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PubMed1997

Pulmonary toxicity in patients with advanced-stage germ cell tumors receiving bleomycin with and without granulocyte colony stimulating factor.

STUDY OBJECTIVES: The purpose of this study is to determine whether co-administration of granulocyte colony stimulating factor (G-CSF) and bleomycin results in enhanced pulmonary toxicity compared with bleomycin alone. DESIGN: A retrospective analysis comparing two groups of patients with advanced germ cell tumors receiving combination chemotherapy that includes bleomycin with or without G-CSF. SETTING: Indiana University Medical Center. PATIENTS: Group A consisted of 29 patients with advanced-stage germ cell tumors who were treated with combination chemotherapy that included bleomycin. All patients received concurrent prophylactic G-CSF. Group B consisted of 57 patients with advanced-stage germ cell tumors who were treated on a phase 3 study comparing standard BEP (bleomycin, etoposide, cisplatin) to BEP with twice the cisplatin dose. None of these patients received growth factor. RESULTS: Of the 29 patients who received concurrent chemotherapy and G-CSF, ten (34%; 95% confidence interval [CI], 17.9 to 54.3%) were believed to have clinically significant bleomycin toxicity. Of the 57 patients who did not receive growth factor, 19 (33%; 95% CI, 21.4 to 47.1%) had bleomycin-related toxicity. There was no difference in the incidence of pulmonary toxicity between the groups (p = 1.00 by Fisher's Exact Test). CONCLUSIONS: There is no increase in pulmonary toxicity with co-administration of G-CSF and bleomycin compared to bleomycin alone in patients with advanced germ cell tumors.

Adolescent↗
PubMedDate not supplied

Vitamin E reduces bleomycin-induced lung fibrosis in mice: biochemical and morphological studies.

Bleomycin is a widely used antineoplastic drug which produces dose- and time-dependent interstitial pulmonary fibrosis in humans. The mechanism of bleomycin-induced lung injury is not well understood. However, current data show that bleomycin can generate reactive oxygen species such as superoxide and hydroxyl radicals. The antioxidant role of vitamin E in biological systems is well known. We investigated the effect of vitamin E on bleomycin-induced lung fibrosis in mice biochemically and histologically. Animals were divided into four groups: control, saline + vitamin E (S/Vit E), bleomycin + saline (Bleo/S) and bleomycin + vitamin E (Bleo/Vit E). Bleomycin was administered subcutaneously at a dose of 10 mg/kg in Bleo/S and Bleo/Vit E groups, and vitamin E was administered intraperitoneally at a dose of 15 mg/animal in S/Vit E and Bleo/Vit E groups twice weekly for 4 weeks. The control group received saline. As a marker of collagen amount or fibrosis in lung tissue, hydroxyproline and soluble protein content were measured and hydroxyproline/soluble protein ratio per gram wet lung tissue was calculated. For hydroxyproline and protein determinations, and histologic examination of lung tissue, 6 mice from the control and S/Vit E groups and 7 mice from the Bleo/S and Bleo/Vit E groups were killed at at 4, 6 and 8 weeks after administration of bleomycin. The mean hydroxyproline/soluble protein ratio of the Bleo/Vit E group was significantly lower than that of the Bleo/S group and significantly higher than those of the control and S/Vit E groups at 6 and 8 weeks (p < 0.05). Parallel with the biochemical findings, the grade of the histological lesions in the Bleo/Vit E group was lower than that in the Bleo/S group, but higher than those of the S/Vit E and control groups (p < 0.05). These results suggest that a high dose of vitamin E considerably reduces the fibrotic effect of bleomycin on lung tissue in mice.

Animals↗
PubMed1985

Inhibition of bleomycin lung toxicity by N-acetyl cysteine in the rat.

N-acetyl cysteine (NAC) has recently been shown to have antioxidant properties, and since bleomycin produces pulmonary damage via free oxygen radical toxicity, the possible protective effect of NAC on bleomycin lung toxicity was investigated. Rats received saline (n = 7), NAC (n = 6), bleomycin (n = 7) or bleomycin and NAC (n = 6) by direct intratracheal injection. Seven days later the animals were killed and the lungs processed for histology or morphometry. All rats treated with bleomycin only had typical changes of bleomycin lung toxicity whereas the animals treated with bleomycin and NAC had minimal pathology. The control animals had normal lungs. These results were confirmed by morphometry which demonstrated significantly higher volume densities (p less than .01) of alveolar wall and free alveolar cells in the bleomycin group compared to the other 3 groups. It is concluded that NAC inhibits bleomycin lung toxicity when administered by direct intratracheal injection.

