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PubMed1989

Coordinate regulation of transforming growth factor beta gene expression and cell proliferation in hamster lungs undergoing bleomycin-induced pulmonary fibrosis.

The number of mesenchymal cells, as well as their ability to synthesize extracellular matrix (ECM) components, greatly increase in the interstitium of fibrotic lungs. We have previously shown that the transcription of type I procollagen and fibronectin genes in the lungs is preferentially elevated during the early stages of bleomycin-induced pulmonary fibrosis (Raghow, R., S. Lurie, J. M. Seyer, and A. H. Kang. 1985, J. Clin. Invest. 76:1734-1739. Since a cytokine-like transforming growth factor beta (TGF beta) that is capable of enhancing mesenchymal cell proliferation and ECM synthesis could be potentially involved in this process, we investigated the temporal relationship between the regulation of TGF beta gene transcription and cellular proliferation in the bleomycin-treated hamster lungs. We observed a transient 5-7-fold increase in the accumulation of TGF beta transcripts, a concomitant 3-4-fold elevation in the cellular proliferation, and 8-10-fold stimulation of DNA synthesis in these lungs; all three parameters peaked around day 10 after bleomycin administration. Based on these results, we conclude that regulation of TGF beta gene expression may contribute significantly to the early events that lead to bleomycin-induced pulmonary fibrosis.

Actins↗
PubMed1999

Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice.

TGF-beta plays an important role in lung fibrosis, which is a major cause of suffering and death seen in pulmonary disease. Smad7 has been recently identified as an antagonist of TGF-beta signaling. To investigate whether this novel molecule can be exploited for therapy of lung fibrosis, we determined the effect of exogenous Smad7, introduced by a recombinant human type 5 adenovirus vector, on bleomycin-induced lung fibrosis in mice. C57BL/6 mice with bleomycin-induced lungs received an intratracheal injection of a recombinant adenovirus carrying mice Smad7 cDNA. These mice demonstrated suppression of type I precollagen mRNA, reduced hydroxyproline content, and no morphological fibrotic responses in the lungs when compared with mice administered adenovirus carrying Smad6 cDNA. In addition, we found that expression of Smad7 transgene blocked Smad2 phosphorylation induced by bleomycin in mouse lungs. These data indicated that gene transfer of Smad7 (but not Smad6) prevented bleomycin-induced lung fibrosis, suggesting that Smad7 may have applicability in the treatment of pulmonary fibrosis.

Adenoviridae↗
PubMed1990

Effect of bleomycin on hematoporphyrin derivative phototherapy of solid tumors.

Hematoporphyrin derivative phototherapy (HpD-PT) has been successfully used to localize and treat superficial squamous cell cancers. Bleomycin sulfate is a glycopeptide antibiotic that has antineoplastic properties against squamous cell cancers. Because both HpD-PT and bleomycin chemotherapy are accepted forms of treatment for squamous cell cancer and their cytotoxicity is mediated by singlet oxygen and oxygen radicals, we studied the possibility of enhancing the response of solid tumors to HpD-PT by combining this modality with systemic bleomycin chemotherapy in a murine tumor model. Bleomycin did not enhance HpD-PT significantly. Also, we are not confident that HpD-PT alone or in combination with other agents can eradicate solid tumors; it certainly did not in this syngeneic murine tumor model.

Animals↗
PubMed1980

Bleomycin infusions combined with radiotherapy in the treatment of inoperable esophageal cancer.

A combination of bleomycin, in a 12 h infusion, and radiotherapy was applied in 25 patients with untreated inoperable esophageal cancer. Bleomycin was administered 15 mg/m2 twice weekly, concurrently with irradiation (total dose 3600-4000 rad). Such combined treatment produced 3 complete remissions of the esophageal tumor, 10 partial remissions (response rate 52%--13/25), 3 stable disease cases, while in 9 cases the disease progressed in spite of therapy. The median duration of remissions was 8.7 months in complete responders, 6.0 months in partial responders, and 3.0 months in stable disease cases. Similarly, median survival was the longest in complete remission cases (10.3 months). Patients who did not respond to therapy had a median survival of only 2.8 months. Adverse treatment reactions were of a milder character, except retrosternal pain and burning caused by irradiation mucositis, which occurred in 80% of patients. The trial showed that the combination of bleomycin applied in the form of 12 h infusion and irradiation can produce remissions in 50% of inoperable esophageal cancer cases, i.e., a rate of remission which is similar to that achieved by irradiation and bleomycin applied in the form of rapid (push) i.v. injections.

