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PubMed1977

[Bleomycin lung (author's transl)].

Histological and electron-microscopic study of the lungs of 15 patients who had been treated with bleomycin for advanced squamous cell carcinoma demonstrated marked histological changes in nine. They were typical of bleomycin effects: alveolitis, intra-alveolar and interstitial oedema, pulmonary hyaline membranes, disseminated intravascular coagulation, intraalveolar and interstitial fibrosis, atelectasis, metaplasia and dysplasia of the alveolar lining cells. These lesions had a focal distribution, preferentially in the subpleural and periseptal regions. Each of these lesions alone is a non-characteristic reaction, but their combination makes it a distinct entity (bleomycin lung). Three different clinical courses were noted: (1) cases with no or little abnormality; (2) acute form during or shortly after bleomycin treatment; (3) chronic, progressive form of bleomycin lung which may end fatally as late as 1 1/2 years after bleomycin treatment had been discontinued. Squamous cell metaplasia is the most characteristic sign of bleomycin lung. It should not be confused with pulmonary metastases. To prove the diagnosis of bleomycin lung often requires systematic histological investigation. A schema of the pathogenesis of the bleomycin lung is proposed in which the formation of microthrombi plays an important part.

Aged↗
PubMed1977

Effect of camptothecin and adriamycin on bleomycin-induced tritiated thymidine triphosphate incorporation in a rat nuclear system.

We investigated the effect of camptothecin and adriamycin on [3H]TTP incorporation and bleomycin-stimulated [3H]TTP incorporation in host liver and hepatoma nuclei of rats. Camptothecin neither stimulated nor inhibited incorporation in the regular nuclear incorporating system. Bleomycin stimulated incorporation to a much greater extent in host liver nuclei and slow-growing hepatomas than it did in the fast-growing hepatoma 7777. Addition of camptothecin to bleomycin stimulated incorporation of [3H]TTP even further. This camptothecin stimulation was slightly greater in hepatoma nuclei than it was in host liver nuclei. Adriamycin inhibited [3H]TTP incorporation in the regular system as well as the bleomycin-induced incorporation. Hepatoma nuclei were more sensitive to this inhibition than were host liver nuclei. Sucrose density gradients indicated that camptothecin caused DNA strand scissions in addition to those produced by bleomycin. Camptothecin alone produced some single-strand but no double-strand scissions. The action of bleomycin was dependent on sulfhydryl-reducing agents. Camptothecin could partially substitute for this requirement. Adriamycin did not produce DNA breaks as determined by neutral or alkaline sucrose density gradients. Despite complete inhibition of bleomycin-induced [3H]TTP incorporation, adriamycin did not prevent bleomycin-induced DNA breaks. The inhibitory effect of adriamycin might have been on the repair system.

Animals↗
PubMed1979

The effect of bleomycin on prolyl hydroxylase and DNA chain breakage: structure-activity relationship.

The activity of purified prolyl hydroxylase (proline, 2-oxoglutarate dioxygenase, EC 1.14.11.2) was enhanced about 3-fold by addition of bleomycin in the assay mixture. Various members of the bleomycin family, their derivatives and degradation products were investigated for activities against prolyl hydroxylase together with their activities of DNA chain breakage to determine relationships between the structure of bleomycin and its various actions. All the bleomycins with various terminal amine parts and desamide bleomycin stimulated the enzymatic activity but did not exhibit an effect on DNA chain breakage. The stimulatory activity of bleomycin was not decreased by hydrolysis with 0.3 N H2SO4 at 80 degrees C for 6 hours, conditions which liberates the sugar moiety, but was eliminated by hydrolysis with 6 N HCl at 105 degrees C for 24 hours. In contrast both treatments decreased the DNA chain breakage activity of bleomycin. Optical spectral studies revealed that all the bleomycins and their hydrolysates which stimulated the prolyl hydroxylase activity made complexes with ferrous ion, one of the cofactors of this enyzme.

Bleomycin↗
PubMed1975

Biochemical effects of bleomycin A2 on Novikoff hepatoma ascites cells.

Purified nucleolar DNA was markedly degraded at a concentration of 13 mug/ml by bleomycin A2; bleomycin concentrations 20-30 times greater were required to degrade nucleoplasmic DNA. Whole nuclear DNA was degraded to only a small extent at 13 mug/ml but was markedly degraded at higher bleomycin concentrations. Treatment of the various types of DNA with high concentrations of bleomycin A2 produced low molecular weight (approximately 6S) fragments that were no longer sensitive to degradation by bleomycin A2. Hybridization studies demonstrated a loss of ribosomal DNA sequences from nucleolar DNA treated with bleomycin A2 in vitro. Studies on RNA synthesis in Novikoff hepatoma ascites cells in vitro showed there was a decreased uptake of 32Pi into high molecular weight nuclear RNA in the presence of bleomycin A2. These results indicate that nucleolar function is inhibited by a direct effect of bleomycin A2 on nucleolar DNA.

