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PubMed1987

Quantitative assessment of lung damage due to bleomycin using computed tomography.

Visual assessment and density measurements of the lung using computed tomography (CT) were made in 18 patients undergoing treatment with bleomycin for malignant teratoma of the testis. The results of both visual assessment and density measurements were compared with changes in gas transfer per unit lung volume (KCO). Visual assessment of severity of damage to the lungs caused by bleomycin is unrelated to changes in KCO but is characteristic of bleomycin damage and allows a confident diagnosis to be made. Quantitative density measurement by CT, however, is inversely related to changes in KCO and may therefore be used to monitor the physiological effect on the patient. Examination of the lung by CT in these patients can not only characterise and define the extent of lung damage due to bleomycin but can be used to give a quantitative measurement on which to monitor treatment.

Adult↗
PubMed1979

Bleomycin: its utilization in the treatment of head and neck cancer.

Originally isolated as an antibiotic, bleomycin is a complex mixture of glycopeptides currently utilized against a variety of malignancies, among them epidermoid, cancer of the head and neck. Because of unique independent pharmacological properties, bleomycin may be effectively used at several points in the natural history of tumors. Use of bleomycin as a single agent, as an adjunct to surgery and irradiation and as a palliative drug in head and neck cancer, is now advocated in scattered reports. The rationale for the utilization of bleomycin at the University of California, San Diego and San Diego Veterans Administration Hospitals is discussed. In addition, examples from the authors' personal series of both response and adverse effects, suggestions for appropriate clinical monitoring to detect early toxicity, and tennets for management of side effects are included in the presentation.

Bleomycin↗
PubMed1993

Epithelial-fibroblast interactions in bleomycin-induced lung injury and repair.

Intercellular communication between epithelial cells and fibroblasts of the alveolar wall contributes to regulatory control of each cell type. We examined whether lung injury and subsequent fibrosis are associated with disturbance of this mutual control system. Rats received bleomycin intratracheally, and after 10 days, when acute epithelial injury occurs, and at 6 weeks, when repair with fibrosis is found, pure populations of type 2 epithelial cells and lung fibroblasts were prepared to study interactions with respect to growth control. Epithelial cells were cultured alone, on a permeable filter over fibroblasts, and in co-culture with fibroblasts. The results showed that the low growth rate of normal epithelial cells increased when cells were exposed to fibroblast supernatants. This effect was also seen using cells from the 10-day bleomycin group, but it was diminished in the group treated for 6 weeks. However, epithelial cells from exposed or control rats did not show increased DNA synthesis when grown in contact with fibroblasts in co-culture. In contrast, fibroblast growth was inhibited when exposed to epithelial cell secretions in control cultures and when using cells from the 10-day bleomycin group. No inhibition of fibroblast growth by epithelial cells was found using cells from the fibrotic lungs. These results suggest that after lung injury by bleomycin, a fibroblast-secreted factor promotes epithelial growth; however, during repair, regenerating epithelial cells lose the ability to inhibit fibro-blast proliferation. These local changes in cellular control at the alveolar wall may be sufficient to produce pulmonary fibrosis.

Animals↗
PubMed2001

Bleomycin-induced pneumonitis.

The cytotoxic agent bleomycin is feared for its induction of sometimes fatal pulmonary toxicity, also known as bleomycin-induced pneumonitis (BIP). The central event in the development of BIP is endothelial damage of the lung vasculature due to bleomycin-induced cytokines and free radicals. Ultimately, BIP can progress in lung fibrosis. The diagnosis is established by a combination of clinical symptoms, radiographic alterations, and pulmonary function test results, while other disorders resembling BIP have to be excluded. Pulmonary function assessments most suitable for detecting BIP are those reflecting lung volumes. The widely used transfer capacity of the lungs for carbon monoxide appeared recently not to be specific when bleomycin is used in a polychemotherapeutic regimen. There are no proven effective treatments for BIP in humans, although corticosteroids are widely applied. When patients survive BIP, they almost always recover completely with normalization of radiographic and pulmonary function abnormalities. This review focuses on BIP, especially on the pathogenesis, risk factors, and its detection.

