Bleomycin-induced Toxicity Research Articles

Attenuation of Bleomycin-induced Toxicity on Selected Respiratory Function Metrics in Rabbits by a Polyherbal Preparation

Attenuation of Bleomycin-induced Toxicity on Selected Respiratory Function Metrics in Rabbits by a Polyherbal Preparation

A New Modality for the Diagnosis of Bleomycin-induced Toxicity: Ultrasonography

ObjectiveTo evaluate the role of ultrasonography (USG) in the diagnosis of bleomycin-induced pulmonary toxicity (BT). Material and methodsThe study included patients with suspected BT during treatment with bleomycin due to various oncologic diseases between June 2015 and May 2017. The patients initially underwent clinical and high-resolution computed tomography (HRCT) examinations and pulmonary function tests (PFT)-diffusing capacity of the lung for carbon monoxide (DLCO), followed by registration of USG findings—number of comet tail artifact (CTA) images by a different pulmonologist. We compared the findings from USG, HRCT, and PFT–DLCO tests between BT and non-BT groups. With the diagnosis based on clinical-radiologic and PFT–DLCO assessments taken as the gold standard, we determined the sensitivity and specificity of the USG outcomes for diagnosis of BT. ResultsThe study included a total of 30 patients. Nine patients were diagnosed as having BT according to their clinical and radiologic findings and PFT–DLCO measurements. The mean number of CTA images was 68.7±22 in patients with BT vs 28.2±9.3 in those without BT (P<.001). The difference in CTA images between the patients with and without ground glass density was statistically significant (28.3±9.5 and 64.6±24.5, respectively, P<.001). In patients with BT, there was a negative correlation between the number of CTAs and DLCO% and FVC% values (P=.004; P=.016). USG had a sensitivity of 100%, and a specificity of 95% diagnosing BT in selected patients. ConclusionIn bleomycin-induced toxicity, USG findings are correlated with HRCT and PFT–DLCO findings, with a remarkably increased number of CTAs in BT. Thoracic USG examination is a diagnostic tool with a high sensitivity and specificity for diagnosing BT.

A New Modality for the Diagnosis of Bleomycin-induced Toxicity: Ultrasonography

ObjectiveTo evaluate the role of ultrasonography (USG) in the diagnosis of bleomycin-induced pulmonary toxicity (BT). Material and methodsThe study included patients with suspected BT during treatment with bleomycin due to various oncologic diseases between June 2015 and May 2017. The patients initially underwent clinical and high-resolution computed tomography (HRCT) examinations and pulmonary function tests (PFT)-diffusing capacity of the lung for carbon monoxide (DLCO), followed by registration of USG findings—number of comet tail artifact (CTA) images by a different pulmonologist. We compared the findings from USG, HRCT, and PFT–DLCO tests between BT and non-BT groups. With the diagnosis based on clinical-radiologic and PFT–DLCO assessments taken as the gold standard, we determined the sensitivity and specificity of the USG outcomes for diagnosis of BT. ResultsThe study included a total of 30 patients. Nine patients were diagnosed as having BT according to their clinical and radiologic findings and PFT–DLCO measurements. The mean number of CTA images was 68.7±22 in patients with BT vs 28.2±9.3 in those without BT (P<.001). The difference in CTA images between the patients with and without ground glass density was statistically significant (28.3±9.5 and 64.6±24.5, respectively, P<.001). In patients with BT, there was a negative correlation between the number of CTAs and DLCO% and FVC% values (P=.004; P=.016). USG had a sensitivity of 100%, and a specificity of 95% diagnosing BT in selected patients. ConclusionIn bleomycin-induced toxicity, USG findings are correlated with HRCT and PFT–DLCO findings, with a remarkably increased number of CTAs in BT. Thoracic USG examination is a diagnostic tool with a high sensitivity and specificity for diagnosing BT.