Acetylcysteine↗
PubMed1999

The mutagenic and toxic effects of bleomycin and trifluoperazine in Drosophila melanogaster.

The mutagenic and toxic effects of trifluoperazine and bleomycin on Drosophila were investigated in the progenies of males injected with 0.2 microliter of bleomycin and/or trifluoperazine. The Muller-5 method was used to study the induction of complete- and mosaic-sex-linked recessive lethals induced by 0.1 microgram/ml bleomycin and/or 0.1 mM trifluoperazine in the five successive broods, mainly representing the different stages of spermatogenesis. Trifluoperazine increased the induction rate of sex-linked recessive mutations above the spontaneous rates of the control, but these increases were not statistically significant at the 5% level27 in any of the five different broods. Contrary to trifluoperazine, bleomycin significantly (5% level)27 increased the induction rate of the complete sex-linked recessive lethals over those of the control in the meiotic and premeiotic broods C and D, and the meiotic brood E. As with the separate treatment with bleomycin, the frequencies of the complete sex-linked recessive lethals induced by the simultaneous combination treatment of 0.1 microgram/ml bleomycin and 0.1 mM trifluoperazine were significantly higher than those of the control at the 5%27 level, only in the meiotic and premeiotic broods, but they were not significantly higher than those induced by bleomycin treatment alone19. Treatments with 0.1 mM trifluoperazine enhanced the toxicity, sterility and the number of mutated clusters induced by 0.1 mM bleomycin but did not significantly increase the rates of induced lethals over the additive effects of both drugs in the meiotic and premeiotic stages, suggesting no potentiation effects for trifluoperazine over those of bleomycin in Drosophila. Higher concentrations of the two drugs could not be used due to their high toxicity and sterility effects.

Animals↗
PubMed1987

Effects of dietary fats on bleomycin-induced pulmonary fibrosis.

Bleomycin treatment has been used for the experimental induction of pulmonary fibrosis, but the mechanisms involved are poorly understood. Since alterations in the levels of certain fatty acid metabolites have been associated with bleomycin-induced lung injury, we examined the effects of different dietary fats on the development of bleomycin-induced pulmonary fibrosis. Weanling rats were raised on standard laboratory feed or a diet consisting of a fat-free powder to which was added either coconut oil or beef tallow (25% w/w). After 8 weeks of feeding, animals received either 1.5 units bleomycin or an equivalent volume of saline intratracheally. Bleomycin treatment resulted in significant increases in total lung hydroxyproline content in the groups fed the standard lab diet (p less than 0.001) and beef tallow diet (p less than 0.001), but not in the group receiving the coconut oil diet. Furthermore, the lung hydroxyproline content in bleomycin-treated animals was less with the beef tallow diet compared with standard lab feed (p less than 0.05). Bleomycin treatment resulted in an increase in thiobarbituric acid-reactive products, an index of lipid peroxidation, in lungs from animals fed the standard lab diet, but not in the other diet groups. The percentage of diseased lung, as determined by morphometric analysis, was increased in bleomycin-treated animals from all diet groups (p less than 0.05). We conclude that alterations in dietary fats can reduce the severity of pulmonary fibrosis resulting from bleomycin treatment. Possible mechanisms for this effect include alterations in eicosanoid metabolism or changes in immune or effector cell function.

Animals↗
PubMed1999

Extensive chemical degradation of bleomycin during attempted labelling with 51-Cr.