Animals↗
PubMed1977

Prolonged administration of bleomycin without clinical toxicity. Therapy with 2,700 units over four years.

A 26-year-old white man with stage 4-B Hodgkin's disease resistant to conventional chemotherapy obtained complete remission with administration of bleomycin. Maintenance of this remission required continued therapy with bleomycin. The patient received a total of 2,700 units of bleomycin over a 51-month period without signs or symptoms of pulmonary toxicity. Serial studies of pulmonary function have shown a stable forced vital capacity and minimally decreased total lung volume and pulmonary diffusing capacity. This case demonstrates the ability of a patient to tolerate massive cumulative doses ob bleomycin over a protracted period without severe loss of pulmonary function.

Adult↗
PubMed1990

Systemic toxicity following intracavitary administration of bleomycin.

Bleomycin administered intrapleurally has been demonstrated to be an effective sclerosing agent. The lack of morbidity associated with its use has made it an attractive alternative to other available agents. Pharmacologic data indicate that (1) intracavitary bleomycin is systemically absorbed, and (2) the plasma half-life of bleomycin increases exponentially with renal failure. We report the findings in a patient with renal failure who experienced alopecia and significant mucositis following sclerotherapy. We suspect this systemic toxicity resulted from intrapleural bleomycin and suggest that this treatment be used with caution in patients with renal dysfunction.

Adult↗
PubMedDate not supplied

Antitumoral property of ethanolic extract of propolis in mice-bearing Ehrlich carcinoma, as compared to bleomycin.

Antitumoral effect of ethanolic extract of propolis (EEP) was demonstrated in mature mice-bearing Ehrlich carcinoma. Survival rate after EEP treatment was compared to that of bleomycin, given alone or in combination every two days for 36 days and followed up for 14 additional days. The survival rate at 50 days was 55% after EEP and 40% after bleomycin, while all the mice-treated with EEP + bleomycin combination demonstrated shorter survival than the controls. It is concluded that while the in vivo activity of bleomycin is reduced in the presence of cytochrome-C-reductase inhibitors (like some of the EEP components are), the antitumoral property of EEP in the tumored animal model studied is significant and lasting.

Animals↗
PubMed1987

Elastic recoil pressure arising from surface tension in hamster lungs treated with intratracheal bleomycin.

Lung elastic recoil pressure arising from surface tension (Ps) was evaluated in normal and bleomycin-treated lungs. Twenty two male golden hamsters were separated into a control group (group A, n = 10) and a bleomycin group (group B, n = 12). Group B was given a single intratracheal instillation of bleomycin and group A was given normal saline as a control. Thirty days after instillation, three cycles of static air -and saline-filled pressure-volume curves (P-V curve) were measured. Ps was graphically derived from air- and saline-filled P-V curves. The Ps of groups A and B were compared at the same lung volumes. Mean body weight and nose-to-tail length of the two groups did not differ significantly. Total lung capacity, defined as lung air volume at a transpulmonary pressure of 25 cmH2O, was significantly smaller in group B (mean +/- S.E. was 4.08 +/- 0.20 ml) than in group A (mean +/- S.E. was 5.23 +/- 0.12 ml) (p less than 0.01). The Ps of group B was significantly larger than that of group A at all lung volumes studied (p less than 0.01-0.05). These results indicate that the lung elastic recoil pressure component due to the surface tension was increased by intratracheal instillation of bleomycin in hamsters.

Animals↗
PubMed1993

Changes in pulmonary hemodynamics during normoxia and hypoxia in awake rats treated with intratracheal bleomycin.