Ascitic Fluid↗
PubMed1975

Chemical and biologic properties of isolated radiolabeled bleomycin preparations.

Cobalt-57-bleomycin is a diagnostically useful radiopharmaceutical, but little is known about the nature of its individual fractions in regard to their metal-binding capacity and their in vivo distribution. Bleomycin was separated by high performance liquid chromatography (HPLC) into four major components. These were labeled and the distribution studied in tumor-bearing rats at 2 and 24 hr. In vivo radiochemical purity was also determined. Of the nine HPLC systems studied, Porasil A eluted with a mobile phase of 0.3% ammonium formate in methanol gave the best separation of the fractions. These fractions were copper free and retained their biologic activity and purity. An in vitro competitive binding study of 57Co-bleomycin with either 57Co-human serum albumin (HSA) or 57Co-ethylenediaminetetraacetic acid (EDTA) showed the labeled bleomycin to be a strong chelate. The biologic distribution in tumor-bearing rats showed significantly higher concentration in tumors at 2 hr for fractions A2 and B2 as compared to the bleomycin mixture. The other fractions, A1 and demethylA2, gave lower tumor concentrations than the bleomycin mixture. The tumor-to-blood ratios for A2 and B2 were not significantly different from the bleomycin mixture, suggesting that the concentration of the bleomycin in the tumor was related to blood concentration. Tumor-to-blood ratios of greater than 10:1 at 2 hr were achieved for A2, B2, and the mixture; ratios of greater than 31:1 were achieved at 24 hr for all three. From these data it appears that the major components A2 and B2 are the most useful for diagnostic tumor imaging.

Animals↗
PubMed1975

Tumor imaging after administration of 99mTc-labeled bleomycin.

Bleomycin, an anticancer drug, was labeled with 99mTc using stannous chloride and ascorbic acid and specific activities of 1-3 mCi/mg-eq with labeling efficiencies of 50-75% were achieved. Very rapid excretion of 99mTc-bleomycin through the kidney and concomitant rapid decrease of radioactivity in blood, various tissues and organs, and whole body were observed after intravenous administration of the radiopharmaceutical into tumor-bearing mice. In such animals, approximately 1% of the label was found in a transplanted fibrosarcoma within 30 min while 0.58% was recovered in such lesions even after 24 hr. In patients positive tumor images were obtained by scintigraphy as early as 1 hr after intravenous administration of 3-5 mCi of 99mTc-bleomycin. A total of 142 cases were examined by scintigraphy after administration of 99mIc-bleomycin and/or 67Ga-citrate. In 93 cases with various malignant tumors, tumor was detected in 80% using 99mTc-bleomycin and in 63% using 67Ga-citrate. Technetium-99m-bleomycin scintigraphy successfully detected tumors of the thyroid, lung, face, breast, extremity, and digestive tract and was also useful in finding metastatic lesions and brain tumors. However, 67Ga scintigraphy gave superior results in detecting lesions in patients with malignant lymphomas. In patients with inflammatory diseases, accumulation in lesions was detected in 13% using 99mTc-bleomycin and in 48% using 67Ga-citrate. The further use of 99mTc-bleomycin scintigraphy for tumor detection in patients appears to be warranted.

Abdominal Neoplasms↗
PubMed1976

Effect of bleomycin on deoxynucleotide-polymerizing enzymes from human cells.

DNA polymerases alpha and beta from Molt-4 cells are inhibited by bleomycin, whereas DNA polymerase gamma assayed with poly-(A)-(dT)12-18 as the template primer or terminal deoxynucleotidyl transferase assayed with activated DNA, poly(dA), (dG)12-18 or (dA)12-18 as the initiator are not inhibited by this antibiotic. Inhibition by bleomycin increased the Km for template DNA but not that for dTTP. Increasing amounts of bleomycin did not affect the Vmax for DNA polymerase alpha or beta when the amount of template DNA was varied but it reduced the Vmax for these enzymes when dTTP was varied. Moreover, the addition of extra template reversed the bleomycin inhibition but the addition of extra enzyme did not. Although dithiothreitol was required for bleomycin inhibition of DNA polymerase activity, bleomycin preincubated with dithiothreitol (or beta-mercaptoethanol) at pH 6.5 to 9.0 lost its inhibitory activity. This was not the case when DNA was also included in the preincubation mixture. The results obtained in this study indicate that bleomycin inhibits DNA polymerases alpha and beta by a thiol reagent-dependent interaction with the template. Thus, the antitumor activity of bleomycin may be greatly influenced by the concentration of sulfhydryl compounds and their proximity to DNA in the target cells.