Adenocarcinoma↗
PubMed1985

Bleomycin pneumonitis potentiated by oxygen administration.

A case of a 53-year-old man who developed acute pneumonitis after bleomycin and moderate oxygen administration is presented. The patient received bleomycin 189 U over five days for preoperative control of a squamous cell carcinoma of the right tongue and tonsil. Surgery to remove the remaining tumor was performed 19 days later. The highest intraoperative oxygen concentration was 33 percent, but 40 percent oxygen was administered for four days postoperatively. He became febrile and developed a productive cough and pulmonary infiltrates on postoperative day 4. Despite antibiotic therapy, his pulmonary function deteriorated and 100 percent oxygen was required to maintain adequate oxygenation. He sustained a myocardial infarction on postoperative day 7 and progressively deteriorated and expired five days later. Autopsy findings were consistent with bleomycin and oxygen-induced pulmonary damage. Oxygen potentiation of bleomycin-induced pulmonary toxicity is discussed.

Bleomycin↗
PubMed1991

In vitro evaluation of bleomycin-induced cell lethality from plastic and glass containers.

To optimize cancer chemotherapy, a considerable amount of research has been expended to study pharmacologic, pharmacokinetic, biochemical, and pharmaceutic properties of antineoplastic agents. However, published data on the stability and compatibility of these agents in various administration fluids and containers are few in number. Evidence of a significant decrease in stability as shown by high-performance liquid chromatography has been reported when bleomycin was infused in plastic containers for prolonged periods (over 24 hours) as compared with the same procedure with glass containers. Because administration of bleomycin is usually given as a continuous infusion, we undertook this study to determine whether the drug loss of stability that occurs in plastic containers results in a therapeutic loss of efficacy (cytotoxicity). By using a tumor stem-cell assay we compared the quantitative effects of bleomycin in plastic and glass containers on cell lethality. The results from our assay showed no significant difference in cell lethality by bleomycin from its aqueous solution stored in glass and plastic containers over the time periods observed. If these results had been statistically significant, the tumor stem-cell assay may have been shown to be a more sensitive means of determining the clinical significance of these stability studies.

Bleomycin↗
PubMed2001

Changes in xylosyltransferase activity and in proteoglycan deposition in bleomycin-induced lung injury in rat.

Several lines of evidence support the hypothesis of the involvement of altered proteoglycan deposition in the development of lung diseases. UDP-D-xylose: core protein beta-D-xylosyltransferase (UDP-xylosyltransferase; EC 2.4.2.26) is a key enzyme for the glycosylation of proteoglycan core proteins. This study examined the catalytic activity of UDP-xylosyltransferase in lung tissue and in isolated fibroblasts, as well as the deposition of the proteoglycans versican, biglycan and decorin in rat lung tissue during bleomycin-induced lung injury. Rats were given, endotracheally, a single dose of bleomycin. Deposition of proteoglycans in lung tissue was assessed by immunohistochemistry and the catalytic activity of xylosyltransferase was determined with an acceptor peptide of the sequence Q-E-E-E-G-S-G-G-G-Q-G-G as a substrate. The results show coincidence of increasing xylosyltransferase activities in lung tissue with accumulation of versican at alveolar entrance rings and in fibrotic regions in close proximity to alpha-smooth muscle actin-positive cells. In contrast, no changes in biglycan and decorin deposition in fibrotic lungs were observed, except for decorin in alveolar type II pneumocytes and alveolar macrophages. Bleomycin treatment of isolated rat lung fibroblasts resulted in a concentration-dependent increase of xylosyltransferase activity up to 2 mU bleomycin x mL(-1). The data suggest a participation of myofibroblasts with increased xylosyltransferase activities in accumulation of versican in fibrotic foci of injured lung tissue at the early stages of development of lung fibrosis.

