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PubMed1997

Gene characterization, promoter analysis, and chromosomal localization of human bleomycin hydrolase.

The human gene encoding bleomycin hydrolase, a cysteine proteinase involved in chemotherapy resistance, has been cloned, and its overall organization has been established. The gene is composed of 12 coding exons and 11 introns and spans more than 30 kilobases. The number and distribution of exons and introns differ from those reported for other human cysteine proteinases, indicating that these genes are only distantly related. Nucleotide sequence analysis of about 1.2 kilobases of the 5'-flanking region of the human bleomycin hydrolase gene revealed a high GC content, a ratio of CpG/GpC close to unity, and the absence of consensus transcriptional sequences such as TATA box or CCAAT box. All these features are characteristic of housekeeping genes and provide an explanation for the widespread expression of bleomycin hydrolase in human tissues. The 5'-flanking region of the gene also contains a polymorphic CCG trinucleotide repeat that may be a target of genetic instability events and affect its transcriptional activity. Chromosomal localization of the human bleomycin hydrolase gene revealed that it maps to chromosome 17q11.2, very close to the locus of the neurofibromatosis type 1 gene. This location is unique for any cysteine proteinase mapped to date. Finally, Southern blot analysis of DNA from leukocytes and autologous breast tumors has shown that the bleomycin hydrolase gene is not a frequent target of amplification in human breast carcinomas.

Amino Acid Sequence↗
PubMed1976

Fatal pulmonary reaction from low doses of bleomycin. An idiosyncratic tissue response.

There were two cases of fatal interstitial pneumonia secondary to bleomycin sulfate administration. Although bleomycin pulmonary toxicity is generally thought to be dose-related and occurs infrequently with a total cummulative dose less than 300 to 400 units, the two reactions reported here occurred with doses of 105 and 165 units. Fatal bleomycin-induced pneumonia has been previously reported at these low dosages, and physicians should be aware that this toxic reaction may occur as an idiosyncratic response. Previous thoracic irradiation may be a predisposing factor. Patients receiving bleomycin should be meticulously monitored by interrogation for cough, dyspnea, and chest pain; by auscultation for rales; by serial chest roentgenograms; and by determinations of vital capacity and single-breath carbon monoxide diffusing capacity.

Adenocarcinoma↗
PubMed1978

Reversibility of severe bleomycin-induced pneumonitis.

The use of bleomycin sulfate as an antineoplastic agent has been limited by its substantial pulmonary toxic effects. The exact incidence and prognosis of bleomycin-pneumonitis is unresolved. Although bleomycin pulmonary toxicity is thought to be dose-related, recent reports have emphasized severe reactions at low doses. Furthermore, severe pulmonary toxicity has been suggested to be progressive, irreversible, and ultimately, fatal. We report clinical, roentgenographic, and pathophysiologic recovery after severe, bleomycin-induced pneumonitis.

Bleomycin↗
PubMed1998

Collagenase and gelatinase activities in bronchoalveolar lavage fluids during bleomycin-induced lung injury.

Basement membrane degradation can be indicative of tissue injury, but the process may also release matrix-bound cytokines to stimulate cell regeneration. To investigate this process, acute lung injury was induced in rats by intratracheal bleomycin and animals were killed from 3 days to 8 weeks later. The lungs were lavaged with saline to collect bronchoalveolar lavage (BAL) fluid and cell proliferation was assessed by pulse incorporation of tritiated thymidine. Bleomycin induced rapid inflammation with increased cell numbers and protein levels in BAL. Collagen degradation products were also increased in BAL fluid from 3 days to 4 weeks. Incubating samples of BAL fluid with radiolabelled collagens I and IV showed that high levels of activity, particularly for the degradation of type IV collagen, were present as early as 3 days post-bleomycin and persisted over the 8-week period. Zymograms demonstrated the highest level of gelatinase A (MMP-2) activity in BAL fluid in the first 2 weeks after bleomycin. Coincident with peak basement membrane degradative activity was the onset of a phase of epithelial cell proliferation, as measured by labelled nuclei in autoradiographs. The results show that enzymes capable of degrading the alveolar basement membrane are secreted early in the lung injury phase and that their presence in BAL fluid can be used as a measure of alveolar wall damage. It is possible that this enzyme action may release bound cytokines from the basement membrane, since maximal gelatinase activity correlates with alveolar epithelial cell proliferation.

Animals↗
PubMed1998

Topical bleomycin for the treatment of dysplastic oral leukoplakia.