Bleomycin↗
PubMed1979

Role of single-breath carbon monoxide-diffusing capacity in monitoring the pulmonary effects of bleomycin in germ cell tumor patients.

Serial pulmonary function tests including single-breath carbon monoxide-diffusing capacity (DLCO), forced vital capacity (FVC), and forced expiratory volume in 1 sec were performed in a relatively homogeneous group of male patients with germ cell tumors treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum. Of the pulmonary function tests used, the DLCO was shown to be the most sensitive indicator of subclinical bleomycin pulmonary effects. Decreases in DLCO were both total dose and schedule dependent. Patients receiving their total dose of bleomycin at a rate of 25 +/- 2 (S.D.) units/week developed a linear decrease in DLCO with increasing total doses of bleomycin. Changes in FVC did not correlate with bleomycin total dose. Although both the mean DLCO and FVC decreased after completion of bleomycin therapy, the mean FVC returned to base-line levels rapidly, whereas the decrease in mean DLCO was persistent for several months. When routine volumetric tests (FVC and forced expiratory volume in 1 sec) and DLCO are used in a systematic manner, DLCO is the most sensitive indicator of the subclinical pulmonary effects of bleomycin in germ cell tumor patients treated with vinblastine, bleomycin, and cis-diamminedichloroplatinum.

Adult↗
PubMed1977

Clinical pharmacology of bleomycin following intravenous infusion as determined by radioimmunoassay.

The clinical pharmacology of bleomycin administered by continuous intravenous infusion over a 4 to 5 day period was examined by nine patients. Patients receiving 30 units per day attained an average steady state plasma level of 145.8 (+/- 43.1) ng/ml bleomycin. Elimination of bleomycin was initially described by first order rate kinetics (t 1/2 = 1.32 +/- 0.39 hour). However, at times greater than 12 hours following termination of infusion, a second elimination phase was observed (t 1/2 = 8.9 +/- 2.7 hour). There was also a high correlation between renal bleomycin clearance and creatinine clearance. The importance of renal clearance was indicated in a patient with renal impairment. This patient attained a steady state bleomycin concentration of 1046 ng/ml and exhibited a terminal elimination half-life of 33 hours. Overall plasma clearance of bleomycin (Qbeta) was generally greater than renal clearance, indicating that a nonrenal clearance mechanism was also important in bleomycin elimination. This nonrenal mechanism became especially apparent during renal failure.

Adult↗
PubMed1978

Experimental results with the combination of bleomycin plus mitomycin C.

This investigation has established the following: 1. Bleomycin, in combination with mitomycin C or other quinone-containing anticancer agents, stimulated the damage to KB cells in culture. 2. In AH66 tumor-bearing rats, the simultaneous treatments of bleomycin plus mitomycin C extend the lifespan. 3. The bleomycin-induced DNA chain breakage was enhanced by the NADPH-dependent microsomal electron transport system. The enhancement was also observed at the level of isolated nuclei and cells. Vitamin K2 and mitomycin C increased breakage at the cellular level by bleomycin and NADPH. 4. Bleomycin-Cu2+ had tendency to increase the lipid peroxidation reaction by the microsomes. However, the reaction was effectively inhibited by antioxidants. 5. Bleomycin induced aldehyde formation from DNA breakage. The formation was effectively inhibited by scavenging reactions with hydralazine hydrochloride or isoniazid. The possibility of suppressing the side effect of bleomycin was discussed in relation to TBA reactive compounds.

Antibiotics, Antineoplastic↗
PubMed1978

Biochemical and cytological studies of bleomycin actions on chromatin and chromosomes.

Interaction of bleomycin with nuclei isolated from a variety of mammalian cells resulted in the release of nucleosomes. When isolated mononucleosomes (core plus linker) were re-treated with bleomycin, no further degradation of DNA occurred. The results suggest that the bleomycin cleavage sites in chromatin are present only in the linker region and that there are probably only one or two cleavage sites per linker. The repeat lengths of nucleosomal DNA released by bleomycin from nuclei of different species are different; this variability is considered to reflect the length of the linker. Incorporation of BrdU into DNA did not alter the bleomycin action on nucleosomes. When mitotic cells were held at metaphase for a prolonged period, bleomycin caused a gradual disintegration of chromosomes, although the bleomycin cleavage sites in metaphase chromosomes were found to be the same as those in interphase nuclei.