Animals↗
PubMed2005

Effect of rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 on bleomycin-induced lung injury.

Thiazolidinedione rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), are two peroxisome proliferator-activated receptor (PPAR)-gamma ligands. The aim of this study was to investigate the effect of rosiglitazone and 15d-PGJ2 on the lung injury caused by bleomycin administration. Mice subjected to intratracheal administration of bleomycin developed significant lung injury. An increase in immunoreactivity to nitrotyrosine, poly(ADP ribose) polymerase (PARP) and inducible nitric oxide synthase as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated mice. Administration of the two PPAR-gamma agonists rosiglitazone (10 mg x kg(-1) i.p.) and 15d-PGJ2 (30 microg x kg(-1) i.p.) significantly reduced the: 1) loss of body weight, 2) mortality rate, 3) infiltration of the lung with polymorphonuclear neutrophils (myeloperoxidase activity), 4) oedema formation, and 5) histological evidence of lung injury. Administration of rosiglitazone and 15d-PGJ2 also markedly reduced the nitrotyrosine, PARP and inducible nitric oxide synthase formation. In addition, treatment with the PPAR-gamma antagonist bisphenol A diglycidyl ether (1 mg x kg(-1) i.p. 30 min before the rosiglitazone or 15d-PGJ2) significantly antagonised the effect of the two PPAR-gamma agonists. These results demonstrate that the two peroxisome proliferator-activated receptor-gamma agonists, rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, significantly reduce lung injury induced by bleomycin in mice.

Analysis of Variance↗
PubMed1997

Pleurodesis in malignant pleural effusions: a randomized study of tetracycline versus bleomycin.

Malignant pleural effusions are commonly managed with tube thoracostomy drainage followed by chemical pleurodesis. Both tetracycline and bleomycin have been shown to be effective for intrapleural instillation, although neither agent has definitively proved advantages over the other. The aim of the present study was to compare these two agents in terms of response rate and toxicity profile. A prospective, randomized trial was carried out in a single centre. Between May 1993 and January 1996, 62 evaluable patients with proved malignant pleural effusion were allocated to receive either intrapleural tetracycline (1.5 g) or bleomycin (60 mg) after the same drainage procedure. Demographic, clinical and fluid parameter data were comparable in both groups. Response was evaluated at 1, 3 and 6 months after pleurodesis. Mean survival and time to relapse did not differ between the two groups. No statistically significant differences were found in terms of efficacy at each evaluation time. Overall, 16 (52%) and 20 (64%) patients had a recurrence of pleural effusion during follow-up in the tetracycline and bleomycin arms, respectively. Fever was most common in bleomycin-treated patients (p=0.024) while pain was most frequent in the tetracycline arm (nonsignificant). Since no study agent was superior to the other in this trial, we suggest that economic costs, drug availability and medical skill should be considered in the choice of a sclerosing agent.

Adult↗
PubMed1987

Subcutaneous infusion of bleomycin--a practical alternative to intravenous infusion.

The phase specificity and short half-life of bleomycin make it likely that it would be more effective when administered by continuous infusion. This is supported by studies using cell lines, as well as by animal studies and clinical experience in humans. This study was conducted to compare the pharmacokinetics of intravenous (IV) and subcutaneous infusions of bleomycin. The serum concentrations of bleomycin were measured using a sensitive and specific radioimmunoassay. The results demonstrate similar plasma concentrations and area under the curve for both routes. The subcutaneous infusions were well tolerated, without local discomfort or excoriation. Subcutaneous infusion of bleomycin may thus offer a practical alternative to IV infusions and can be administered to patients who are ambulatory and out of hospital.

Bleomycin↗
PubMed1987

Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial.