BACKGROUND: Because malignant transformation of dysplastic oral leukoplakia has been reported in up to 43% of cases, these lesions must be managed. METHODS: This study evaluated the use of topical 1% bleomycin in dimethylsulfoxide for the treatment of dysplastic oral lesions. Bleomycin was applied once daily for 14 consecutive days to lesions of the oral mucosa in 19 patients. Immediate posttreatment biopsies and the clinical response were evaluated and clinical follow-up was conducted for as long as possible. RESULTS: The mean age of the patients at diagnosis was 59.4 years and 74% were tobacco users. Seventy-five percent of patients had resolution of dysplasia at follow-up biopsy, with a mean improvement of two histologic grades of dysplasia after topical chemotherapy. Ninety-four percent of the patients attained at least partial responses. After a mean follow-up period of 3.4 years, 31.6% of patients had no clinically visible lesions and 47.4% of patients had clinically benign lesions of homogeneous leukoplakia or minimal visible leukoplakia. In 2 patients (11%) malignant transformation occurred a mean of 1.75 years after bleomycin treatment. CONCLUSIONS: Topical bleomycin may prevent the potential progression of leukoplakia through dysplasia to carcinoma. Close follow-up of all patients with dysplasia is required.

Administration, Topical↗
PubMed1999

Phase II trial of chemotherapy with 5-fluorouracil, bleomycin, epirubicin, and cisplatin for patients with locally advanced, metastatic, or recurrent undifferentiated carcinoma of the nasopharyngeal type.

BACKGROUND: The aim of this study was to evaluate the toxicity and efficacy of the combination of 5-fluorouracil, bleomycin, epirubicin, and cisplatin (FBEC) in the treatment of patients with undifferentiated carcinoma of nasopharyngeal type (UCNT). The study included patients with metastatic or recurrent disease (Group A) and previously untreated patients with locally advanced nonmetastatic disease (T >/= 3 or any T, N >/= 2, M0, according to 1987 criteria of the International Union Against Cancer and the American Joint Committee on Cancer (Group B). METHODS: From January 1992 to November 1996, 49 patients with histologically proven UCNT were treated with intravenous (i.v.) 5-fluorouracil (700 mg/m(2)/day by continuous infusion for 4 days), epirubicin (70 mg/m(2) i.v. on Day 1), Bleomycin (10 mg i.v. bolus on Day 1 followed by 12 mg/m(2)/day by continuous infusion for 4 days), and cisplatin (100 mg/m(2) on Day 5); this regimen was repeated every 21 days. Six cycles were given to Group A (26 patients), with bleomycin omitted during the last 3 cycles. In Group B (23 patients), only 3 cycles were given, followed by conventional radiotherapy (70 gray for 7 weeks). RESULTS: Of the 26 patients entered in Group A, 23 were evaluable for response. Nine complete responses (CRs) and 9 partial responses (PRs) were assessed, for a 78% objective response rate (ORR) (95% CI: 56-92). Three patients are alive with no evidence of disease after 43, 61, and 73 months, respectively. These patients achieved a CR with chemotherapy followed by consolidating radiotherapy to their target lesions. In Group B, the ORR was 91.5%, with 5 CRs (22%) and 16 PRs (69.5%) assessed in the 23 patients. Three months after the end of radiotherapy, the ORR was 87% (20 patients). After a median follow-up of 51 months (range, 24-67 months), 15 patients (65%) are alive without evidence of disease. Forty percent of cycles (51% in Group A, 25% in Group B) resulted in Grade 4 neutropenia, with fever and/or sepsis in 9.5%. Mucositis was seen in 42% of pretreated patients. There were 3 treatment-related deaths (2 from complications of infection and 1 bleomycin fibrosis at a total dose of 160 mg/m(2)), all of them in Group A. CONCLUSIONS: The FBEC regimen has good activity, with durable responses in patients with locally advanced, metastatic, or recurrent UCNT. This regimen is safe for patients with locally advanced disease, but close follow-up and supportive measures are needed when it is used to treat those with metastatic or recurrent disease.

Adolescent↗
PubMed1975

A clinical evaluation of indium-111 bleomycin as a tumor-imaging agent.