Pulmonary hemodynamics of bleomycin-induced interstitial fibrosis model (group-BLM, n = 10) and saline-treated control (group-C, n = 12) were studied in awake rats. Four weeks before hemodynamic study, bleomycin sulfate and normal saline was intratracheally instilled to the group-BLM and the group-C, respectively. Pulmonary artery and abdominal aortic catheters were indwelled two days before the hemodynamic study. In room air, mean pulmonary artery pressure (Ppa) was significantly higher and systemic artery pressure was significantly lower in group-BLM than in group-C; Ppa = 21 +/- 1 cmH2O (mean +/- S.E.) for group-C and 38 +/- 4 cmH2O for group-BLM. Cardiac output did not differ among the groups. Mean pulmonary vascular resistance (PVR) of group-BLM was double that of group-C. Right ventricle was hypertrophic in group-BLM. When exposed to 10% O2, PVR of group-C significantly rose, whereas PVR of group-BLM showed very little increase, showing attenuation of the hypoxic pulmonary vasoconstriction (HPV). Magnitude of the HPV was inversely related to Ppa during air breathing. We conclude that notable pulmonary hypertension and right ventricular hypertrophy occur, and HPV is blunted four weeks after bleomycin instillation, at the most severe period of this lung fibrosis model. We speculate that the high intravascular pressure partly contributed to the blunted HPV in bleomycin-treated group.

Animals↗
PubMed1989

Studies on bleomycin-induced repair DNA synthesis in permeable mouse ascites sarcoma cells.

To study the mechanism of DNA excision repair, a DNA repair system employing permeable mouse sarcoma (SR-C3H/He) cells was established and characterized. SR-C3H/He cells were permeabilized with a 0.0175% Triton X-100 solution. The permeable cells were treated with 1 mM ATP and 0.11 mM bleomycin, and then washed thoroughly to remove ATP and bleomycin. Repair DNA synthesis occurred in the bleomycin-damaged, permeable SR-C3H/He cells when incubated with ATP and four deoxyribonucleoside triphosphates. The repair nature of the DNA synthesis was confirmed by the BrdUMP density shift technique, and by the reduced sensitivity of the newly synthesized DNA to Escherichia coli exonuclease III. The DNA synthesis was optimally enhanced by addition of 0.08 M NaCl. Studies using selective inhibitors of DNA synthesis showed that aphidicolin-sensitive DNA polymerase (DNA polymerase alpha and/or delta) and DNA polymerase beta were involved in the repair process. The present DNA repair system is thought to be useful to study nuclear DNA damage by bleomycin, removal of the damaged ends by an exonuclease, repair DNA synthesis by DNA polymerases and repair patch ligation by DNA ligase(s).

Animals↗
PubMed1985

Effects of intratracheal administration of bleomycin on prostaglandins and thromboxane-B2 and collagen levels of the lung in hamsters.

The effects of intratracheal administration of one unit of bleomycin on the lung levels of different prostaglandins (PGs), thromboxane B2 (TxB2), and total collagen were investigated in hamsters in two separate sets of this study. Averaging the values from two sets, the lung levels of 6-keto-PGF1 alpha (stable metabolite of PGI2), TxB2 (stable metabolite of TXA2), PFG2 alpha, and PGE in bleomycin-treated animals were increased by 11-, 7.5-, 7-, and 3-fold over the saline control at 14 days post treatment, respectively. The total lung collagen content in bleomycin-treated animals was significantly increased to 180% of the control during the same period. A number of possibilities for a marked variation in the levels of rise for different PGs and TxB2 and their significance in bleomycin-induced lung fibrosis have been discussed. It was concluded from the findings of the present study that there is a relationship between the lung levels of various metabolites of arachidonic acid cascade and bleomicin-induced increases in the synthesis and accumulation of lung collagen. The nature of this relationship, however, remains to be elucidated.

6-Ketoprostaglandin F1 alpha↗
PubMed1988

Effect of corticosteroids on lung volume-pressure curves in bleomycin-induced lung injury in the rat.