Between 1978 and 1984, the Northern California Oncology Group (NCOG) conducted a randomized trial to study the efficacy of combined radiotherapy (RT) and chemotherapy (CT) for stage III or IV inoperable head and neck cancer. One hundred four patients were randomized to receive: (1) RT alone, or (2) RT plus CT. RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk. CT consisted of bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT. Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable. The local-regional complete response (CR) rate was 45% v 67% (P = .056); the 2-year local-regional control rate, including salvage surgery, was 26% v 64% (P = .001); and the incidence of distant metastasis was 24% v 38% (P greater than .25), for the RT alone and RT plus CT groups, respectively. The relapse-free survival curves were significantly different (P = .041), favoring the combined treatment. However, the survival curves were not significantly different (P = .16). Patient compliance to maintenance CT was poor. Bleomycin significantly increased the acute radiation mucositis, although the difference in late normal tissue toxicity was not statistically significant. Thus, bleomycin and concurrent RT produced a more favorable CR rate, local-regional control rate, and relapse-free survival, but the difference in survival was not statistically significant.

Adult↗
PubMed1993

The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group.

PURPOSE: In an effort to maintain the excellent long-term results achieved with combination chemotherapy for good-prognosis germ cell carcinoma, but to reduce the toxicities encountered, a randomized trial was conducted comparing cisplatin and vinblastine with or without bleomycin. PATIENTS AND METHODS: Two hundred eighteen assessable patients with a good prognosis were randomized to receive induction chemotherapy with cisplatin 100 mg/m2 intravenously (IV) day 1 and vinblastine 6 mg/m2 IV days 1 and 2 every 3 weeks (PV) with or without bleomycin 30 mg intramuscularly (IM) weekly (PVB) for a maximum of 12 weeks. Once maximum response was achieved, patients with a complete remission (CR) received two courses of consolidation chemotherapy, while those with residual abnormalities and normal tumor markers underwent surgical resection whenever possible. RESULTS: Toxicities encountered in this study were clearly greater for those patients who received bleomycin, with significantly more leukopenia, thrombocytopenia, anemia, alopecia, and renal and pulmonary toxicities. The proportion of patients who achieved CR and had no evidence of disease (resection of all viable malignancy) was 89% for PV and 94% for PVB (P = .29). After a minimum of 4 years of follow-up, relapses have occurred in 7% of patients who received PV and 5% who received PVB. A total of five patients on each therapy arm were successfully treated with further salvage chemotherapy and surgery. Thus, deaths from progressive malignancy have occurred in 15% of patients on PV and 5% on PVB (P = .02), a rate that was partly offset by the higher proportion of toxic deaths with PVB (P = .06). CONCLUSION: Despite the toxicities encountered with bleomycin in cisplatin-based combination chemotherapy for these patients, complete deletion of this drug compromises therapeutic efficacy.

Adolescent↗
PubMed1994

Continuous infusion bleomycin in AIDS-related Kaposi's sarcoma.

PURPOSE: To determine the toxicity, response, and survival rate of 72-hour continuous infusion bleomycin administered to patients with AIDS-related Kaposi's sarcoma. PATIENTS AND METHODS: Seventeen patients with biopsy-proven and measurable-disease AIDS-related Kaposi's sarcoma were treated with a continuous infusion of bleomycin at a dose of 20 mg/m2/d for 3 days every 3 weeks. All patients were evaluated for toxicity, response, and survival using the National Cancer Institute common toxicity criteria, and both the Eastern Cooperative Oncology Group (ECOG) and AIDS Clinical Trials Group (ACTG) response criteria. Fourteen of 17 patients (82%) enrolled had at least two on-study poor-risk factors by ACTG staging criteria. RESULTS: A total of 59 cycles of therapy were administered. Only one cycle (2%) was complicated by an absolute neutrophil count less than 500, and there were no episodes of febrile neutropenia. Fifty-four percent of cycles were associated with fever during the infusion, and five cycles (8%) were complicated by grade 3 rash. There were no other clinically significant (> or = grade 3) toxicities. There were seven partial remissions (41%) by ECOG criteria (95% confidence interval, 18% to 64%) and 11 partial remissions (65%) by ACTG criteria (95% confidence interval, 42% to 88%). Three of five (60%) previously treated patients had a partial remission with this schedule of bleomycin. The median survival duration was 7 months, with a range of 2.5 to 25 months. CONCLUSION: This continuous infusion schedule of bleomycin is active in patients with advanced-stage AIDS-related Kaposi's sarcoma and has acceptable toxicity. This regimen should be further evaluated in patients with earlier stage Kaposi's sarcoma and as salvage therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial.