In an evaluation of indium-111-bleomycin as a tumor-imaging agent, 357 whole-body tumor scans were performed in 293 patients. Of 246 studies performed in patients with a variety of active solid tumors, 218 (89%) were true-positive studies and 28 (11%) were false-negative. Of 69 scans in patients thought to be free of tumor after therapy, 32 (46%) were false-positive studies and 37 (54%) were true-negative. The true-positive rates by major tumor type were: adenocarcinoma of gastrointestinal tract origin (95%), lymphoma (88%), melanoma (87%), sarcomas (82%), lung (77%), breast (77%), childhood tumors (71%), gynecologic tumors (70%), and genitourinary tumors (68%). Soft tissue and lymphatic sites of tumor, both above and below the diaphragm, were easily visualized, whereas hepatic and bone marrow sites of involvement were less easily discerned. False-positive uptake with 111In-bleomycin was noted in lungs (6%), gut (3%), mediastinum (2%), normal breast tissue (0.8%), and in occasional inflammatory lesions. In 19 patients with multiple myeloma or leukemia, a pattern of diminished bone marrow uptake associated with abnormal accumulation of 111In-bleomycin in extramedullary sites of involvement was the rule. In another 23 patients in whom scans were performed because an occult tumor was suspected, scanning did not lead to specific diagnosis of tumor in a single instance. We conclude that 111In-bleomycin is a safe, effective, and useful new tumor-imaging agent in the initial staging and followup of patients with a variety of solid tumors. Significant advantages of this agent over other currently available radiopharmaceuticals include: A) a broader spectrum of tumors taking up the radio-pharmaceutical, and B) generally better delineation of abdominal and pelvic disease due to lack of interference from gut uptake.

Adenocarcinoma↗
PubMed1977

Bleomycin serum pharmacokinetics as determined by a radioimmunoassay and a microbiologic assay in a patient with compromised renal function.

Serum and plasma bleomycin concentrations were determined in a patient with renal dysfunction at two creatinine clearances. The results obtained with a new radioimmunoassay and the microbiologic assay were compared. It was shown: 1) that the clearance of bleomycin from the blood is markedly retarded in severe renal dysfunction, 2) that clearance of bleomycin varies with creatinine clearance, 3) that bleomycin is probably not dialyzable, 4) that determinations on serum and plasma were equivalent, and 5) that the radioimmunoassay and microbiologic assays gave equivalent results (P less than 0.001).

Acute Kidney Injury↗
PubMed1978

Pulmonary complications after bleomycin, irradiation and surgery for esophageal cancer.

Eight patients with epidermoid carcinoma of the esophagus were given radiotherapy of 3000 rads and 120 mg of bleomycin. Esophageal resection was performed five to six weeks later. Four of these patients died within six weeks, three from respiratory failure, and one from complications secondary to an anastomotic fistula. Of the remaining four patients, three showed varying degrees of pulmonary infiltration for several weeks. Interstitial pneumonitis was demonstrated in all the fatal cases. Four patients given the same irradiation and bleomycin doses were only subjected to exploratory surgery. They had no postoperative pulmonary complications. Ten patients given the same irradiation and bleomycin treatment without surgery also showed no pulmonary complications. Sixteen patients received higher doses of radiotherapy and bleomycin. Seven of these developed lung infiltrations terminating fatally in four. The likely mechanism of the observed postoperative pulmonary complications is that the preoperative treatment sensitized the lungs, while the subsequent surgical trauma triggered a reaction in the lungs leading to respiratory failure.

Aged↗
PubMed1981

Bleomycin-induced pulmonary fibrosis mimicking recurrent metastatic disease in a patient with testicular carcinoma: case report of the CT scan appearance.

Pulmonary fibrosis is a well-recognized complication of bleomycin therapy. Detection of bleomycin-induced pulmonary fibrosis by computed axial tomographic scanning (CT) has not been reported. We report on a patient in whom the development of lesions on chest CT scan following cessation of chemotherapy (including bleomycin) was interpreted as representing recurrent metastatic disease. At bilateral thoracotomy, only pulmonary fibrosis was found. In this patient, the CT scan appearance of bleomycin-induced pulmonary fibrosis mimicked recurrent disease.

Adolescent↗
PubMed1986

An assessment of the long-term results of controlling the reaccumulation of malignant effusions using intracavity bleomycin.