In this study we investigated changes in volume-pressure curves at various stages after bleomycin induced lung injury (6 h, and 3, 7, and 28 days) and tested the ability of steroids to influence these changes. The most significant decreases in volume-pressure curves were observed at 3 days post bleomycin, a time point that correlates to the peak period of inflammation. Steroids as drugs of high antiinflammatory potency were used in order to modulate the inflammatory response and possibly the volume-pressure curve changes observed during the natural course of bleomycin induced lung injury. Dexamethasone treatment significantly inhibited the decreases in volume pressure curves observed at 3 days post bleomycin, whereas methylprednisolone did not. Also both steroids significantly inhibited inflammation as measured by histological evaluation and the presence of cells in the bronchoalveolar lavage fluid.

Adrenal Cortex Hormones↗
PubMed1990

A phase I trial of combination chemotherapy employing carboplatin, vinca alkaloids, with or without bleomycin in patients with advanced malignant tumors.

A Phase I trial of three carboplatin-based combination chemotherapy regimens was conducted. These included: carboplatin plus vindesine; carboplatin, vindesine, plus bleomycin; and, carboplatin plus vinblastine. Carboplatin was administered every 28 days as an intravenous bolus. The initial dose was 150 mg/m2 and doses were escalated by 50 mg/m2 in each successive group of patients. Vindesine was given at a dose of 3 mg/m2 weekly for 5 doses, then every other week thereafter. Bleomycin, 10 units/m2 IV bolus, was followed by 10 units/m2/day infusion for 4 days (3-7 and 31-35). Vinblastine was given at 5 mg/m2 every other week. Doses of vindesine, vinblastine, and bleomycin were not escalated. The maximum tolerated dose (MTD) of the carboplatin, vindesine +/- bleomycin regimens was reached at a carboplatin dose of 250 mg/m2 and the MTD was influenced by the weekly vindesine in the initial 4 weeks of therapy. The MTD of the carboplatin and vinblastine regimen was reached at a carboplatin dose of 500 mg/m2. Dose-limiting toxicity of all three regimens was leukopenia. Although nonhematological toxicity of the carboplatin and vinblastine regimen included peripheral neuropathy and emesis, therapy was easily administered in an outpatient setting. The recommended Phase II dose of carboplatin is 450 mg/m2 in combination with vinblastine at this dose and schedule for previously untreated patients. Twelve patients demonstrated major responses with the various regimens including 5 of 24 patients with adenocarcinoma of the upper gastrointestinal tract.

Adult↗
PubMed1992

Enhanced Ia expression by alveolar macrophages following intratracheal administration of bleomycin to rats.

Bleomycin is an important anticancer drug that causes severe, and sometimes life-threatening, pulmonary toxicity. Initially, there is an acute inflammation followed by an irreversible pulmonary fibrosis. Our studies have focussed on the effects of the acute pulmonary inflammation on the state of alveolar macrophage activation. To study this, we administered a single dose of 3.6 mg bleomycin/kg body weight intratracheally to rats and obtained alveolar macrophages at selected times thereafter. Ia expression was determined by fluorescent microscopy of cells labelled with a fluorochrome-tagged antibody against rat Ia molecules. We report that: 1.) alveolar macrophages have elevated Ia expression shortly after receiving intratracheally administered bleomycin; 2.) Ia expression is not limited to a specific subpopulation of alveolar macrophages; 3.) Ia expression is transient in nature returning to control levels 7-14 days after bleomycin administration; and, 4.) the degree of upregulation of Ia expression is directly related to the dose of bleomycin administered.

Animals↗
PubMed1987

Liver nuclear NADPH-cytochrome P-450 reductase may be involved in redox cycling of bleomycin-Fe(III), oxy radical formation and DNA damage.

