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PubMed1982

Demonstration that the temporary sequestering of adventitious iron accounts for the inhibition of microsomal lipid peroxidation by bleomycin A2.

One of the manifestations of the interaction of bleomycin with the microsomal mixed-function oxidase system is an inhibition of NADPH-dependent, reactive oxygen-mediated lipid peroxidation. The results of this investigation demonstrate that this effect by bleomycin can be attributed to the sequestering of adventitious iron. However, as a result of the microsome-catalyzed, iron-facilitated activation of bleomycin and the concomitant spontaneous decay of the activated bleomycin intermediate, iron can apparently no longer be bound by the bleomycin molecule; consequently, the inhibition of microsomal lipid peroxidation by bleomycin is only temporary.

Animals↗
PubMed1982

The effect of alpha-difluoromethylornithine on the development of bleomycin-induced pulmonary fibrosis in hamsters.

The development of bleomycin-induced lung fibrosis was studied in hamsters drinking tap water or 2% alpha-difluoromethylornithine (DFMO) dissolved in tap water for 14 days. The fibrotic lesions in the lung were evaluated by biochemical measurements of total neutral salt soluble (NSS) and insoluble (NSI) collagens and by morphometric histopathologic techniques. Daily ingestion of DFMO failed to offer any protection against bleomycin-induced lung fibrosis; instead, it increased the deposition of total lung NSI collagen to 396% of control, as compared with 145% of control caused by bleomycin treatment alone. Daily intake of DFMO by itself increased the accumulation of total lung NSI collagen to 250% of control, as opposed to a 145% increase caused by bleomycin treatment alone. Histopathologically, the lung lesions in hamsters treated with bleomycin and DFMO were qualitatively similar to those of hamsters treated with bleomycin alone. However, morphometric estimates revealed that of lung lesions were more diffuse and severe in the former than in the latter group.

Animals↗
PubMed1982

DNA interaction with 57Co-bleomycin.

Tumor-diagnostic 57Co-bleomycin is a mixture of two isomers: types I and II. Interaction between these and DNA was studied by fluorescence spectrometry and thermal denaturation. The fluorescence study indicated that cobalt chelation resulted in a remarkable increase in the apparent DNA-bleomycin association constant and a slight increase in bleomycin-DNA binding; a remarkable difference was observed between the two isomers. In the thermal denaturation study, the difference of DNA binding behavior was also observed. The tumor affinity of these isomers was slightly different, and type I isomer showed higher tumor affinity than type II. These results indicate that cobalt chelation to bleomycin enhances DNA-bleomycin binding and its DNA binding stability, and these mechanisms, although not fully understood, appear to underly the difference in tumor affinity of cobalt-bleomycin isomers.

Animals↗
PubMed1982

[Tissue levels of bleomycin administered as suppository].

We prepared a bleomycin suppository, aiming not only at allowing bleomycin to be transferred into the malignant tumor tissue of the intrapelvic organs and their regional lymph nodes at high levels but also at preventing transient elevation of its level in the blood. This administration route might be effective on the primary lesions of urogenital malignant tumors and their metastases to the regional lymph nodes, and prevent systemic adverse reactions. To prove these effects, we determined the levels of bleomycin in the tissue, blood, lymph nodes, urine and stools following intrarectal application of the bleomycin suppository. The pattern of bleomycin uptake by the intrapelvic tissues showed that the drug was retained by tumor tissue at high levels for a long time, compared with that by the normal tissue. Its levels in the blood suggested the reduction in systemic adverse reactions. Its uptake by the regional lymph nodes was unexpectedly low, but this may be attributed to an early collection of the tissue after the application. We think it necessary to follow up changes in bleomycin level in the tissues collected at predetermined intervals.

Adult↗
PubMed1983

Hyperthermic modification of bleomycin--DNA interaction detected by electron spin resonance.

Electron spin resonance spectra of DNA labeled with each of four spin-labeling compounds have been studied to detect interaction between the antibiotic bleomycin and DNA. Only one of these labels, compound IV, resulted in a modified spectrum when bound to DNA and the latter was subjected to bleomycin. This property has been used to monitor DNA-bleomycin interactions under physiological and hyperthermic conditions. Bleomycin produced an increase in rotational correlation time of the residue bound to DNA at 37 degrees C and a significantly higher increase at 43 degrees C. Some effect was still detected with bleomycin at 37 degrees C after preheating at 43 degrees C. Parallel studies have revealed enhanced binding of 59Fe-bleomycin to DNA during and after hyperthermic treatment.