AIM: Labelling of the cytostatic agent bleomycin with 51-Cr and use of the product for biodistribution studies have been reported in the literature. The labelling procedure involves incubation for 40 min at 130 degrees C. Since bleomycins are polar glycopeptides sensitive to hydrolytic cleavage we were concerned about possible degradation of the drug during these unfavourable conditions. We have therefore investigated the stability of bleomycin as a function of temperature and pH of the solution and attempted to achieve the maximum labelling efficiency with minimal degradation of the two principal bleomycin components. METHODS: The chemical stability of unlabelled bleomycin was investigated under labelling conditions at 130 degrees C and in buffer of pH 1-6 at room temperature (23 degrees C) and 60 degrees C. The samples were assayed by high-performance liquid chromatography (HPLC). The labelling efficiency of the 51-Cr-bleomycin complex was determined by thin layer chromatography and activity measurement with a high pure Germanium (HPGe)-detector at various incubation temperatures and times. RESULTS: Comparisons of rates of degradation of bleomycin with labelling efficiency as functions of temperature and time showed that under no condition could satisfactory labelling (> 97%) be obtained without considerable degradation of bleomycin. CONCLUSION: Labelling of bleomycin with 51-Cr does not yield a product suitable for investigations in patients.

Bleomycin↗
PubMed1999

An allele of the yeast RPB7 gene, encoding an essential subunit of RNA polymerase II, reduces cellular resistance to the antitumor drug bleomycin.

Bleomycin is an antitumor drug that kills cells by introducing lesions in DNA. Thus, normal cells exposed to bleomycin must rely on efficient DNA repair mechanisms to survive. In the yeast Saccharomyces cerevisiae, the transcriptional activator Imp2 is required to fend off the toxic effects of bleomycin. However, it remains unclear whether Imp2 controls the expression of a protein that either repairs bleomycin-induced DNA lesions, or detoxifies the drug, and or both. To gain further insight into the mechanisms by which yeast cells mount a response towards bleomycin, we began to sequentially characterize the genetic defect in a collection of bleomycin-sensitive mutants that were previously isolated by mini-Tn3 transposon mutagenesis. A rescue plasmid designed to integrate at the site of the mini-Tn3 insertion was used to identify the defective gene in one of the mutant strains, HCY53, which was not allelic to IMP2. We showed that in strain HCY53, the mini-Tn3 was inserted at the distal end of an essential gene RPB7, which encodes one of the two subunits, Rpb4-Rbp7, that forms a subcomplex with RNA polymerase II. Since rpb7 null mutants are nonviable, it would appear that the rpb7::mini-Tn3 allele produces a protein that retains partial biological function thus permitting cell viability, but which is unable to provide bleomycin resistance to strain HCY53. The defective phenotype of strain HCY53 could be corrected by a plasmid bearing the entire RPB7 gene. Two dimensional gel analysis revealed that the expression of several proteins were diminished or absent in the rpb7::mini-Tn3 mutant when challenged with bleomycin. These results are in accord with our previous report that bleomycin resistance in yeast is controlled at the transcriptional level.

Alleles↗
PubMed1998

[Gene expression of messenger RNA coding for procollagen and tumour necrosis factor-alpha in lungs undergoing bleomycin-induced pulmonary fibrosis].

OBJECTIVE: mRNA for tumour necrosis factor-alpha(TNF-alpha) and procollagen I [pro alpha 1(I)] and III (pro alpha 1(III) was measured in bleomycin treated mice to evaluate their roles in pulmonary fibrosis. METHOD: 30 male Wistar rats were divided into normal control group and groups treated by bleomycin on days 3, 7, 14, 21, 30. Each group included 5 rats, and the rats were treated by single intratracheal instillation with sterile saline solution or with 5 mg/kg body weight of bleomycin. The rats were sacrificed at different days, and total RNA from the lungs of bleomycin or saline solution instilled rats was extracted. Expression of TNF-alpha, pro alpha 1 (I) and pro alpha 1 (III) mRNA was measured by dot blot and Northern blot hybridization. RESULT: The levels of TNF-alpha mRNA in lungs of bleomycin groups on days 3,7 were significantly higher than those of control group (t = 10.33 and 12.54 respectively; P < 0.01). The levels of pro alpha 1 (I) and pro alpha 1(III) mRNA in lungs of bleomycin group on day 7 were higher than those of control group(t = 10.56 and 24.23 respectively; P < 0.01), After reaching the peak levels in two weeks, the levels of pro alpha 1(III) mRNA in lungs of bleomycin group on day 30 declined slowly to approximately the values of normal control group (t = 1.95; P > 0.05); but the levels of pro alpha 1(I) mRAN on day 30 after bleomycin administration were higher than those of control group (t = 16.67; P < 0.01). The mRNA coding pro alpha 1(I) and pro alpha 1(III) in lungs of rats had two mRNA species. CONCLUSION: The results suggested that the metabolism of mRNAs for pro alpha 1 (I) and pro alpha 1 (III) may be preferentially perturbed, and that increase of collagen gene expression in the transcriptional level might be involved in the mechanism of collagen accumulation. The increased expression of TNF-alpha gene may play an important role in the early events of bleomycin-induced pulmonary fibrosis.