Fifty-four consecutive patients with malignant effusions either pleural or peritoneal were treated by a simple aspiration followed by the administration of bleomycin to prevent a recurrence. All patients were followed up until reaccumulation of the effusion or death, with assessments being made of the patient's response at 30 days, 60 days, 90 days, 6 months, 1 year and then annually. There were 42 evaluable patients at 30 days, when the overall response rate for pleural effusions was 80.5% (21/26) and 62.5% (10/16) for peritoneal effusions. Patients who developed an effusion from primary breast neoplasms responded better than other groups, with an overall rate of 81% and 80% for pleural and peritoneal effusions respectively. Thirty percent (13) of the patients whose effusions was controlled by bleomycin required a further aspiration due to a recurrent effusions 9% (4) within the first 90 days and the remainder 21% (9) between 3 and 45 months after initial treatment. Altogether 19% (8/42) of the evaluable patients were effusion free at 1 year and 12% (5/42) clear at 3 years, but only two patients were still alive at four years. Side effects were minimal as 92% (50/54) patients treated experienced no adverse effects and there was no evidence of myelosuppression. The dose of bleomycin instilled varied between 60 mg and 180 mg, with 60 mg being given to 58% of patients and 90 mg to 30%, but there was no evidence to suggest that doses higher than 60 mg were more effective. The author concludes that the instillation of bleomycin following the simple aspiration of a malignant effusion is a safe, effective treatment which can benefit patients with this distressing complication of their malignant disease.

Adult↗
PubMed1987

Acute chest pain syndrome during bleomycin infusions.

The authors describe 12 episodes of severe chest pain suggesting acute cardiac or pulmonary events which occurred during infusions of bleomycin. The incidence of the syndrome was low, occurring in 2.8% of those receiving the drug. Typically, the chest pain was sudden in onset and described either as substernal pressure or pleuritic in character. Few associated symptoms were noted. Evaluations for the etiology of the pain were unrevealing except for electrocardiographic changes suggestive of pericarditis in two cases and radiographic evidence of a small pleural effusion in one. The syndrome was self-limited or relieved with analgesics. There were no long-term cardiac or pulmonary sequelae. Discontinuation of bleomycin was not necessary although improvement was seen when the infusions were stopped. Further courses of bleomycin did not lead to recurrent episodes in most patients and are not contraindicated. Chest pain during continuous bleomycin infusion should suggest the possibility of a drug effect.

Adult↗
PubMed1987

Fatal bleomycin toxicity from a low cumulative dose in a patient with renal insufficiency.

A 54-year-old man with advanced non-Hodgkin's lymphoma and chronic renal insufficiency was treated with combination chemotherapy which included bleomycin. Fatal pulmonary toxicity developed after administration of a total bleomycin dose of only 60 U. Transbronchial biopsy and autopsy demonstrated pathologic findings consistent with bleomycin-induced pulmonary fibrosis. High-dose corticosteroid therapy did not appear to alter the clinical course. Extreme caution should be exercised when administering bleomycin to patients with renal insufficiency.

Bleomycin↗
PubMed1990

A randomized comparison of methotrexate dose and the addition of bleomycin to CHOP therapy for diffuse large cell lymphoma and other non-Hodgkin's lymphomas. Cancer and Leukemia Group B study 7851.

In 1978, Cancer and Leukemia Group B initiated a randomized study to determine the usefulness of the addition of bleomycin and/or high-dose methotrexate to standard therapy for the treatment of certain adult non-Hodgkin's lymphomas. Between 1978 and 1985, 177 patients with diffuse large cell lymphoma (DLCL) and 97 patients with other intermediate-grade non-Hodgkin's lymphoma were randomized to receive therapy with three courses of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) every 3 weeks with or without low-dose bleomycin by continuous IV infusion. Responders after three courses were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 gm/m2/week intravenously with leucovorin rescue) or standard-dose methotrexate (30 mg/m2/week orally without rescue). Therapy was concluded with three additional courses of CHOP. Neither the addition of low-dose infusion bleomycin nor the use of high-dose rather than low-dose methotrexate had significant effects on response for patients with DLCL; complete response rates for the four treatment programs ranged from 47% to 51%. Median failure-free survival (FFS) for the entire group of DLCL patients was 12 months; 5-year FFS was 27%. There was no significant effect on FFS from the addition of either low-dose bleomycin to CHOP (5-year FFS: CHOP, 28%; CHOP-B, 26%, P = 0.81), or from the use of different doses of methotrexate (5-year FFS: high-dose, 34%; standard-dose, 33%, P = 0.51). Patients with follicular large cell lymphoma, with or without diffuse areas, had a better FFS (5-year FFS, 47%) than patients with DLCL (5-year FFS, 27%), while the patients with the other histopathologic subtypes of diffuse lymphomas had the poorest FFS (5-year FFS, 16%).

Aged↗
PubMed2000

Induction of apoptosis in head-and-neck squamous carcinoma cells by gamma-irradiation and bleomycin is p53-independent.

