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PubMed1979

Use of PM-2 DNA degradation as a pharmacokinetic assay for bleomycin.

The PM-2 DNA fluorescence assay has been shown to be a rapid, sensitive, and reproducible assay for bleomycin biochemical activity. The assay can detect bleomycin in human serum in the nmol range. The method measures DNA degradative activity of bleomycin and could be used to determine activity of bleomycin analogs and metabolites. The usefulness of the assay to perform bleomycin pharmacokinetic studies in cancer patients has been demonstrated. Linear regression analyses of parallel bleomycin assays with the radioimmunoassay gave a coefficient of correlation of 0.98 to 0.78 with trichloroacetic acid-treated serum. These results indicate excellent agreement between the two assays.

Adult↗
PubMed1997

[Pentoxifylline inhibits experimental bleomycin-induced fibrosing alveolitis].

Therapy of idiopathic pulmonary fibrosis (IPF) is directed at 1) inhibition of alveolitis and tissue damage, and 2) inhibition of matrix deposition. We and others have identified pentoxifylline (POF) as a promising drug in achieving these aims. For further clarification, we established a model of bleomycin-induced fibrosing alveolitis. Fisher 344 rats (n = 7 per group) were given bleomycin intratracheally once (0.7 U/100 g bw) and treated with POF (1.5 or 3 mg/kg bw per day i.p.), prednisolone (15 mg/kg bw i.m. per day), or sodium chloride solution (NaCL). The extent of inflammatory reactions was determined after 8 days by differentiation of cells of broncho-alveolar lavage (BAL) and by quantification of proliferating cells in lung interstitium subsequent to staining of the Ki-67 antigen. POF inhibited neutrophil alveolitis in BAL and reduced the amount of proliferating cells in the lungs significantly while prednisolone and NaCL did not. Both POF and prednisolone exerted a positive influence on postoperative weight loss as well as on lung weight increase subsequent to bleomycin instillation. The postoperative body weight loss and the lung weight increase after bleomycin instillation are most likely due to an inflammatory reaction subsequent to operation and bleomycin deposition. Tumor necrosis factor alpha (TNF-alpha) has been shown to be a key cytokine in bleomycin-induced fibrosing alveolitis as well as in IPF; it also exerts catabolizing effects. Since both POF and prednisolone are known to effectively inhibit proinflammatory cytokines and, among those, TNF-alpha, nonspecific antiinflammatory effects probably explain the benefits. Additionally, however, this study proved POF to be more effective in inhibition of BAL neutrophils and number of proliferating cells in lung interstitium. Further, it has been shown that POF, but not prednisolone, inhibits activation of neutrophil granulocytes and formation of reactive oxygen species. Thus we believe that the mechanism of action of xanthines might contribute to therapy of IPF. For further clarification, a prospective clinical study of POF in IPF therapy has been initiated.

Animals↗
PubMed1995

The effects of imidazole on pulmonary damage induced by bleomycin.

Bleomycin may produce diffuse pulmonary damage. Our objective was to evaluate the effect of imidazole, a thromboxane-synthetase inhibitor, on pulmonary damage induced by endotracheal instillation of bleomycin in rats. Bleomycin 1 U/100 g body weight produced diffuse pulmonary damage and increased number of inflammatory cells after 3 days, hemorrhage and focal fibrosis after 7 days, and diffuse fibrosis and pneumocyte hyperplasia after 14 to 30 days. Imidazole 5 mg/100 g body weight, given intraperitoneally 30 min before bleomycin, decreased the 3rd day lesions without altering the histopathology in subsequent periods. Imidazole reduced (p < 0.05) the increases in cell number (3rd and 14th days) as well as in proteins in bronchoalveolar lavage (3rd day), without modifying the increase in phospholipids observed in rats treated with bleomycin. We conclude that imidazole decreases initial bleomycin-induced pulmonary damage, but it does not interfere with fibrosis and late development of epithelial hyperplasia.

Animals↗
PubMed1997

[Steroid resistance and lung-tissue cytokines in experimental bleomycin-induced lung fibrosis].

To examine the mechanism of steroid resistance in lung fibrosis, cytokines expressed in the lung tissue of mice with bleomycin-induced lung fibrosis were studied. 1. Glucocorticoid administration (1 mg/kg/day) did not affect the grade of lung fibrosis induced by intratracheal injection of bleomycin (3.76 micrograms/g). 2. Cytokines expressed in the lung tissue were studied with the reverse-transcriptase polymerase chain reaction. Levels of promotor cytokines, such as TNF alpha, TGF beta, INF gamma, and IL-2, were significantly higher in lung tissue from the bleomycin group. The expression of these cytokines in the glucocorticoid group was low, especially the peak value. Expression of IL-4 was high in the bleomycin group, and was not inhibited in the glucocorticoid group. Expression of the down-regulator cytokine IL-10 was also high in the bleomycin group and very low in the glucocorticoid group. 3. The non-selectivity of glucocorticoids with respect to promotor and suppressive cytokines may account in part for steroid resistance in bleomycin-induced pulmonary fibrosis.