When NADPH-cytochrome P-450 reductase isolated from rat liver microsomes was aerobically incubated with bleomycin, FeCl3, NADPH and DNA parallel NADPH and oxygen were consumed and malondialdehyde was formed. A similar parallelism of NADPH- and oxygen-consumption and malondialdehyde formation was observed when cell nuclei isolated from rat liver were incubated under the same conditions. The formation of malondialdehyde which was identified by HPLC and which was most likely released from oxidative cleavage of deoxyribose of nuclear DNA required oxygen, bleomycin, FeCl3 and NADPH. This indicates that a nuclear NADPH-enzyme, presumably NADPH-cytochrome P-450 reductase, is able to redox cycle a bleomycin-iron-complex which in the reduced form can activate oxygen to a DNA-damaging reactive species. The data suggest that the activity of this enzyme in the cell nucleus could play an important role in the cytotoxicity of bleomycin in tumor cells.

Animals↗
PubMed1991

Protective effects of human recombinant MnSOD in adjuvant arthritis and bleomycin-induced lung fibrosis.

We have previously shown that human recombinant methionyl manganese superoxide dismutase (MnSOD) is more efficient than CuZnSOD as an anti-inflammatory agent in a model of acute inflammation (Carrageenan-induced paw edema). This effect was attributed to the prolonged half-life of MnSOD in blood (t1/2 = 6 h vs. 10 min, respectively). In the present study, the two enzymes were compared in terms of their effectiveness in two systems: (1) Adjuvant-induced arthritis in rats, which is considered to be a model for the chronic situation of rheumatoid arthritis and (2) Bleomycin-induced lung fibrosis, which is a chronic situation believed to be mediated by oxygen free radicals. Rats inflicted with adjuvant arthritis were treated during the period of maximal joint swelling (Days 15-21 after adjuvant injection) with MnSOD or CuZnSOD (12 to 50 mg/kg, i.p. daily). MnSOD administration resulted in a 50-75% reduction of paw swelling, as well as inhibition of the elevation of serum globulins. A similar treatment with CuZnSOD gave merely marginal effects. In the second system, lung fibrosis was induced in rats by intratracheal administration of bleomycin. MnSOD (50 mg/kg, s.c.), administered 2 h before and then 2 and 4 days after bleomycin, markedly inhibited lung fibrosis, as evident from lung weight and collagen content measured by the 3rd week. By contrast, CuZnSOD administration did not give a significant effect. The results indicate that MnSOD is superior to CuZnSOD in the treatment of chronic inflammatory processes. In addition, they lend further support to the involvement of oxygen free radicals in bleomycin toxicity.

Arthritis, Experimental↗
PubMed1988

The antitumor effect of bleomycin combined with bestatin against Ehrlich ascites carcinoma in mice.

The effect of bleomycin against Ehrlich ascites carcinoma transplanted subcutaneously to mice used in combination with bestatin was investigated. Male Balb/c mice weighting approximately 20 g and bred in our laboratories were used in this study. Each mouse was injected in its left lateral abdominal region subcutaneously with 7 X 10(6) tumor cells in 0.2 ml of ascites fluid. The mice were divided into four groups: control, bestatin alone (5 mg/kg intraperitoneally on Days 9-14), bleomycin alone (10 mg/kg intraperitoneally on Days 7 and 8), and bestatin plus bleomycin. Our results show that bestatin enhances the antitumor effect of bleomycin against Ehrlich ascites carcinoma as measured by the increased survival rates. Being an agent of very low toxicity, bestatin should be considered as a part of the chemoimmunotherapy protocol.

Adjuvants, Immunologic↗
PubMed1996

A case of bleomycin-induced scleroderma.

The association of exposure to bleomycin with the development of scleroderma-like cutaneous abnormalities has been reported. We experienced a case of scleroderma involving the hands, feet, and forearms after bleomycin chemotherapy. The present report supports the possible causal relation of bleomycin with scleroderma. Regarding the widespread use of bleomycin, this complication is thought to be under appreciated.

Bleomycin↗