Animals↗
PubMed2004

The influence of hyperoxia on cough reflex intensity in guinea pigs treated with bleomycin.

Inhalation of high concentration of oxygen produces a lung injury in men and experimental animals. In our previous experiment we have found suppression of cough reflex in healthy guinea pigs after an exposure to 100% O2 for 60 hours. This study was designed to find the effect of hyperoxia on cough reflex in guinea pigs with lungs damaged by bleomycin. We used 48 animals (300-400 g) in two separated experiments. 32 of them were intratracheally injected with 1.5 mg bleomycin (Bleocin, Nippon Kayaku Co., Ltd., Tokyo, Japan) for induction of lung damage according to the method described by Parizada et al (20). 16 animals were given saline, only (control). Animals of experimental group were divided into two subgroups according to the lapse of time from bleomycin application. 13 days after bleomycin application animals of the 1st subgroup (16) were exposed to 100% O2 (8) or to room air (8) for 48 h. Similarly, 20 days after bleomycin application guinea pigs of the 2nd subgroup (16) were exposed to 100% O2 (8) or air (8), respectively. Cough was provoked in conscious animals placed in bodyplethysmograph box by inhalation of citric acid aerosol (0.3 mol/L) before, then 13 or 20 days after bleomycin application, and finally at the end of 48-h exposition to 100% O2 (air). The number of coughs was counted from airflow trace recorded by pneumotachograph. Cough was also induced by mechanical stimulation of laryngopharyngeal (LPh) and tracheobronchial (TBr) region in anaesthetized animals (Urethane, 1.1 g/kg, i.p.) just after the end of oxygen exposition and was evaluated from the interpleural pressure record. The results have shown a tendency to inhibition of citric acid cough reflex in animals 13 days treated with bleomycin and exposed to 100% O2, and significant decrease in citric acid induced cough in animals 20 days treated with bleomycin and exposed to 100% O2. Significant changes were present in cough intensity induced by mechanical stimulation of TBr region of the guinea pigs airway treated with bleomycin and exposed to oxygen, too. (Tab. 1, Fig. 3, Ref: 29.)

Animals↗
PubMed1985

[Clinical research on prevention of recurrence of superficial bladder cancer--comparative study on clinical efficacy of bleomycin intravesical instillation and bestatin].

Objectives and methods of the study: Although superficial bladder carcinoma can be surgically eliminated by TUR, recurrence is common. Various attempts have been made to prevent recurrence, but to date an excellent prophylactic method with few adverse reactions has not been established. We conducted a clinical trial study for prophylaxis of bladder carcinoma recurrence, using intravesical instillation of bleomycin, a drug which cause little local irritation, in combination with bestatin, a recently developed immunomodulator. Bleomycin was selected on the bases of experimental results. That is, in beagle dogs, the 1-hour intravesical instillation of bleomycin gained a drug concentration in the bladder wall of 2.08 micrograms/g, which is approximately 4 times higher than that in the intravenous administration of the same dose. The above bleomycin concentration was thought enough to obtain a good clinical effect. A total of 124 patients were randomly divided into the two treatment groups: An only bleomycin intravesical instillation group (60 mg on each treatment day) (58 patients) and a bleomycin with bestatin (60 mg per every day) group (66 patients). In the 2-year follow-up period the recurrence of bladder carcinoma in the two treatment groups was studied. Analysis of non-recurrence rate by life-table method and Kaplan-Meier method: The non-recurrence rate of the bladder carcinoma every three months was calculated by the life-table and Kaplan-Meier methods. The non-recurrence rate in the bleomycin group was approximately the same as the rates in adriamycin or mitomycin reported in the literature. In the bleomycin + bestatin group, the recurrence rates at 9 months and 12 months were significantly (at P = 0.09 and P = 0.08, respectively) lower, and in addition, even the 2-year overall non-recurrence rate curves showed a nearly significant difference (P = 0.179). Especially in the case of papillary pedunculated tumors, the difference in the non-recurrence rate curves was almost statistically significant (P = 0.104). The stratified analysis on the basis of various tumor factors, were as follows. Pathological grade: Although no differences were found in Grades 1 and 2, the bleomycin + bestatin group had a lower recurrence rate in Grade 3 cases (P = 0.1).(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1988

Internucleosomal cleavage and chromosomal degradation by bleomycin and phleomycin in yeast.