Animals↗
PubMedDate not supplied

Pharmacokinetics of tallysomycin and bleomycin in the beagle dog.

The pharmacokinetics of tallysomycin, a third-generation bleomycin analog, and bleomycin have been determined and compared in the beagle dog. Both compounds exhibited biphasic plasma elimination characteristics and were extensively absorbed after in injection. The elimination half-lives of tallysomycin after iv and im administration were 1.51 +/- 0.41 hours and 2.40 +/- 0.667 hours respectively. These values were longer than the comparable iv (1.01 +/- 0.19 hours) and im (1.12 +/- 0.39 hours) elimination half-lives for bleomycin. The volume of distribution in the central compartment after iv administration was 0.111 +/- 0.039 liter/kg for tallysomycin and 0.125 +/- 0.0723 liter/kg for bleomycin. The total apparent volumes of distribution were 0.706 +/- 0.255 liter/kg and 0.388 +/- 0.245 liter/kg for tallysomycin and bleomycin respectively after iv injection. These values were significantly different (P less than 0.05). Total urinary recovery in 24 hours for tallysomycin was significantly (P less than 0.05) less than that for bleomycin after both iv and im injections. These observed differences in pharmacokinetic behavior may, in part, account for differences in in vivo antitumor activities and toxic effects which have been reported for these drugs.

Animals↗
PubMed1997

Electroporation and bleomycin in glaucoma-filtering surgery.

PURPOSE: To develop a new treatment in glaucoma-filtering surgery using combined treatment with electroporation and the antiproliferative drug bleomycin. METHODS: Pigmented rabbits were treated with both bleomycin (10 micrograms/ml) and localized electric pulses (EP) using a special probe (5 V/cm, 100 msec, 8 pulses) (n = 10; group A). After EP treatment, bleomycin was washed out with 50 ml balanced salt solution, and then a posterior lip sclerectomy was performed on the same area. We also studied rabbits undergoing a posterior lip sclerectomy with bleomycin treatment alone (n = 10; group B), a posterior lip sclerectomy with EP treatment alone (n = 5; group C) and a posterior lip sclerectomy alone using the same operation (n = 5; group D, negative control). The intraocular pressure (IOP) was measured before and 1, 3, 5, 7, 10, 15, and 20 days after surgery. The formation of blebs, the conjunctiva, and the cornea were periodically examined by slit-lamp biomicrography. RESULTS: In every group, the IOP decreased until day 7, and no significant difference was observed among the four groups. In groups B, C, and D (control), the IOP increased gradually from day 10 and thereafter returned to the preoperative level after 15 days. However, in group A, the IOP remained lower than the preoperative level for 20 days; it was also significantly lower than each of the other three groups (P < 0.01). The survival rate of a filtering bleb was significantly higher in group A than in groups B, C, or D, but the survival rate in group B was not higher than groups C or D. No adverse effects were clinically observed in the ocular tissue, such as the cornea and conjunctiva. CONCLUSIONS: The combined treatment with EP and bleomycin was found to decrease IOP more prominently than EP or bleomycin treatment alone in filtering surgery. This treatment thus makes filtering surgery effective by decreasing the dose of the antiproliferative drug and by possibly localizing the drug delivery.

Animals↗
PubMed1997

[A trial of applying an oily suspension of bleomycin endolymphatically in patients with Hodgkin's disease of the extraperitoneal lymph nodes].

This study summarized results of treatment of the extraperitoneal lymphatic nodes in patients with Hodgkin's disease with infusion of oily form of bleomycin into the lymphatic vessels. Sixty patients aged 17-69 yr. (mean 43 yr.), 24 women and 36 men with Hodgkin's disease staged IIIA-IVB after 6 cycles of chemotherapy with MOPP or MOPP/ABVD were investigated. Three months after the last cycles of chemotherapy neoplastic changes in the extraperitoneal lymphatic nodes were found in 18 patients only. These patients were treated with bleomycin injected within 30 min. in a daily dose of 30 mg up to total dose 60 mg. Total remission was found in 7 patients, in 4 patients the nodes were shrunken and in the remaining 7 patients there was no visible sings of the disease. Serum level of bleomycin was the highest a few minutes after injection (217-680 ng/ml) and was followed rapid decrease. The obtained results have led to the following conclusions: 1. Oily suspension of bleomycin is a method of chose in the treatment of patients with Hodgkin's disease with changes in the extraperitoneal node. 2. High dose of bleomycin applied directly to the lymphatic vessels leads to total or subtotal remission of the nodal changes. 3. The highest serum concentration of bleomycin was found after the injection. 4. The method in painless and safe the patients, fever may occur for a few hours only.