Bleomycin↗
PubMed1984

Kinetics and extent of repair of bleomycin-induced chromosome damage in quiescent normal human fibroblasts and human mononuclear blood cells.

The kinetics of chromosome damage repair after bleomycin treatment was studied in quiescent mononuclear human blood cells and human fibroblasts using the technique of premature chromosome condensation. Quiescent cells were treated with bleomycin for 30 min, washed free of drug, and fused with mitotic HeLa cells after various repair times. The amount of chromosome damage remaining was assayed in the G1 prematurely condensed chromosomes. The chromosome repair kinetics profile exhibited fast- and slow-repair components. The fast chromosome repair component was apparent within 2 hr after bleomycin treatment, with a significant amount of repair having occurred within 30 min. The absolute rate of chromosome repair then significantly slowed beyond 2 hr after treatment. The rate of chromosome repair was slightly dependent on dose with a higher rate observed at a higher dose. Interestingly, while quiescent fibroblasts were more sensitive to bleomycin than were mononuclear blood cells, both cell populations exhibited similar repair kinetics. These results suggest the following: (a) quiescent human fibroblasts and mononuclear blood cells show similar chromosome repair kinetics after bleomycin treatment; (b) there exist both fast- and slow-repair components after bleomycin treatment; and (c) the rate of chromosome repair is dependent on the degree of initial damage.

Bleomycin↗
PubMed1984

Proliferative kinetics and chromosome damage in trisomy 21 lymphocyte cultures exposed to gamma-rays and bleomycin.

Lymphocytes from patients with Down's syndrome (trisomy 21) have been investigated for cell cycle kinetics, cell proliferation delays, and chromosomal aberrations after exposure to gamma-rays or bleomycin. Analysis by sister chromatid differential staining revealed that trisomy 21 lymphocytes started cell cycling about 5 hr earlier than did normal diploid lymphocytes after phytohemagglutinin stimulation as a whole, but that cycling trisomic and normal cells had the same mean cell cycle times. When exposed to gamma-rays or bleomycin in G0, trisomy 21 lymphocytes showed a 30% or, on average, 50% longer duration of cell turnover times, respectively, than normal cells; only bleomycin-treated trisomic cells had a biphasic dose-response. Frequencies of dicentrics and rings in first-division cells after gamma-ray or bleomycin exposure were twice as high in trisomic cells as in normal cells. The frequency of aberrations decreased by 50% (gamma-ray-exposed) or 65 to 85% (bleomycin-treated) through successive divisions; trisomic cells showed a more marked decline in aberration yields compared to normal cells after bleomycin treatment. These data support the idea that circulating lymphocytes in trisomy 21 patients have a shorter average life span or a younger average age.

Bleomycin↗
PubMed1983

Interactions of ascorbic acid supplementation and bleomycin instillation on murine lung connective tissue metabolism.

The effects of ascorbic acid supplementation on the pulmonary toxicity induced by bleomycin were examined. Swiss-Webster mice were fed an ascorbate-free diet supplemented with ascorbic acid at 0%, 0.2%, or 1.0% of the diet for 2 weeks. Bleomycin (0.15 units) was instilled intratracheally and the mice were killed 1 week later. Bleomycin caused pulmonary inflammation and edema as noted by the increases in lung wet weight and lung wet-weight-to-dry-weight ratios. The activity of prolyl hydroxylase was increased 1.4-fold to 1.6-fold in response to bleomycin, but only minor increases were observed in the collagen and elastin content of the lung. Prior dietary ascorbic acid supplementation did not reverse the effects induced by bleomycin. Interestingly, each dietary level of supplemental ascorbic acid resulted in a slight increase in the elastin and collagen content of the lung in comparison with lungs from mice consuming no ascorbic acid in their diet. The data suggest that high levels of ascorbic acid supplementation may aggravate the response to bleomycin.

Animals↗
PubMed1984

[Results of combined therapy of irradiation and bleomycin suppository for advanced uterine cervical cancer].