Native chromosomal structure, breakage, and overall degradation were studied following the reaction of whole cells with the anticancer drug bleomycin and structurally related phleomycin. Electrophoretic analyses of cellular DNA established that phleomycin was more reactive with DNA than equimolar bleomycin in the range of 0.67-33 x 10(-6) M, produced an optimally visible, though less-extended, oligonucleosomal series at concentrations 12 to 35 times lower than bleomycin, and degraded DNA within nucleosomes. Chromosomes were cleaved into nucleosomes and degraded by phleomycin over substantially narrower dose ranges (1 to 2 x 10(-6) M) than by bleomycin (about 1 to 17 x 10(-5) M). Bleomycin exhibited higher specificity for internucleosomal cleavage than phleomycin, and trimmed but did not degrade nucleosomes at less than or equal to 3 x 10(-5) M. Identical nucleosomal repeat sizes (166 +/- 3.8 base pairs) were produced by the analogues. The higher reactivity of phleomycin does not result solely from its higher rate of internucleosomal and intranucleosomal chromatin cleavage, since short phleomycin reactions always resulted in more extensive chromatin cleavage than long bleomycin reactions at low concentrations. In vivo (cellular) repair of chromatin damage was comparable (approximately 90% in 1 h) after cells were exposed to low drug concentrations which produced similar numbers of chromatin breaks, and thus also does not account for the higher chromosomal breakage caused by phleomycin than bleomycin at low doses. At high doses, unrepaired breaks are substantially higher after phleomycin treatments than after bleomycin treatments, and thus contribute to the higher lethal effects of phleomycin than bleomycin.

Bleomycin↗
PubMedDate not supplied

Bleomycin differentially inhibits picornavirus, herpesvirus and poxvirus replication in a human carcinoma cell line.

MS-757, a cervix carcinoma cell line, was exposed to bleomycin at concentrations up to 200 microM for periods of 1 to 24 hours. Bleomycin treatment caused the level of DNA synthesis in uninfected cells to drop to 13% of the level achieved in the controls. Protein synthesis fell to 50%, but RNA synthesis was not affected. Exposure of uninfected cells to 200 microM bleomycin for 24 h did not induce significant cell death measured as permeability to Trypan Blue). A tetrazolium dye-reduction assay, however, showed that cell viability measured as mitochondrial activity was reduced by 50%. In contrast, the clonogenicity of the treated cells (measured as colony-forming ability) fell to less than 1% of the level in untreated controls. Bleomycin effected a highly selective inhibition of virus replication measured as production of infectious progeny virus. The replication of the RNA virus, coxsackievirus B5, was largely unaffected by bleomycin, whereas the replication of the DNA virus, herpes simplex virus type 2, was inhibited to the same extent as cellular DNA synthesis. In contrast, bleomycin caused a 2 to 3 log10-fold suppression of the production of progeny virus after infection with the DNA virus, vaccinia virus. When an early gene product (expressed prior to virus DNA replication) of vaccinia virus was assayed, little inhibitory effect of bleomycin could be demonstrated, indicating that the early transcription and translation of vaccinia virus was only modestly influenced by bleomycin. The results argue against a DNA-based replication as the bleomycin-susceptible function independent of genome, replication enzymes, and site of synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiviral Agents↗
PubMed1994

Partial reversal of established bleomycin-induced pulmonary fibrosis by rh-urokinase in a rat model.

