Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “bleomycin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources
PubMed1986

Effects of a calmodulin inhibitor on bleomycin-induced lung inflammation in hamsters. Biochemical, morphometric, and bronchoalveolar lavage data.

Previous studies have shown that bleomycin-induced pulmonary fibrosis is accompanied by elevated levels of calcium and calmodulin, which are important in the regulation of many biologic processes. The authors have further extended these observations and assessed the effect of a calmodulin inhibitor, trifluoperazine, on bleomycin-induced lung damage with biochemical, morphometric, and bronchoalveolar lavage techniques. The cumulative mortality due to bleomycin was not significantly reduced in animals receiving trifluoperazine. Trifluoperazine had no apparent effect on lung levels of collagen and DNA elevated by bleomycin. However, morphometric studies showed that the volume density of the lesion, the volume of amorphous material and interstitial inflammation, and the number of monocytes within lesions were less in the lungs of bleomycin-treated hamsters receiving trifluoperazine daily. When compared with hamsters treated with bleomycin alone, animals treated with both bleomycin and trifluoperazine had significantly fewer lymphocytes in their bronchoalveolar lavage fluid. The data suggest that trifluoperazine reduced the acute inflammation which accompanies bleomycin pneumotoxicity but did not affect the subsequent development of pulmonary fibrosis. It has been postulated that the observed antiinflammatory action of trifluoperazine may be due to inhibition of calmodulin-dependent leukocyte functions.

Animals↗
PubMed1987

Isolation and characterization of bleomycin-sensitive Chinese hamster ovary cells.

Nineteen bleomycin-sensitive Chinese hamster ovary cell mutants have been isolated using a replica plating and photography approach. As judged by the dose which reduces cell survival to 37% of the untreated control, these mutants are from 2.5- to 32-fold more sensitive to a 16-h bleomycin treatment than the parental cell, while for chronic bleomycin exposure, the increase in sensitivity was 5 to 58 times that of the parental cell. Four bleomycin-sensitive mutants had increased sensitivities to killing by gamma-rays (2- to 3-fold), mitomycin C (2-fold), and ethyl methane sulfonate (4- to 5-fold), while six other mutants were resistant to these agents. Nine other bleomycin-sensitive mutants displayed a variable pattern of cross-sensitivities to these agents. Using the technique of alkaline elution, the relative frequency of single-strand DNA breaks introduced by varying concentrations of bleomycin was examined in one mutant and its parent cell. The elution profiles of both cells were similar, suggesting that the bleomycin sensitivity of this mutant is not due to a greater frequency of single-strand breaks introduced by bleomycin.

Aminacrine↗
PubMed1987

Bleomycin-induced pulmonary endothelial cell injury: evidence for the role of iron-catalyzed toxic oxygen-derived species.

Bleomycin, an effective cancer chemotherapeutic agent, is associated with serious pulmonary toxicity. As an in vitro model of bleomycin pulmonary toxicity, this study examined the ability of bleomycin to injure chromium 51-labeled bovine pulmonary artery endothelial (BPAE) cells in an 18-hour cytotoxicity assay. The data indicate that bleomycin-mediated injury to cultured BPAE cells can be quantified by 51Cr release, expressed as cytotoxic index (CI). Bleomycin-mediated injury to 51Cr-labeled BPAE cells (CI 19.4 +/- 1.6) could be significantly reduced by the iron chelator deferoxamine, 10(-3) mol/L (CI 7.5 +/- 1.1, P less than 0.001), but not by ethylenediaminetetraacetic acid, 10(-5) mol/L (CI 19.8 +/- 2.2). Similarly, bleomycin-mediated injury to BPAE cells (monitored by lactate dehydrogenase release) with a CI 27.1 +/- 4.8 could be reduced by 10(-3) mol/L deferoxamine to CI 10.5 +/- 2.6 (P less than 0.01). In contrast, hyperoxia (95% O2) accelerated bleomycin (1 to 100 mU/ml) toxicity to BPAE cells (P less than 0.01, all comparisons). This study suggests that bleomycin-induced injury of pulmonary endothelial cells may be dependent in part on two critical factors in the cellular environment: the availability of iron to the cell and the ambient O2 concentration.

Animals↗
PubMed1989

Cleavage of cellular and extracellular Saccharomyces cerevisiae DNA by bleomycin and phleomycin.

Low-molecular-weight phleomycin (Mr approximately 1500-1600) is considerably less active on a per mol basis than structurally related bleomycin in degrading purified Saccharomyces cerevisiae DNA. Phleomycin also exhibits a substantially higher requirement than bleomycin for ferrous ions. However, phleomycin (0.13 to 3.3 x 10(-6) M) produced 7 to 350 times more breaks than bleomycin in prelabeled intracellular [2-14C]DNA and [6-3H]DNA and is considerably more cytotoxic than bleomycin. Phleomycin and bleomycin produced equivalent numbers of DNA breaks at equivalent, physiologically meaningful levels of survival, indicating that DNA breaks are related to lethal properties of the anticancer glycopeptides. Phleomycin degradation of extracellular DNA was only detectable at greater than or equal to 1.7 x 10(-4) M, approximately two orders of magnitude higher than the concentrations of phleomycin which yielded equivalent fragmentation of intracellular DNA, indicating that phleomycin causes substantially more degradation of intracellular DNA than extracellular DNA. In contrast, bleomycin (greater than or equal to 1.7 x 10(-5) M) degradation of purified DNA is quite extensive and considerably greater than the degradation of DNA in cells incubated with the same or higher concentrations of bleomycin. Neither phleomycin nor bleomycin cleaved extracellular DNA in the absence of ferrous ions, although both chemical analogues cleaved intracellular DNA without adding iron. Therefore, the requirement for metal ion in stimulating DNA degradation by the two structural families of glycopeptidic antibiotics is met by the cell itself.