Adolescent↗
PubMed1976

Unresectable squamous cell carcinoma of the lung and its management by combined bleomycin and radiotherapy. A clinical study of the enhanced results.

The interaction between the antibiotic bleomycin and x-radiation has been studied in vitro and in vivo. Tissue culture results appear to reflect in vivo sensitivities correctly. Simultaneous exposure to bleomycin and gamma radiation enhances killing of both sensitive and resistant lines. Data from a pilot study combining bleomycin with conventional radiation for unresectable squamous cell carcinoma of the lung suggest that the simultaneous administration of bleomycin (10 mg/m2 intravenously twice weekly) with short-course radiation treatment is well tolerated and without dangerous pulmonary complications. Tumor response was greater in the combined-therapy group (46%) than in radiation-only controls (26%); median survivals were 13 and 6 months, respectively. Unlike previously published data, responders appeared to have a significant survival advantage over nonreponders, suggesting that bleomycin may be slightly effective in inhibiting the development of systemic metastasis, and that it positively enhanced local control of primary disease.

Adult↗
PubMed1982

Cyclophosphamide, doxorubicin, vincristine, and low-dose continuous infusion bleomycin in non-Hodgkin's lymphoma: Cancer and Leukemia Group B Study No. 7804.

Fifty-eight evaluable patients with non-Hodgkin's lymphoma were treated with a low dose, 120-hour continuous intravenous infusion of bleomycin in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone. Pharmacokinetic data, obtained in six patients, confirm that steady-state plasma concentrations of bleomycin can be attained even with the administration of 2 units/day of the drug. Neither clinical pulmonary toxicity nor subclinical pulmonary changes, as determined by serial measurement of the single breath carbon monoxide-diffusing capacity, were observed. Compared to similar chemotherapeutic programs utilizing bolus administration of bleomycin, pulmonary toxicity may be reduced. Response frequencies among 37 previously untreated patients were similar to those obtained using the same chemotherapeutic agents but with intravenous bolus administration of bleomycin. In addition, 18 of 21 patients who had received prior chemotherapy responded. Low dose, continuous intravenous infusion of bleomycin may improve the therapeutic index of combination chemotherapy programs for non-Hodgkin's lymphoma.

Adult↗
PubMed1983

Mode of invasion, bleomycin sensitivity, and clinical course in squamous cell carcinoma of the oral cavity.

Forty patients with squamous cell carcinoma of the oral cavity were treated with bleomycin prior to undergoing surgery. The degree of the clinical effect of bleomycin and the postoperative clinical course of each case were estimated from the viewpoint of correlation with the mode of invasion. A strong correlation was found among the mode of invasion, bleomycin sensitivity, and clinical course. A slight effect of bleomycin and poor prognosis existed in the group with a diffuse invasion of mode of invasion, while the greatest effect of bleomycin and good clinical course were achieved in the group with a well-defined tumor-host borderline.

Adult↗
PubMed1990

Treatment of the acquired immune deficiency syndrome-related Kaposi's sarcoma with bleomycin as a single agent.

A nonrandomized trial was conducted to assess the efficiency and toxicity of bleomycin as a single agent in treatment of non-life-threatening AIDS-related Kaposi's sarcoma (KS). Sixty patients were enrolled in this study. They all had a disseminated and progressive non-life-threatening AIDS-related KS associated with systemic symptoms and/or CD4 lymphocyte count less than 400/mm3. Thirty patients were treated with intramuscular bleomycin (5 mg/d for 3 days every 2 or 3 weeks) and 30 others with a slow continuous intravenous infusion of bleomycin (6 mg/m3/d for 4 days every 4 weeks). The mean duration of therapy was 5 months (range, 2 to 24 months). A partial response was observed in 29 patients (48.3%) and the disease was stabilized in 18 additional patients (30%). Bleomycin failed in 21.6% of patients. Therapy had to be discontinued in two patients because of side effects. Thus bleomycin as a single agent is a good alternative therapy for AIDS-related KS.

Acquired Immunodeficiency Syndrome↗
PubMed1991

In vivo measurements of the fraction of dose of bleomycin labeled with cobalt 57 delivered to human tumors.