Efficacy, survival rats and adverse effects of the combined therapy of irradiation with intravaginal bleomycin suppositories were analyzed and discussed in 49 patients with uterine cervical cancer. The results were as follows: Histological examination of biopsy specimens from the uterine cervix taken just after the completion of this treatment showed favorable control over the primary lesions. However, the efficacy of the bleomycin suppositories was too mild to form a basis for treatment without intracavitary irradiation. Because of the low concentration of bleomycin in serum after suppository administration, it is thought that bleomycin would have little effect on distant metastases. Survival rates in stage III patients were 83% at 12 months, 77% at 24 months and 70% at 36 months. These were superior to those for irradiation alone. The major adverse effect of bleomycin suppositories was fever, reduction of the bleomycin dose in each suppository but controlled this to some extent Lung fibrosis or severe damage to the liver, kidney and bone marrow were not found.

Adult↗
PubMedDate not supplied

Clinical use of combined bleomycin and radiation therapy for head and neck tumours and testicular cancers.

The Bleomycin advantages are resumed with special reference to the use in combination with irradiation. More vigorous effect were seen in patients given Bleomycin one hour before irradiation twice to three times weekly than after irradiation alone. For head and neck tumours the effect of two weeks Bleomycin treatment alone showed 40 per cent distinct shrinkage and in this group 73 per cent of the patients were tumour-free after a full course of radiotherapy, compared to 38 per cent in the group showing no response to Bleomycin-pretreatment. Moderately differentiated squamous cancer showed just as good response as highly differentiated tumours. The one year survival using subsequent treatment of Bleomycin and irradiation, compared to an historical material showed improved survival rate for T3 laryngeal cancers, as well as all stages of testicular carcinomas given simultaneous Bleomycin twice weekly under the full course of postoperative irradiation to regional lymph nodes.

Bleomycin↗
PubMed1976

Growth parameters of the hairless mouse epidermis after bleomycin treatment: possible interaction with epidermal chalones.

Hairless mice were given two injections of 2 mg bleomycin i.p. on two successive days. By a stathmokinetic method, micro-flow fluorometry and autoradiography, many kinetic parameters were measured. Bleomycin affected cell proliferation in epidermis by depressing the number of cells in and the passage of cells through the different cell cycle phases, i.e. S, G2 and M in a biphasic manner. The time between the two minima corresponded to the mean generation time of the basal cells. Skin extracts produced from animals at different time intervals after the bleomycin injection show that bleomycin interferred only slightly with the G1-chalone, but had a more pronounced effect on the content of G2 of the skin, increasing and reducing the chalone effect in a biphasic manner. The study gives some support to the theory that the particularly good effect of bleomycin in squamous cell epithelium may be due to an interference of bleomycin with keratinization and chalone production. The protein synthesis showed only a minimal depression where the kinetic parameters were heavily depressed.

Animals↗
PubMed1993

Nuclear localization of bacterial Streptoalloteichus hindustanus bleomycin resistance protein in mammalian cells.

Prokaryotes produce a variety of toxins that affect genomic function of both eukaryotes and prokaryotes. The 375-base pair bacterial gene Streptoalloteichus hindustanus (Sh) ble encodes a small protein, Streptoalloteichus hindustanus bleomycin resistance protein (BRP), that inhibits in vitro DNA cleavage by the prokaryotic glycopeptide bleomycin, which is a clinically used anticancer drug. NIH/3T3 cells infected with a retroviral vector containing Sh ble (SH-9 cells) were highly resistant to the cytotoxicity of bleomycin-like drugs but not to the cytotoxicity of other, structurally unrelated, DNA-cleaving agents. Expression of BRP did not markedly alter total cellular content or distribution of bleomycin-like compounds. Fluorescently labeled bleomycin was primarily localized in cytoplasmic vesicles in NIH/3T3 and SH-9 cells, whereas BRP, which has no established nuclear localization sequence, was segregated to the nucleus and more specifically to euchromatin. This karyophilic BRP may intercept bleomycin in the nucleus.

3T3 Cells↗
PubMed1994

Pulmonary platelet trapping induced by bleomycin: correlation with fibrosis and involvement of the beta 2 integrins.

