturated transferrin in their plasma leading to the presence of bleomycin-detectable iron.

APACHE↗
PubMed1997

Restoration of macrophage tumoricidal activity by bleomycin correlates with the decreased production of transforming growth factor beta in rats bearing KDH-8 hepatoma cells.

To explore the mechanisms of immuno-modulatory activities of bleomycin, we investigated interferon gamma (IFN gamma) mRNA expression, tumor necrosis factor alpha (TNF alpha) production, nitric oxide (NO) production and macrophage tumoricidal activities in rats bearing KDH-8 hepatoma cells, which secreted a large amount of transforming growth factor beta (TGF beta), and these processes in KDH-8 tumor-bearing rats treated with bleomycin. We found that IFN gamma mRNA expression, TNF alpha production, NO production and macrophage cytotoxic activities were lower in the KDH-8-bearing rats than in normal rats. On the other hand, low-dose bleomycin restored the macrophage cytotoxic activities, NO production, IFN gamma mRNA expression and TNF alpha production in the KDH-8-bearing rats. In vitro experiments showed that KDH-8-derived TGF beta decreased the IFN gamma mRNA expression and TNF alpha production in splenocytes, and NO production in peritoneal macrophages. These results suggest that low-dose bleomycin restored the cytokine production and macrophage tumoricidal activities in the KDH-8-bearing rats by decreasing KDH-8-derived TGF beta.

Animals↗
PubMed1999

Pharmacokinetics of paclitaxel administered in combination with cisplatin, etoposide and bleomycin in patients with advanced solid tumours.

PURPOSE: To evaluate the pharmacokinetics of paclitaxel and cisplatin administered in combination with bleomycin and etoposide and Granulocyte Colony-Stimulating Factor (G-CSF) in patients with advanced solid tumours. METHODS: Patients were recruited to a phase I trial where escalating doses of paclitaxel (125 to 200 mg/m(2)) were administered in combination with etoposide 100 or 120 mg/m(2), and fixed dose of cisplatin 20 mg/m(2) and bleomycin 30 mg, with the concomitant use of G-CSF. Paclitaxel (3-h infusion) was followed by 1-h etoposide, 4-h cisplatin and 30-min bleomycin infusions, respectively. Pharmacokinetics sampling for paclitaxel analysis was performed in ten patients from dose levels II-V. RESULTS: The mean paclitaxel area under the plasma concentration-versus-time curves (AUC) for the 125-mg/m(2) dose level (II) was 7.0 +/- 3.6 h micromol(-1) l(-1), for the 175-mg/m(2) dose level (III) 10.6 +/- 2. 8 h micromol(-1) l(-1), for the 200-mg/m(2) dose level (IV) it was 16.0 +/- 5.0 h micromol(-1) l(-1), and for the 175-mg/m(2) dose level (V) it was 12.5 +/- 6.1 h micromol(-1) l(-1). The mean peak plasma concentration (C(max)) values for dose levels II-V were 1.9 +/- 1.1 micromol/l, 3.4 +/- 1.2 micromol/l, 4.3 +/- 1.0 micromol/l and 3.8 +/- 1.2 h micromol/l, respectively. CONCLUSION: In this study, relevant pharmacokinetic parameters of paclitaxel like AUC, C(max) and the paclitaxel plasma concentration above the pharmacologically relevant 0.1-micromol/l threshold concentration (t > 0.1 microM) when administered in combination with cisplatin, etoposide and bleomycin (PEB) were not statistically different from paclitaxel data of historical controls. However, given the trial design, pharmacokinetic interactions between the agents cannot be excluded.

Adenocarcinoma↗
PubMed2004

Structural study of copper(I)-bleomycin.

Previous NMR studies on Cu(I)-bleomycin have suggested that this adduct has a geometry distinct from Fe(II)BLM. The coordination chemistry of this bleomycin derivative has been investigated through the extension of the NMR data reported previously, and the use of molecular dynamics calculations. The data collected from the NMR experiments support the coordination to the metal center of the primary and secondary amines in beta-aminoalanine and the pyrimidine ring. The detection in the NMR spectra of the signal derived from the amide hydrogen in beta-hydroxyhistidine indicates that this amide is protonated in Cu(I)-bleomycin, precluding participation of the pyrimidinyl carboxamide nitrogen in the coordination of Cu(I), as previously reported. Three-dimensional solution structures compatible with the NMR data have been assayed for Cu(I)-bleomycin for the first time by way of molecular dynamics calculations, and two models showing four and five coordination have been found to be those that better fit the experimental data. In both models the primary amine in beta-aminoalanine is coordinated such that it is located on the same side, with respect to the coordination cage, as the peptide linker fragment. This result seems important for the favored models to be compatible with either their possible oxidation to become one of the reported structures for Cu(II)BLM, or their transformation into Fe(II) adducts able to cause DNA damage.

Bleomycin↗
PubMed1983

Cisplatin, vindesine, and bleomycin chemotherapy of local-regional and advanced esophageal carcinoma.

Seventy-one patients with epidermoid carcinoma of the esophagus were treated with a three-drug combination of cisplatin, vindesine, and bleomycin. Forty-five patients had local-regional tumor and received chemotherapy prior to surgery or radiation therapy. Twenty-six patients with extensive disease were treated primarily with chemotherapy alone. The overall major objective response rate to cisplatin-vindesine-bleomycin was 53 percent (36 of 68 evaluable patients). Patients with local-regional disease had a higher response rate than those with extensive disease (63 and 33 percent, respectively). Following preoperative chemotherapy, 34 patients with local-regional disease underwent exploration. Resectable disease was present in 82 percent. There was no increase in operative morbidity or mortality (5.6 percent), when compared with historical control groups. The median survival for the preoperative chemotherapy group was 16.2 months, which is superior to that of a historical control group (p = 0.023). For patients with extensive disease, treated primarily with chemotherapy alone, the median duration of response was seven months. Toxicities of cisplatin-vindesine-bleomycin were in general well-tolerated, and included nausea and vomiting (seen less frequently because of extensive use of metoclopramide), alopecia, nephrotoxicity, and peripheral neuropathy. The dose-limiting toxicity was myelosuppression. Although conventional chemotherapeutic agents have little activity, these results indicate that the investigational combination of cisplatin, vindesine, and bleomycin can induce major regressions in a substantial proportion of patients with esophageal cancer. When this drug combination is used preoperatively, high resection rates and possibly improved survival are seen.

Adult↗