Late pulmonary complications of treating Hodgkin lymphoma: bleomycin-induced toxicity

Introduction: Survival of Hodgkin lymphoma (HL) patients has significantly improved in recent decades. The current first-line therapy is doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) ± irradiation and may cause pulmonary toxicity. Strategies to reduce late toxicity as well as increase survival rate are of interest.Patients and methods: Pulmonary function of previously treated HL patients was collected over a 12-month period using St. George Respiratory Questionnaire (SGRQ), chest X-ray, dynamic inhalation lung scintigraphy and spirometry.Results: A total of 137 patients’ data were reviewed. Median time elapsed since diagnosis was 11 years (range was 2 – 30 years). Chest irradiation did not significantly worsen pulmonary function. Number of ABVD cycles with consequential bleomycin dose showed significant correlation with SGRQ total score in patients receiving ABVD plus chest irradiation (p = 0.01). Scintigraphy results correlated with bleomycin dose in patients receiving ABVD without chest irradiation (right side: p = 0.099, left side: p = 0.051).Discussion: An additive negative effect of chest irradiation was not confirmed as reflected in the literature; however, increasing cumulative bleomycin dose worsened pulmonary function.

862P - Continuous Infusion Bleomycin in the Bep Regimen: A Therapeutic Alternative in the Management of Patients with Germ-Cell Tumors?

ABSTRACT Introduction Germ-cell tumors (GCTs) are highly curable with cisplatin-based chemotherapy. The BEP chemotherapy (Indianapolis) has become a standard in the management of GCT. The aim of this study was to evaluate the long-term side effects of a modified BEP regimen, with of bleomycin as a continuous infusion. Patients and methods The military hospital of Val de Grâce has developed a modified BEP regimen with the aim of reducing bleomycin-induced toxicity in patients with GCTs: bleomycin 15mg/d (d1-5) as an IV continuous injection, etoposide 100mg/m2 (d1-5) and cisplatin 20mg/m2 (d1-5), repeated every 3 weeks. Survivors were asked in 2011 to participate to this study on late toxicity, including assessment of laboratory tests, pulmonary function tests (PFT) and a semen analysis. Results Between March 1998 and January 2009, 68 patients with GCTs received first line chemotherapy with this modified BEP. Distribution of patients' was as following: Good prognosis (GP): 42, Intermediate and Poor-prognosis (IPP): 20, stage I with High risk factors (HP): 6. The median follow-up was 75 months. The 2-years overall survival was 90%. The relapse rate was 13%. The main immediate adverse events reported grade III-IV were neutropenia (25%), anemia (1%), thombopenia (1%), digestive (6%), infection (4%), decreased DLCO (4%) and tromboembolic events (3%). Thirty four patients were assessable for the late toxicity of this regimen (18 patients in GP, 14 patients in IPP and 2 patients in HP).The 5-years overall survival was 82%. The analysis of late side effects revealed one patient developed a haematologic malignancy (myelodysplasia).Abnormal PFT was observed in 4 patients, and only 1 patient was clinically symptomatic. In post-treatment analysis, we evaluated the fertility of 30 patients. The fertility was preserved in 22 patients (73%). Twenty patients have realized a semen analysis after the chemotherapy, and azoospermia was observed in only 3 pts (15%). Among 10 patients remaining, 5 patients had children after the treatment. Conclusion Using bleomycin as a continuous infusion is feasible and seems to produce similar results in terms of response rates and overall survival compared to the classic BEP chemotherapy regimen, with a total dose less important than standard. These results will be compared with those of conventional BEP Disclosure All authors have declared no conflicts of interest.

Prevention of bleomycin-induced pulmonary fibrosis after adenovirus-mediated transfer of the bacterial bleomycin resistance gene.

A serious limitation in the use of the DNA-cleaving, antitumoral-antibiotic, bleomycin during chemotherapy is pulmonary toxicity. Lung injury induced by bleomycin is characterized by an increased deposition of interstitial extracellular matrix proteins in the alveolar wall that compromises respiratory function. Several drugs have been tested in animal models to prevent the pulmonary toxicity of bleomycin, but have not led to a useful clinical treatment because of their adverse effects on other tissues. We have shown that transgenic mice expressing Streptoalloteichus hindustanus (Sh) ble bleomycin resistance protein in pulmonary epithelial cells in the lungs are protected against bleomycin-induced toxicity in lungs. In the present study, we used intranasal administration by adenovirus-mediated gene transfer of the bleomycin resistance Sh ble gene to mouse lung for prevention of bleomycin-induced pulmonary fibrosis. We constructed recombinant adenoviruses Ad.CMVble and Ad.RSVble harboring the bleomycin resistance Sh ble gene under the control of the cytomegalovirus early promoter and the Rous sarcoma virus early promoter, respectively. Transgene expression was detected in epithelia of conducting airways and alveolar septa by immunostaining with a rabbit polyclonal antibody directed against the bleomycin resistance protein and persisted for the duration of drug treatment; i.e., up to 17 d. No toxic effect was seen in adenovirus-treated mice. Pretreatment of mice with Ad.CMVble or Ad.RSVble completely prevented collagen deposition 42-133 d after bleomycin treatment, as measured by lung OH-proline content. Histologic studies indicated that there was little or no lung injury in the adenovirus/bleomycin-treated mice compared with the bleomycin-treated mice. These observations may lead to new approaches for the prevention of bleomycin-induced pulmonary fibrosis.