Concentrations of bleomycin labeled with cobalt 57 (Co-bleo) over time were measured in vivo in 17 patients with 32 sites of lymphoma and 18 patients with lung tumors after administration of the same dose of bleomycin. There were marked variations in individual tumor drug concentrations even among tumors with the same histologic type, indicating that the tumor concentration of this drug in individuals cannot be predicted from the administered dose. Also, tumor concentration could not be predicted from the area under the concentration over time curve (AUC) of Co-bleo in the blood; there was no correlation (r = 0.53) between the AUC and the concentration in the tumor at any point in time between 30 minutes and 8 hours after injection. There was no significant difference in the percent of the injected dose per milliliter (%ID/ml) which was delivered to the tumor when low and high amounts of bleomycin were administered to the same patient. Also, a good correlation (r = 0.88) between the %ID/ml over time was found when injection of low and high doses of bleomycin were compared. The results indicate that using quantitative single photon emission computed tomography (SPECT) and a labeled tracer dose it is possible to predict what fraction of the dose of a chemotherapeutic drug will concentrate in an individual patient's tumor in vivo. They also show that, for bleomycin, escalation of dose will result in a proportional increase of tumor concentration. This increase depends on individual properties of tumors which can be measured quantitatively in vivo by SPECT and are expressed as percent of %ID/ml of tumor tissue.

Adolescent↗
PubMed1994

Neoformation of blood vessels in association with rat lung fibrosis induced by bleomycin.

We have used intratracheal instillation of bleomycin in rats to study the microanatomical changes of blood vessels associated with lung fibrosis. Bleomycin is a toxic cytostatic drug employed in classical models of lung fibrosis. Wistar rats were submitted to intratracheal injection of 1.5 units of bleomycin and sacrificed 2.5 months later, a timing when marked fibrosis of the lung is observed. We casted the vascular tree of the rat lungs by perfusion with a methacrylate resin. These casts were studied by scanning electron microscopy. Lung tissue was also studied by light microscopy and thin section electron microscopy. The major vascular modifications observed in the bleomycin-treated rats were: (1) neoformation of an elaborate network of vessels located in the peribronchial domains of the lung, and (2) distortion of the architecture of alveolar capillaries. By light microscopy, it was clear that the newly formed vascular network was located in regions of fibrosis (which in the resin casts were digested away). These neoformed vessels appeared to originate from bronchial arteries. Thin section electron microscopy revealed that endothelial cells of the neoformed vessels were plump, presented large nuclei, and showed numerous pinocytotic vesicles that were also observed in subendothelial pericytes. The alveoli of the bleomycin-treated rats were heterogeneous in size and shape in contrast with the homogeneity of alveoli of control animals. The alveolar capillaries of fibrotic lungs appeared to occupy a larger volume of the alveolar wall than alveolar capillaries of control rats. Our findings indicate that lung fibrosis encompasses marked changes of the vascular system, namely, the neoformation of vessels and the rearrangement of alveolar capillaries. These structural changes suggest that fibrotic transformation of the lung is associated with the local generation of angiogenic stimuli.

Animals↗
PubMed2003

Expression of FACIT collagens XII and XIV during bleomycin-induced pulmonary fibrosis in mice.

Collagens XII and XIV are members of a subfamily of fibril-associated collagens with interrupted triple-helices (FACITs) that facilitate the interactions of adjacent collagen fibrils. Using immunohistochemistry and in situ hybridization, we analyzed the spatial and temporal expression pattern of collagens XII and XIV during bleomycin-induced pulmonary fibrosis. C57Bl mice were treated with bleomycin (1 U, i.p., every other day for 8 days) or saline (control), and lung tissue samples were analyzed 2-12 weeks later. Collagen I protein expression was increased in the lung 2 weeks post bleomycin treatment and persisted for at least 12 weeks. In contrast, collagen XII and XIV expression was low until 4 weeks after bleomycin treatment. Whereas collagen XII expression was greatest between 4 weeks and 8 weeks, expression of collagen XIV persisted from 4 to 12 weeks, which suggests that these two proteins may play distinct roles in the fibrotic process. The mRNA for lysyl oxidase (LOX), an enzyme for cross-linking of collagens, had a delayed increase in the lung after bleomycin administration. It reached a maximum after 8 weeks, and persisted throughout the 12 weeks of the study. These data support the hypothesis that fibrosis is a multistep process that involves both collagen accumulation and changes in the molecules that modulate the biomechanical properties of fibrils.

Animals↗
PubMed1994

Polymerase chain reaction-directed DNA sequencing of bleomycin-induced "nondeletion"-type, 6-thioguanine-resistant mutants in Chinese hamster ovary cell derivative AS52: effects of an inhibitor and a mimic of superoxide dismutase.