Bleomycin↗
PubMed1985

Ultrarapid recovery from lethal effects of bleomycin and gamma-radiation in stationary-phase human diploid fibroblasts.

An ultrarapid phase of cellular recovery, as measured in liquid holding type experiments, was studied in stationary-phase human fibroblasts exposed to bleomycin or cobalt-60 gamma-irradiation yielding comparable levels of cell killing. This rapid recovery was both faster and considerably greater in magnitude after bleomycin treatments. Bleomycin survival curves were multiphasic, indicating the presence of treated cells with varying sensitivities either at the beginning of treatments or as a result of resistance which developed during the treatment period. The amount of both ultrarapid (within 2 to 10 min) and slower recovery was dose dependent after irradiation with 200 to 800 rads or 30-min exposures to bleomycin (5 to 100 micrograms/ml). Following bleomycin treatments resulting in surviving fractions of 1 to 2%, survival increased up to 8-fold after only 2 min of posttreatment incubation. This rapid increase in survival was followed by a slower increase over time periods up to 3 h. In contrast, the rates of cellular recovery after gamma-irradiation were more gradual from 0 to 3 h. Recovery at all posttreatment intervals was always greater after bleomycin than after gamma-treatments, following doses yielding 1 to 50% survival. The ultrarapid component of cellular recovery after bleomycin treatments may have implications for both clinical cancer management and cellular studies directed toward determining mechanisms of action of bleomycin.

Bleomycin↗
PubMed1985

Rapid and slow DNA rejoining in nondividing human diploid fibroblasts treated with bleomycin and ionizing radiation.

The rejoining of DNA single-strand breaks produced after bleomycin treatment or gamma-irradiation of human diploid fibroblasts was studied by the alkaline elution technique. DNA rejoining occurred at slower rates in bleomycin-treated human fibroblasts than in gamma-irradiated fibroblasts. These comparisons were made at similar levels of survival or DNA single-strand breaks (including alkali-labile lesions). Significant numbers of DNA single-strand breaks were detected routinely after 2 micrograms/ml (1.34 X 10(-6) M) bleomycin treatments (for 30 min, survival greater than 70%). Dose-dependent losses of approximately 3 to 15% of total radioactivity were measured in preelution samples from cells treated with bleomycin (2 to 100 micrograms/ml), but only 2 to 3.5% of total radioactivity was assayed in lysis samples from cells irradiated with 200 to 1000 rads. This result suggests that DNA was more degraded by or after bleomycin treatment. DNA was rejoined extremely rapidly after bleomycin or radiation treatments, and the rejoining was both agent- and dose-dependent. Over dose ranges yielding surviving fractions of 75 to 0.056%, considerable DNA rejoining occurred after only 2.5 min posttreatment incubation in conditioned medium. Cellular recovery occurred at faster rates after bleomycin treatments than after gamma-irradiation, while DNA rejoining occurred at faster rates after gamma-irradiation, thus uncoupling DNA repair and cellular recovery in relating the cellular action of these 2 agents. No consistent differences were observed among 3 normal fibroblast strains and fibroblasts from a Gardner's syndrome patient (deficient in their capacity for cellular recovery) or a Turcot's syndrome patient in the formation and rejoining of single-strand breaks after bleomycin or radiation treatments.

Adult↗
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↗
PubMed1980

Assessment of bleomycin lung toxicity using angiotensin-converting enzyme in pulmonary lavage.

Activity of the dipeptidyl hydrolase angiotensin-converting enzyme has been observed to be altered by treatment with bleomycin. We used an animal model of bleomycin lung toxicity to study the effects on angiotensin-converting enzyme activity in various lung fractions. Serum activity of angiotensin-converting enzyme increased only 23% after a single intratracheal instillation of bleomycin. Lung tissue angiotensin-converting enzyme activity fell to 40% of control level (p < 0.05) and returned toward and eventually exceeded control values during the ensuing 6 weeks. However, angiotensin-converting enzyme activity in alveolar lavage fluid from bleomycin-treated rats was elevated 30-fold above the barely detectable levels found in control animals. Angiotensin-converting enzyme activity in lavage fluid was soluble and was not associated with the alveolar cell pellet. Maximum elevation of lavage angiotensin-converting enzyme activity occurred 3 days following bleomycin instillation. Significant transudation of serum into alveolar lavage fluid occurred in bleomycin-treated rats. Nevertheless, this phenomenon would not explain the high levels of angiotensin-converting enzyme activity found in lavage fluid. Elevated lavage angiotensin-converting enzyme levels were detected after doses of bleomycin too low to cause significant sequelae of pulmonary fibrosis. Lavage angiotensin-converting enzyme is a sensitive monitor of tissue response to bleomycin.