Pulmonary fibrosis was induced in male Sprague-Dawley rats by intratracheal instillation of bleomycin. By 30 d post-bleomycin, the lungs exhibited elevated interstitial collagen levels. Thirty d after exposure to bleomycin, animals were further treated by intratracheal administration of phosphate-buffered saline (PBS) or 12,500 units of recombinant human urokinase (rh-UK). Three days later, the animals were sacrificed and the lungs fixed, sectioned, and assessed for fibrosis. The presence of interstitial collagen was quantitated using a BioQuant Image Analysis System (R and M Biometrics, Inc., Nashville, TN). Urokinase treatment of animals with established pulmonary fibrosis induced by exposure to 0.5 units of bleomycin was found to diminish the collagen content of lungs to near control levels by 3 d post-UK treatment. By 36 d post-UK treatment (66 d post-bleomycin), values for interstitial collagen were again partially elevated, indicating that UK treatment interfered with established fibrosis but did not stop the bleomycin-mediated process. However, the extent of fibrosis was less than that observed in lungs from non-UK treated animals 66 d post-bleomycin. UK treatment initiated 63 d post-bleomycin exposure again revealed a decline in the extent of fibrosis, but the values did not return to baseline levels. A repeat of the short-term experiment with a higher dose of bleomycin (0.85 units) again revealed that UK treatment was effective in diminishing the extent of fibrosis from 22% to 12% collagen. These results indicate that exogenous UK may be an effective therapeutic modality in the treatment of pulmonary fibrosis induced by some stimuli or developing in association with diseases such as scleroderma.

Animals↗
PubMed1993

Effects of bleomycin with iododeoxyuridine, 5'-amino-5'-deoxythymidine, and radiation in a human bladder cancer cell line.

In vitro bleomycin cytotoxicity in 647V, a human bladder cancer cell line, is enhanced when the cells are preincubated for one cell cycle (24 h) with clinically relevant concentrations (2 microM) of iododeoxyuridine (IdUrd). Bleomycin cytotoxicity after a 1-h exposure is further enhanced by a 24-h preincubation with 2 microM IdUrd plus 30 microM 5'-amino-5'-deoxythymidine (5'-AdThd). Chemosensitization of clinically achievable plasma levels of bleomycin (1-10 mU/ml for 1 h) by IdUrd (+/- 5'-AdThd) is associated with the level of DNA incorporation of IdUrd in 647V cells and with enhanced bleomycin-induced damage in IdUrd-substituted DNA compared to control DNA, as measured by rapid alkaline elution. We also studied the in vitro effects of bleomycin (+/- IdUrd) treatment on the subsequent radiation response of 647V cells. We found that a 1-h preirradiation exposure of 647V cells to low concentrations of bleomycin (1 mU/ml) can radiosensitize the cells with an even greater interaction exhibited by pretreatment with 2 microM IdUrd (24 h) plus bleomycin (1 h) vs control. Since the principal normal tissue toxicities of IdUrd (involving bone marrow and gut) and bleomycin (involving lung) do not overlap, these in vitro data suggest that chemosensitization of bleomycin by IdUrd may provide a new therapeutic regimen for chemotherapy and a significant enhancement for radiotherapy in human bladder cancer and possibly other epithelial cancers.

Bleomycin↗
PubMed1993

Vitamin A pretreatment and bleomycin induced rat lung injury.

Possible antioxidant effects of pretreatment with vitamin A on bleomycin-induced rat lung injury were studied. Intratracheal bleomycin was administered to rats pretreated with vitamin A (50,000 IU/day) or vehicle control. Analysis of bronchoalveolar lavage fluid (BAL) total and differential cell counts, lung weight, lung pathology, and alveolar macrophage superoxide anion production were performed before and at various time points after the instillation of bleomycin. Bleomycin with vehicle raised total BAL cell count and the per cent of BAL neutrophils at day 7 post injury. The percent of lung involved with pneumonitis, the lung wet weight/body weight ratio and the alveolar macrophage superoxide anion production were also increased after bleomycin alone compared to the group pretreated with vitamin A. Rats pretreated with vitamin A demonstrated a statistically significant reduction in total BAL cell count and in alveolar macrophage superoxide anion production 7 days after bleomycin compared with vehicle control. Lung wet weight/body weight ratio 7 days after bleomycin was reduced in the vitamin A treated rats. There was a trend to less pneumonitis in the vitamin A pretreated group. These data suggest that vitamin A attenuates bleomycin induced pulmonary damage by a mechanism which involves inhibition of bleomycin-induced alveolar macrophage superoxide anion production.