BLH1 codes for a yeast thiol aminopeptidase, the equivalent of mammalian bleomycin hydrolase.

We have cloned the BLH1 gene of the yeast Saccharomyces cerevisiae coding for a peptidase with significant homology to rabbit bleomycin hydrolase. Bleomycin is a glycopeptide antibiotic used for the treatment of human cancers. The antitumor activity of the drug is limited by its metabolic inactivation caused by bleomycin hydrolase, a member of the cysteine protease family. The open reading frame of BLH1 consists of 1,449 base pairs encoding a 55.4-kDa protein consistent with the molecular mass found in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The consensus sequence within the active site region of cysteine proteases is conserved in the yeast enzyme. Biochemical studies on the purified enzyme confirm its classification as a thiol protease. The nonvacuolar enzyme has a molecular mass of 220 kDa, suggesting a homotetrameric structure. It exhibits an aminopeptidase activity with broad substrate specificity. Biochemical and genetic linkage data give evidence that the BLH1 and the LAP3 (Trumbly, R. J., and Bradley, G. (1983) J. Bacteriol. 156, 36-48) encoded aminopeptidases are identical. Deletion of the BLH1 gene is not lethal under normal growth conditions. However, blh1 mutants show hypersensitivity to bleomycin, indicating that bleomycin hydrolase is able to inactivate bleomycin in vivo and to protect cells from bleomycin-induced toxicity.

Alterations in pulmonary protective enzymes following systemic bleomycin treatment in mice

Repeated bleomycin administration in animals and humans produces significant lung fibrosis. The pathogenesis of this toxicity may be multifactorial, but it appears to be initiated through the production of radical oxygen species by an activated bleomycin-iron-oxygen ternary complex. Protection of lung tissue from bleomycin-induced toxicity may occur through both specific metabolic inactivation of bleomycin by the enzyme bleomycin hydrolase, as well as by such non-specific antioxidants as catalase and the glutathione system. The effect of chronic, systemic administration of bleomycin on the activities and levels of these enzymes and proteins in pulmonary tissue is unknown. C57BL/6 mice were injected subcutaneously with saline, non-fibrogenic (2mg/kg) and fibrogenic (10mg/kg) doses of bleomycin twice-weekly for 6 weeks. Animals were killed at 0, 1.5, 3, and 6 weeks after initiation of bleomycin treatment. Catalase activity was increased more than 50% at 3 weeks in the low-dose animals, and was decreased over 40% at 6 weeks in the high-dose animals. Total lung glutathione levels were unaffected in both groups, although glutathione reductase activity was increased significantly (over 2-fold) at 1.5 and 3 weeks in the high-dose animals. At 6 weeks glutathione reductase was increased 7- and 12-fold in low and high-dose animals respectively. Glutathione peroxidase activity also was elevated more than 2-fold above control values at 6 weeks in both sets of animals. There was no evidence of induction of bleomycin hydrolase activity at any time point. Rather, bleomycin hydrolase activity was decreased significantly to 30 and 40% of control values at 3 and 6 weeks, respectively, in mice receiving the fibrogenic doses of bleomycin. These results demonstrate that chronic, systemic administration of non-fibrogenic and fibrogenic doses of bleomycin produces changes in activity of lung antioxidant defense mechanisms. The early loss of lung bleomycin hydrolase activity may contribute to the pathogenesis of bleomycin-induced pulmonary toxicity following repeated drug exposure.