Platelet trapping was explored during the course of bleomycin induced pulmonary fibrosis by the injection of indium-111 labelled platelets and by light and electron microscopy (EM) of the alveolar capillaries. An i.v. injection of bleomycin markedly increased the localization of labelled platelets in the lung (but not in other organs) for about 3 weeks. On day 7 after bleomycin injection, a significant increase in the number of platelets in contact with the alveolar endothelium was seen with EM. Platelet trapping was strongly correlated (P < 0.005) with collagen deposition when examined in mouse strains genetically susceptible (CBA, C57BL/10, BL10 A.2R), or resistant (Balb/c, BL10.D2, BL10.A), to bleomycin induced fibrosis. In addition, several treatments known to decrease bleomycin induced collagen deposition and synthesis, namely administration of antibodies against CD11a, CD11b, TNF-alpha and IL-1ra, also decreased platelet trapping. As evaluated by EM, anti CD11a mAb significantly decreased the number of platelets in contact with the alveolar endothelium. This study indicates that bleomycin induced pulmonary fibrosis is strongly correlated with platelet trapping and that platelets probably interact, via their CD11a, with the CD54 born by the alveolar endothelium.

Animals↗
PubMed1978

Subcellular localization of 57Co-bleomycin in normal and tumor tissues.

57Co-bleomycin appears to be one of the best tumor detecting agents at the moment. The localization within the cells is not yet known. This preclinical investigation had the aim to study the subcellular distribution of 57Co-bleomycin in liver, spleen and tumors of rats and mice. Mice with transplanted lymphosarcoma and osteosarcoma were used and rats with transplanted rhabdomyosarcoma. The concentration of 57Co-bleomycin was 2 to 10 times higher in the tumors as compared to the (normal) liver. This accumulation property was not found with the control substance: 57CoCl2. The highest radioactivity of 57Co-bleomycin (cpm/mg protein) was observed in subcellular fractions containing mitocohndria and lysosomes. After treatment of these fractions with hypertonic solutions it could be shown that enzymes of the mitochondrial matrix remained inside the vesicles under conditions of almost complete release of 57Co-bleomycin. Half of the lysosomal enzyme acid phosphatase was released too. From these experiments it is concluded that 57Co-bleomycin is preferentially localized in heavy secondary lysomes which are more fragile than the lighter lysosomes in the cells.

Animals↗
PubMed1993

Phase I clinical and pharmacological study of iododeoxyuridine and bleomycin in patients with advanced cancer.

Studies previously performed in our laboratory demonstrated synergistic cytotoxicity and DNA strand break formation in human tumor cells following exposure to a combination of bromodeoxyuridine and bleomycin. Synergy was evident when bromodeoxyuridine was administered prior to or simultaneously with bleomycin and occurred over a wide range of concentration ratios. We therefore undertook a phase I clinical trial of the combination of iododeoxyuridine (IdUrd) and bleomycin to determine the maximally tolerated dose of IdUrd that could be administered with a standard dose of bleomycin and to determine the toxicities of the combination. Eligible patients were those with advanced cancer refractory to standard therapy who had a performance status of 0-2, measurable or evaluable disease, and adequate organ function. IdUrd was administered as a 5-day continuous i.v. infusion beginning at a dose of 250 mg/m2/day with escalation in cohorts of 3-6 patients according to a modified Fibonacci scheme. Bleomycin was administered at a dose of 15 mg/m2/day as a continuous i.v. infusion during the last 3 days of the IdUrd infusion. Cycles of therapy were repeated every 28 days. Plasma levels of IdUrd and iodouracil were determined by high performance liquid chromatography. Thirty patients received a total of 79 cycles of IdUrd/bleomycin. Dose-limiting toxicity was bone marrow suppression. At the maximally tolerated IdUrd dose of 2780 mg/m2/day, the median neutrophil nadir after the first cycle of therapy was 805/microliters and the median platelet nadir was 48,000/microliters. Other toxic effects included mucositis, fatigue, nausea, diarrhea, fever, and skin toxicity. Plasma steady-state concentrations of IdUrd increased proportionally to administered IdUrd dose. IdUrd clearance varied from 0.253 liters/min/m2 to 0.503 liters/min/m2 and did not correlate with IdUrd dose. IdUrd dose and concentration correlated significantly with granulocyte and platelet nadirs, and a pharmacodynamic model for white blood cell count nadir could be defined by pretreatment white blood cell count, IdUrd dose, and gender. The recommended IdUrd dose for phase II testing of this combination is 2140 mg/m2/day. Phase II studies will be of particular interest in those diseases, such as carcinomas of the head, neck, and esophagus, where bleomycin has documented activity as a single agent.