Animals↗
PubMed1997

[Acrosyndromes induced by bleomycin in HIV 1 related Kaposi's disease. 5 cases].

OBJECTIVES: Raynaud's syndromes may be observed in HIV-infected patients, particularly those with Kaposi disease treated with bleomycin. This complication occurs in 10% of patients given bleomycin although only 7 cases have been reported in the literature. The aim of this study was to determine the frequency of certain biological abnormalities observed in HIV patients with Kaposi disease given bleomycin and who develop Raynaud's syndromes. PATIENTS AND METHODS: A survey was conducted from 1989 to 1995 among 1074 patients infected with HIV-1. There were 121 patients with Kaposi disease and 73 of these were treated with bleomycin. The clinical features and laboratory results (cryoglobulinemia, free protein-S, protein-C, anticardiolipin antibodies, von Wille-brand factor (vWF.ag) endothelin-1) were obtained in 5 patients who developed biomycin-induced Raynaud's syndrome. RESULTS: Amont the 73 patients with Kaposi disease treated with bleomycin (total mean dose = 227 mg (120-380 mg)), 5 patients (12.6%) developed a severe Raynaud's synchrome including two who suffered digital necrosis Withdrawal of bleomycin led to improved symptomatology (n = 2) or an aggravation (n = 1) in the 3 patients followed. CONCLUSION: Raynaud's syndromes are frequent (12.6%) in HIV patients with Kaposi disease treated with bleomycin. The vascular toxicity of bleomycin, demonstrated in animals, would appear to be the causal factor among others. Release of endothelial factors (vWF.ag endothelin-1) and perturbed hemostasis related to the HIV infection (protein-S deficiency, anti-cardiolipin antibodies) could be an expression of and aggravate the vascular toxicity of bleomycin.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Cloning and expression analysis of human bleomycin hydrolase, a cysteine proteinase involved in chemotherapy resistance.

A cDNA encoding human bleomycin hydrolase, a member of the cysteine proteinase family of proteins, has been cloned from a human brain cDNA library. The isolated cDNA contains an open reading frame coding for a polypeptide of 456 amino acids that contains all of the structural features characteristic of cysteine proteinases, including the cysteine, histidine, and asparagine residues that are essential for the catalytic properties of these enzymes. The deduced amino acid sequence for human bleomycin hydrolase shows 92, 40, and about 35% of identities with those determined for rabbit bleomycin hydrolase, yeast bleomycin hydrolase, and bacterial aminopeptidase C, respectively. Northern blot analysis of poly(A)+ RNAs isolated from a variety of human tissues demonstrated that human bleomycin hydrolase is expressed in all examined tissues, which is consistent with a putative role of this protein as a proteolytic enzyme involved in norman cellular protein degradation and turnover. Preliminary expression analysis of bleomycin hydrolase in different human tumors showed increased expression of the enzyme in a series of head and neck carcinomas when compared with paired adjacent normal mucosa. We also observed a variable degree of bleomycin hydrolase expression in different types of lymphoma, with low or undetectable levels in Hodgkin's disease samples and higher levels in Burkitt's lymphomas. These results are consistent with a proposed role for human bleomycin hydrolase in resistance of some tumor to bleomycin chemotherapy.

Amino Acid Sequence↗
PubMed1998

Induction of tumor necrosis factor-alpha as a cause of bleomycin-related toxicity.

BACKGROUND: The application of bleomycin is characterized by acute side effects, such as fever, chills, and sometimes hypotension and tachypnea. Furthermore, bleomycin is known to induce pneumonitis. There are several indications that the induction of cytokines by bleomycin is involved in the development of these side effects. METHODS: In this study, the authors determined the plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and transforming growth factor-beta (TGF-beta) before and after bleomycin infusion in 14 patients treated for disseminated nonseminomatous germ cell tumor. RESULTS: Compared with the pretreatment value, TNF-alpha was significantly increased 3, 4.5, and 24 hours after bleomycin infusion. For IL-1beta and TGF-beta, no significant alterations were observed within 24 hours after administration of bleomycin. CONCLUSIONS: The increase in TNF-alpha after administration of bleomycin suggests a role for this cytokine in the development of the acute side effects and probably also in the occurrence of bleomycin-induced pulmonary toxicity. The involvement of IL-1beta and TGF-beta deserve further study.

Adolescent↗