Animals↗
PubMed1977

Effects of bleomycin on the epidermal content of growth-regulatory substances (chalones).

Hairless male mice were given 2 mg Bleomycin i.p. on two successive days. At different time intervals from 1 to 10 days after the last Bleomycin injection, groups of animals were killed and water extracts of hemogenized skin were made. These extracts, supposed to contain the epidermal G1 and G2 chalones, were injected into female hairless mice, and their growth inhibitory potency determined by two methods. 5 mg of lyophilized crude skin extract were injected i.p. together with Colcemid, and the animals killed 4 hr later. The number of Colcemid-arrested mitoses was determined, and was considered to be a measure of the G2 inhibitor present in the skin extracts. 10 mg of the same extracts were injected i.p., and these animals also got 3H-TdR i.p. 12 hr later, and were killed after a subsequent 30 min. The epidermal LI was determined, and was considered to be a measure of the epidermal G1 factor in the skin extracts. The results obtained were compared to the effect of Bleomycin alone and to the effects of skin extracts from non-Bleomycin-treated animals. The results show that Bleomycin provoked slight alterations in the growth-inhibitory potency of the G1 chalone, whereas significant effects were seen in the G2 chalone, There was an increased amount of growth-inhibiting factors on days 2 and 3, and on days 8-10. The results are discussed and it is concluded that the most probable hypothesis is that Bleomycin, in addition to its known inhibition by accumulation of cells with high growth inhibitory potency. An initial, additional direct effect of Bleomycin on the chalone system cammot be excluded.

Animals↗
PubMed1979

Bleomycin-induced interstitial pulmonary disease in the nude, athymic mouse.

Evidence from divergent sources suggests that some forms of interstitial pulmonary disease are associated with abnormalities of the cellular immune system. To evaluate whether cellular immune processes are necessary determinants for the development of parenchymal alveolitis and fibrosis secondary to bleomycin, we examined the effect of bleomycin on the NIH, outbred white mouse as compared to the homozygous nude, athymic mouse on the NIH outbred background. The nude mouse has virtually no detectable cell-mediated immune function; we therefore hypothesized that if this component of the immune system were necessary for the development of bleomycin-induced interstitial disease, bleomycin would not induce the same pulmonary lesion in the nude mouse as in the white mouse. However, both white and nude mice developed alveolitis and fibrosis after intraperitoneal administration of bleomycin. Comparison of the frequency and severity of these lesions in the 2 groups revealed no significant differences. These findings suggest that the presence of an intact cell-mediated immune system is not an absolute requirement for the development of bleomycin-induced interstitial disease in the mouse. To the extent that this model is an appropriate approximation of human bleomycin-induced pulmonary disease, these results are consistent with the hypothesis that T-lymphocyte mediated processes are not primary determinants of this lesion.

Animals↗
PubMed1978

Bleomycin-induced diffuse interstitial pulmonary fibrosis in baboons.

Pulmonary fibrosis was induced in eight baboons with bleomycin; five untreated animals were controls. After 45-65 U/kg of bleomycin, lung volumes and diffusing capacity were reduced, and static lung pressure-volume curves were shifted to the right. Right middle lobes were resected at this time in five bleomycin-treated and two control animals. Compared to controls, right middle lobes from bleomycintreated animals had increased weight and contained increased amounts of total protein, collagen, elastin, and DNA; synthesis of collagen and noncollagen protein were also elevated. Occasional alveolar septae were edematous and infiltrated by mononuclear inflammatory cells; a slight increase in collagen was demonstrable histologically. Four of six treated animals died with extensive diffuse interstitial fibrosis after 95 U/kg of bleomycin. Biochemical analyses revealed significantly elevated lobar contents of dry weight, protein, elastin, and collagen. Two animals survived 95 U/kg of bleomycin and were terminated 6 mo after treatment. In these animals, physiologic studies were indicative of restrictive lung disease, but lung histology was nearly normal. Lung weight, total protein, and DNA had returned to control values, but collagen and elastin were increased in amount and concentration. Bleomycin induces an intense inflammatory response in the lung. During this inflammation, connective tissue proliferation occurs in concert with proliferation of other tissue components. Cessation of bleomycin treatment is followed by resolution of inflammation manifested by decreases in tissue mass, cellular content, and nonconnective tissue protein. Collagen and elastin deposited during inflammation are less successfully removed during resolution, leading to a stage characterized by increased concentrations of these proteins. A similar sequence of tissue alterations may occur in idiopathic diffuse interstitial fibrosis of man in response to various lung injuries.