Bleomycin-induced, 6-thioguanine-resistant, "non deletion" mutants pretreated with or without either TRIEN (triethylenetetramine), a superoxide dismutase (SOD) inhibitor, or TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), a SOD mimic, were analyzed by polymerase chain reaction (PCR)-directed DNA sequencing in a Chinese hamster ovary (CHO) cell derivative, AS52. Among the 23 bleomycin-induced mutants, six have 3-bp 5'-TGA-3' deletions in the region of 366-371, five have single-base deletions, seven have base substitutions, three have insertions, and two have possible translocations. Among the 16 bleomycin-induced mutants pretreated with TRIEN, six have the 5'-TGA-3' deletion (366-371), two have single-base deletions, one has a 13-bp deletion, four have single-base substitutions, one has a double-base substitution, and two have insertions. Among the 17 bleomycin-induced mutants pretreated with TEMPOL, six have the same TGA deletions, two have single-base deletions, two have single-base insertions, four have single-base substitutions, one mutant has a 12-bp deletion, one has a 13-bp deletion, and one mutant shows no detectable change in its coding region in the DNA sequence. A possible shift from a ROS-mediated mutational spectrum to a spontaneous mutational spectrum by TRIEN further indicates that reactive oxygen species play an important role in bleomycin mutagenesis in mammalian cells.

Animals↗
PubMedDate not supplied

Topical bleomycin treatment of oral leukoplakia: a randomized double-blind clinical trial.

BACKGROUND: Oral leukoplakia and oral erythroplakia may be associated with benign and dysplastic cellular changes, and are at risk of malignant transformation. Additional means of management of these lesions is needed. The results of nonblinded trials using topical bleomycin in oral leukoplakia indicated the need for phase III study. METHODS: A prospective, double-blind, randomized trial of topical bleomycin versus placebo was conducted. Bleomycin 1% in dimethylsulphoxide (DMSO) or the carrier was applied for 5 minutes for 14 consecutive days. Clinical assessment and pre-application and post-treatment biopsies were conducted. RESULTS: Twenty-two patients were randomized. Of the patients who received bleomycin, decrease in clinical size of the lesion was achieved (p = 0.001), and histological reduction in dysplasia was seen (p = 0.094). CONCLUSIONS: The topical application of bleomycin in DMSO may represent an additional approach to management of oral leukoplakia. The treatment is well-tolerated, and may be considered when the location or extent of the lesion may make surgical excision difficult.

Administration, Topical↗
PubMed1990

Bleomycin binding sites on alveolar macrophages.

Previous work has demonstrated that bleomycin can directly stimulate alveolar macrophage secretion of fibroblast growth factors and monocyte chemotactic factors. In this study, rat alveolar macrophages obtained by bronchoalveolar lavage were examined for the presence of bleomycin binding sites, which might mediate this response. The results indicated that alveolar macrophages have specific, saturable, and reversible binding sites. Both high- and low-affinity binding sites were found; each macrophage possessed 6.7 x 10(4) high-affinity sites, with a Kd of 528 nM, and 2.2 x 10(6) low-affinity sites, with a Kd of 65 microM. The Kd of the high-affinity sites corresponds closely to the ED50 obtained from dose-response curves of the bleomycin-stimulated secretion of both fibroblast growth and monocyte chemotactic factors, suggesting that bleomycin stimulation of alveolar macrophage function responses may be mediated by bleomycin interaction with these sites.

Animals↗
PubMed1989

Molecular basis for potentiation of bleomycin-mediated degradation of DNA by polyamines. Experimental and molecular mechanical studies.

The bleomycin-mediated degradation of DNA is stimulated (amplified) by certain DNA binding compounds, such as polyamines, that distort the double helix. Computer modelling studies suggest that putrescine (1), spermidine (2), and spermine (3) bind preferentially on the floor of the major groove of (dGdC)5.(dGdC)5. This interaction results in a bend of the oligomer helix toward the major groove and enlargement of the minor groove, both effects being in the order 1 less than 2 less than 3. These polyamine-induced distortions, as obtained from theoretical studies, parallel the experimental values of the amplification activities of 1-3 in the bleomycin-mediated degradation of poly(dGdC).poly(dGdC). The amplification mechanism of non-competitive binding of amplifier molecules in the major groove, and bleomycin in the minor groove, is proposed. It is suggested that the amplifier-induced conformational changes of the DNA helix increase affinity of the activated bleomycin complex toward the DNA minor groove and, consequently, result in an increased efficiency of the bleomycin-mediated degradation of the helix.

Base Sequence↗