We have examined the ability of gamma-irradiation and bleomycin to induce apoptosis in a model system consisting of cell lines derived from naturally occurring human head-and-neck squamous-cell carcinomas with contrasting p53 status and expression levels of pro- and anti-apoptotic molecules. Following exposure to gamma-irradiation (20 Gy) or bleomycin (3.5 microM) for 0 to 96 hr, cells expressing either transcriptionally inactive mutant p53 (HN6) or a truncated p53 molecule (HN19) underwent apoptosis, as assessed by fluorescence-activated cell sorting and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, in contrast to cells that express wild-type p53 (HN30), suggesting that apoptosis induced by these agents occurs by p53-independent mechanisms. Apoptosis in HN6 and HN19 cells was preceded by a G(2)/M cell-cycle block, as analyzed by DNA content and BrdU staining. In contrast, HN30 cells remained blocked in both G(1) and G(2)/M and failed to re-enter the cell cycle. Levels of Bcl-2 were elevated in 3 of 10 cell lines, and only marginal differences were observed for Bcl-x(L). Pro-apoptotic proteins bax and Bcl-x(S) were detectable in normal keratinocytes and 4 tumor cell lines. Bax-delta (16 kDa) was highly represented in normal keratinocytes, and levels of bak were variable between cell lines. Elevated expression of Bcl-2 failed to protect HN19 cells from either gamma-irradiation or bleomycin-induced apoptosis. Our data support the existence of p53- and Bcl-2-independent pathways regulating apoptosis in keratinocytes and suggest that efficacy of either radiotherapy or bleomycin treatment for oral squamous-cell neoplasms may not, therefore, be influenced solely by endogenous p53 status.

Antibiotics, Antineoplastic↗
PubMed1999

A systematic approach toward the analysis of drug-DNA interactions using Raman spectroscopy: the binding of metal-free bleomycins A(2) and B(2) to calf thymus DNA.

Bleomycins A(2) and B(2) are the two active components in the antineoplastic drug Blenoxane. DNA is targeted by this drug in cancer cells and the mode of action of this drug involves DNA binding. Ambiguity exists as to the way in which bleomycin binds to DNA. Raman spectroscopy was used to examine both calf thymus DNA and a bleomycin/DNA complex at two temperatures. A curvefitting technique was applied to these spectra for a spectral region obscured by many overlapping bands associated with the nucleotide bases in order to derive information about frequencies, bandwidths, and intensities of the vibrational modes in this region. This allowed identification and analysis of bands associated with specific assigned nucleotide base residues. Upon binding of bleomycin, several significant changes in bandwidth, intensities, and frequencies relative to uncomplexed DNA were observed consistently at both higher (30 degrees C) and lower (19 degrees C) temperature. The data presented here support at least a partial intercalation mode of binding for bleomycin that is temperature dependent and more pronounced at the more physiologically relevant temperature of 30 degrees C.

Animals↗
PubMed1989

Comparison of intracavitary bleomycin and talc for control of pleural effusions secondary to carcinoma of the breast.

In a prospective randomized study, patients with pleural effusions secondary to breast carcinoma were randomly allocated to be treated by pleurodesis using either intracavitary talc or bleomycin. For 25 assessable treatments in 22 patients, recurrence of effusion was observed in 5 of 15 (33 per cent) of the bleomycin group compared with none in the talc group. It is concluded that talc is superior to bleomycin in controlling pleural effusions secondary to breast carcinoma, but bleomycin may have a role in patients unfit for general anaesthesia or with extensive disease elsewhere.

Bleomycin↗
PubMedDate not supplied

Effects of fish oil treatment on bleomycin-induced pulmonary fibrosis in mice.

Bleomycin is an antibiotic used to treat a variety of neoplasms. A major side-effect of bleomycin therapy is the induction of an intense inflammatory response that develops into pulmonary fibrosis. Several studies have shown that certain polyunsaturated fatty acids found in fish oil reduce the inflammatory response in vivo. Fish oil has been employed for the treatment of several pathologies such as glomerulonephritis, cardiovascular diseases, rheumatoid arthritis, and even as an adjuvant in cancer therapy. This study examined the effects of fish oil treatment on the development of bleomycin-induced pulmonary fibrosis. Mice were intraperitoneally treated with bleomycin or with saline daily for 10 days, and 15 days after the last injection they started to receive fish oil by gavage for 14 days. The lungs were processed for light microscopy, biochemical and immunohistochemical investigations. Fish oil did not prevent the development of pulmonary fibrosis after the injury as shown by light microscopy, cytokines immunohistochemical analysis, TBARS content and protein levels in the lung. In addition however, fish oil itself induced a slight inflammatory process in the lung, as observed by the increase in cellularity, vasodilatation in the lung parenchyma, TBARS content, and a slight increase in the lung protein content.

Actins↗