Animals↗
PubMed1975

The effects of bleomycin on immunocompetence in man.

Bleomycin was administered to six patients with advanced cancer. Multiple parameters of both antibody- and cell-mediated immunity were followed serially to characterize the effects of bleomycin on immunocompetence in humans. Antibody-mediated immunity, including primary vaccination with keyhole limpet hemocyanin, was not depressed. While there was no significant suppression of cell-mediated immunity, phytohemagglutinin-stimulated lymphocyte blastogenesis was reduced after treatment with bleomycin. The in vitro effects of bleomycin on lymphocyte stimulation were studied, and while thymidine incorporation was significantly inhibited by bleomycin, leucine incorporation was not reduced even at high concentrations of bleomycin. We have concluded that bleomycin does not suppress immunocompetence in man.

Antibody Formation↗
PubMed1976

Determination of the bleomycin-inactivating enzyme in biopsies.

A method for the determination of the Bleomycin-inactivating enzyme is described. The amount of conversion of active Bleomycin to inactive Bleomycin is used as a measure for the determination of the Bleomycin-inactivating enzyme activity. The active Bleomycin is determined in a DNA-dependent DNA polymerase assay; in a certain Bleomycin concentration range the resulting reduction of the activity of the DNA-dependent DNA polymerase is correlated linearly when plotted semilogarithmically. By application of this method it has been found that the activity of the Bleomycin-inactivating enzyme is highest in liver and present in lower concentrations in testis, spleen, lung, brain, and skin.

Bleomycin↗
PubMed1979

Effects of systemically administered bleomycin or adriamycin with local hyperthermia on primary tumor and lung metastases.

Exposure of cells in tissue culture to bleomycin or Adriamycin during 43 degrees C hyperthermia increased cytotoxicity dramatically compared to exposure at 37 degrees C. This study was designed to test whether this interaction was useful in tumor-bearing animals. C3H mice bearing the KHT tumor were treated with bleomycin (7 or 15 mg/kg) or with Adriamycin (2.5 or 5 mg/kg) with or without local heating of the tumor to 43 degrees C for 30 minutes by 13.56 MHz radiofrequency fields. The effects were assessed by growth delay (mean tumor diameter doubling time) and cure rate. In separate experiments, BALB/c mice bearing EMT6 tumors were treated identically, but tumors were excised 2 hours after treatment and tumor cell survival was assayed by colony formation. Antitumor effects of systemic bleomycin were potentiated by local hyperthermia. The two modalities had to be administered close together in time to observe the potentiation, suggesting a true interaction. There was a "threshold" for bleomycin potentiation in vivo between 42 degrees C and 43 degrees C, just as observed in tissue culture experiments. The antitumor activity of Adriamycin was not potentiated in vivo in these tumor systems except in cell survival experiments at doses higher than those compatible with survival of the host. The toxicity of drug combined with heat was greater than that of either modality alone. Hyperthermia did not adversely affect the incidence or severity of spontaneous lung metastases from KHT tumors. In fact, groups treated with heat and bleomycin had less severe lung metastases than groups treated with bleomycin alone. We conclude that local heating of tumors may be a useful adjunct to systemic bleomycin therapy. In vivo potentiation of Adriamycin by heat, however, could not be demonstrated in these tumor systems.

Animals↗
PubMed1979

Iron-bleomycin interactions with oxygen and oxygen analogues. Effects on spectra and drug activity.

Despite extensive structural dissimilarities, iron . bleomycin complexes and heme-containing oxygenases display remarkable similarities in binding oxygen antagonists and in spectral properties deriving from bound iron. Fe(II)-bleomycin reversibly forms a complex with either CO or isocyanide (lambda max = 384 and 497 nm, respectively), either of which interfere with its oxygen-dependent cleavage of DNA. A similar but paramagnetic complex forms with NO (lambda max = 470 nm; AN = 24 G). In contrast, cyanide enhances bleomycin activity against DNA. Complexes of bleomycin and FE(III), formed either by direct association or by autoxidation of the Fe(II) . bleomycin complex, exhibit indistinguishable EPR and visible spectra, which change characteristically with pH. At neutral pH, Fe(III) . bleomycin is a low spin complex (g = 2.45, 2.18, 1.89; lambda max = 365, 384 nm) and, at low pH, it is a high spin rhombic complex (geff = 9.4, 4.3; lambda max = 430 nm). These complexes are interconvertible (pK 4.3). Fe(II) . bleomycin oxidation, although reversible by spectral criteria, is accompanied by drug inactivation unless DNA is present.

Animals↗