PURPOSE: This prospective, randomized trial was designed to determine if three cycles of cisplatin plus etoposide (PVP16) can produce therapeutic results comparable to three cycles of cisplatin, etoposide, and bleomycin (PVP16B) in patients with disseminated germ cell tumors. PATIENTS AND METHODS: One hundred seventy-eight patients with minimal- or moderate-stage disease (Indiana staging system) were randomized to receive cisplatin (20 mg/m2 on days 1 to 5) plus etoposide (100 mg/m2 on days 1 to 5) with or without weekly bleomycin (30 IU/wk for 9 consecutive weeks). Following three cycles of chemotherapy over 9 weeks, patients with residual radiographic disease underwent surgical resection. If persistent carcinoma was noted, two additional 3-week courses of chemotherapy were administered. RESULTS: One hundred seventy-one patients were fully assessable for response and survival. The two treatment groups were similar with respect to patient characteristics. The toxicities were comparable between the two arms. No clinically significant incidence of pulmonary toxicity occurred with PVP16B. Overall, 81 of 86 patients (94%) who received PVP16B and 75 of 85 patients (88%) who received PVP16 achieved a disease-free status with chemotherapy and/or surgery. However, greater numbers of treatment failures, including persistent carcinoma in postchemotherapy resected residual disease and relapses from complete remission, occurred on the arm without bleomycin (overall adverse outcome, P = .004). The failure-free (86% v 69%; P = .01) and overall survival (95% v 86%; P = .01) rates were inferior on the PVP16 arm. CONCLUSION: Bleomycin is an essential component of PVP16B therapy in patients who receive three cycles of treatment for minimal- or moderate-stage disseminated germ cell tumors.

Adolescent↗
PubMed1997

Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group.

PURPOSE: This prospective randomized trial was designed to compare the efficacy of etoposide plus cisplatin (EP) versus bleomycin, etoposide, and cisplatin (BEP) chemotherapy in patients with good-prognosis metastatic nonseminomatous testicular cancer. PATIENTS AND METHODS: Four hundred nineteen patients with good-prognosis nonseminomatous testicular cancer were randomized to receive four cycles of cisplatin 20 mg/m2 on days 1 to 5 plus etoposide 120 mg/m2 on days 1, 3, and 5 with or without bleomycin 30 mg weekly. RESULTS: Of 395 eligible patients, 169 of 195 patients allocated to EP (87%) and 189 of 200 patients allocated to BEP (95%) achieved a complete response with chemotherapy alone or after postchemotherapy surgery. These results are significantly different (P = .0075). After a median follow-up duration of 7.3 years, eight patients (4%) on each treatment arm relapsed. In view of the low number of unfavorable treatment outcomes (11%), no significant differences were detected in time to progression (P = .136) and survival (P = .262). Both the acute and late pulmonary toxicity and neurotoxicity were significantly greater in patients who received BEP, whereas Raynaud's phenomenon occurred exclusively in patients who received BEP (P < .001). Two patients treated with BEP died of bleomycin pulmonary toxicity. CONCLUSION: BEP is the most effective combination regimen in the treatment of disseminated nonseminomatous germ cell cancer. In this particular BEP regimen with etoposide at a dose of 360 mg/m2 per cycle, even in good-prognosis patients, bleomycin cannot be deleted without compromising treatment efficacy, but its use is associated with more toxicity (particularly pulmonary) and efforts to reduce this merit further exploration.