Adult↗
PubMed1993

Small chest-tube drainage followed by bleomycin sclerosis for malignant pleural effusions.

OBJECTIVE: To review our experience with bleomycin sclerotherapy as treatment of pleural effusions due to gynecologic malignancies. METHODS: Twenty-one women with histologically documented malignant effusions (16 ovarian carcinoma, three uterine sarcoma, and two cervical cancer) were treated with small flexible chest-tube drainage followed by intrapleural bleomycin sclerotherapy (60 units). RESULTS: After placement of the chest tube, suction was required for a median of 5 days (range 3-12) before output was low enough (less than 100 mL/24 hours) to instill bleomycin. Among 24 treated effusions, there was a 71% overall response rate, including ten complete responses (42%) and seven partial responses (29%); seven effusions (29%) did not respond to therapy. Six of the seven patients whose effusions did not respond to bleomycin died of disease within 2 months of attempted sclerotherapy. Fever was the most common side effect, occurring in 13 of 21 patients (62%) following instillation of bleomycin. Pain during sclerosis was reported by only two patients. CONCLUSIONS: Bleomycin sclerotherapy after small flexible chest-tube drainage of malignant pleural effusions is an effective technique, with minimal adverse reactions, for controlling effusions that develop in women with gynecologic malignancies.

Bleomycin↗
PubMedDate not supplied

Disposition of the pulmonary toxin, bleomycin.

The disposition of bleomycin in rats was investigated with the use of a 57Co-labeled bleomycin radioimmunoassay. Bleomycin (1 mg/kg, ip) reached a peak serum level of 0.7-1.0 microgram/ml in 54 +/- 4 min (mean +/- SE) and was eliminated with a t 1/2 of 32 +/- 1 min. The apparent volume of distribution in rats was 184 +/- 11 ml/kg. No change in t 1/2 was observed when rats were pretreated with phenobarbital (1 mg/ml in drinking water for 4 days) or exposed to ozone (3 ppm, 24 hr). Probenecid (0.2 g/kg, ip) given 20 min prior to bleomycin administration increased the t 1/2 2-fold. The order of tissue distribution of 57Co-labeled bleomycin 2 hr after ip administration was: kidney greater than liver greater than lungs greater than spleen greater than heart greater than thymus. The affinity of 57Co-labeled bleomycin for homogenates of lungs, liver, or kidney was equal.

Animals↗
PubMed1996

Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality.

Keratinocyte growth factor (KGF) is a growth factor for type II pneumocytes. Type II pneumocyte hyperplasia, a common reaction to lung injury, has been postulated to play an important role in lung repair. The potential protective effect of KGF was therefore studied in rat models of radiation- and bleomycin-induced lung injury. Intratracheal instillation of KGF (5 mg/kg) 72 and 48 hours before 18 Gy of bilateral thoracic irradiation did not significantly improve survival, although histology showed less pneumonitis and fibrosis in KGF-pretreated as compared with control-irradiated rats. Intratracheal pretreatment with KGF in rats receiving intratracheal bleomycin (2.5 U) improved survival at 3 weeks to 100% (20/20 rats) from 40% (8/20 rats) in controls. All KGF-pretreated rats receiving bleomycin were well at 3 weeks and without histological evidence of pulmonary fibrosis whereas the 8 surviving control rats exhibited severe respiratory distress. Finally, in the most lethal challenge to the lung, rats pretreated with intratracheal KGF or saline were challenged with a combination of bleomycin (1.5 U) and bilateral thoracic irradiation (18 Gy). KGF-pretreated rats did not begin to die or show signs of respiratory distress until 7 weeks, whereas all saline-pretreated control rats receiving radiation and bleomycin died within approximately 4 weeks with severe respiratory distress and weight loss. In conclusion, radiation- and bleomycin-induced pulmonary injury and respiratory death are ameliorated by KGF pretreatment, suggesting a protective role for KGF-induced type II pneumocyte proliferation in lung injury.

Animals↗