Adolescent↗
PubMed2002

Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a gynecologic oncology group study.

PURPOSE: Phase II trial reports have suggested that the addition of bleomycin to the combination of cisplatin and ifosfamide may improve response rates and possible survival in squamous carcinoma of the cervix. This study prospectively evaluates the combination of bleomycin to this regimen in women with histologically proven advanced recurrent or persistent squamous cell carcinoma of the cervix. PATIENTS AND METHODS: Eligible women were randomized to receive either cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CI) versus bleomycin 30 units over 24 hours on day 1 followed by cisplatin (50 mg/m(2)), ifosfamide (5 g/m(2) over 24 hours), and mesna (6 g/m(2) during ifosfamide infusion and the following 12 hours) (CIB). Three hundred three women were enrolled onto this trial, of which 287 were assessable. RESULTS: There were no significant differences between CI and CIB with regard to response rates (32% v 31.2%, respectively), progression-free survival (PFS), or overall survival. PFS and survival were associated with initial performance status (PS). Patients with a PS of 0 experienced a lower rate of failure (P =.013) and a lower risk of death (P =.009) compared with patients with PS of 2. The most frequent grade 3/4 toxicities were leukopenia, neutropenia, anemia, thrombocytopenia, and nausea and vomiting. Neither regimen was associated with a significant increase in incidence of these toxicities. CONCLUSION: The CI regimen was virtually identical to CIB with regard to response rate, PFS, survival, and toxicity profile. Thus, the addition of bleomycin in the dose-schedule employed to cisplatin and ifosfamide did not improve outcome in patients with advanced cervical cancer.

Adult↗
PubMed2000

The encapsulation of bleomycin within chitosan based polymeric vesicles does not alter its biodistribution.

Polymeric vesicles have recently been developed from an amphiphilic chitosan derivative--palmitoyl glycol chitosan. Their potential as a drug delivery system was evaluated using the anti-cancer compound bleomycin as a model drug. Palmitoyl glycol chitosan (GCP41) was synthesised by conjugation of palmitoyl groups to glycol chitosan. Bleomycin-containing vesicles (669 nm diameter) were prepared from a mixture of GCP41 and cholesterol by remote loading. The vesicles were imaged by freeze-fracture electron microscopy and their in-vitro stability tested. Incubation of the larger vesicles with plasma in-vitro led to a reduction of mean size by 49%, a reaction not seen with control sorbitan monostearate niosomes (215 nm in size). They also showed a higher initial drug release (1 h), but GCP41 and sorbitan monostearate vesicles retained 62% and 63% of the encapsulated drug after 24h, respectively. The biodistribution of smaller vesicles (290 nm) prepared by extrusion through a 200-nm filter was also studied in male Balb/c mice. Encapsulation of bleomycin into polymeric vesicles did not significantly alter the pharmacokinetics of biodistribution of bleomycin in male Balb/c mice although plasma and kidney levels were slightly increased. It is concluded that the extruded GCP41 vesicles break down in plasma in-vivo and hence are unlikely to offer any therapeutic advantage over the free drug.

Animals↗
PubMed1994

Antimetastatic effect of yeast mannan-bleomycin conjugate against mouse Lewis lung carcinoma.

A conjugate of bleomycin (BLM) and the mannan of bakers' yeast (Saccharomyces cerevisiae wild type strain) (WNM) was synthesized. The assay of its antimetastatic effect on Lewis lung carcinoma (3LL) implanted in C57BL/6 mice showed that this conjugate exhibited a higher antimetastatic effect and longer life-span elongation than those of free bleomycin and mannan with corresponding doses. This conjugate was also found to kill the 3LL cells in vitro. 14C-Labeled mannan-bleomycin conjugate was much more bound than 14C-labeled dextran-bleomycin conjugate to the 3LL. It was concluded that the anti-cancer mechanism of this conjugate, WNM-BLM possessed a specific binding effect to the tumor cells and exhibited a cytocidal effect on the 3LL target cells.

Animals↗