Animals↗
PubMed1981

A 1H nuclear relaxation study of the Mn2+ . bleomycin complex. Proximity of the metal to the DNA-binding site.

The antineoplastic action of bleomycin is thought to involve the aerobic degradation of DNA by the Fe2+ . bleomycin complex. Different parts of the bleomycin molecule have been implicated in metal binding and DNA binding. To probe the structure of a metal-containing bleomycin, we studied the effects of the high spin Mn2+ ion in the Mn2+ . bleomycin complex on the longitudinal nuclear relaxation rates of various protons in the molecule. Complexation of Mn2+ to bleomycin was also studied by EPR, and a Scatchard plot of the EPR data revealed a single tight divalent cation-binding site per molecule. From the magnitudes of the paramagnetic effects of Mn2+ on the nuclear relaxation rates of several assigned resonances, we calculate the relative distances of the corresponding protons from the metal. Using a pyrimidine methyl to metal distance of 6.5 A, consistent with the metal coordination of this aromatic group of bleomycin established on the basis of other studies, we find from our data that the bithiazole and COOH-terminal portions of the molecule are located spatially very close to the metal. These groups have previously been implicated in DNA binding. Our metal to bithiazole proton distances (approximately 5.4 A) are consistent with bithiazole as a metal ligand, although possible involvement of interactions other than direct coordination in maintaining close proximity cannot be excluded. Our distance data also argue against the imidazole ring of beta-hydroxyhistidine as a ligand. The short distance between the metal- and DNA-binding sites indicated by our studies would help ensure that the reactive reduced oxygen radicals produced at the metal site during Fe2+ oxidation in the aerobic Fe2+ . bleomycin complex reach the substrate DNA before the destruction of these radicals can occur in other ways.

Bleomycin↗
PubMed1982

Effects of nicotinamide, isonicotinamide, and bleomycin on DNA synthesis and repair in rat hepatocytes and hepatoma cells.

Because inhibitors of poly (ADP-ribose) synthetase have been found to influence DNA synthesis in some systems, the possibility that nicotinamide or isonicotinamide might potentiate the effect of bleomycin on DNA replication and repair was examined. After a 30-minute incubation with bleomycin (200 micrograms/ml), tritiated thymidine ([3H]dThd) incorporation into DNA was stimulated during a subsequent 30-minute incubation with hepatocytes of inbred BUF rats but was decreased in HTC cells of BUF rats. When unscheduled DNA synthesis was measured in the presence of 10 mM hydroxyurea, bleomycin (200 micrograms/ml) increased [3H]dThd incorporation in both cell types. A dose of 20 mM nicotinamide and isonicotinamide caused an approximately 50% inhibition of total [3H]dThd incorporation in HTC cells. Significant inhibitory effects of 20 mM nicotinamide and isonicotinamide on unscheduled DNA synthesis were observed after preincubation of hepatocytes and HTC cells with bleomycin. When the effects of bleomycin on DNA structure were assessed fluorometrically with ethidium bromide after mild alkaline incubation, nicotinamide and isonicotinamide did not significantly affect the damage revealed with bleomycin alone. When HTC cells were incubated for 48 hours with bleomycin (20 micrograms/ml), the increase in cell numbers was about 50% of that in control cultures. Nicotinamide and isonicotinamide also inhibited the proliferation of HTC cells, but the effects were not additive with the effect of bleomycin.

Animals↗
PubMed1982

[Computation of a radiodosage equivalent of the effect of bleomycin].

The responses of in vitro cultured mammalian cells to X-rays and bleomycin were compared for establishing a general rule to convert X-ray dose to bleomycin dose for a given biological effect. There was no significant difference in the radiosensitivities according to cell lines used in this experiment, while the responses of cells to bleomycin varied from cell to cell. The X-ray dose-response curves for the cells were convex upward if plotted on a semilogarithmical scale, while bleomycin dose-response curves were convex downward. These results indicated that the ratio of X-ray dose and bleomycin dose required for a comparable biological effect would vary with the X-ray dose and from cell to cell. Preliminary treatment with bleomycin sensitized mammalian L5 cells to X-rays. When the cells were exposed to bleomycin following irradiation, no significant synergestic effect was observed, in spite of the fact that the bleomycin dose was sufficient to result in a survival of 4.5%.

Adolescent↗
PubMed1997

Protective effect of liposomal alpha-tocopherol against bleomycin-induced lung injury.

The clinical use of bleomycin in the treatment of squamous cell carcinomas, lymphomas and testicular tumours has been limited by its toxic effects, the most serious being pulmonary injury. The present study was undertaken to investigate whether alpha-tocopherol, incorporated in liposomes and delivered directly to the lung, could offer protection against bleomycin-induced lung damage and fibrosis in the rat. Animals were administered, intratracheally, plain liposomes (composed of dipalmitoylphosphatidylcholine, DPPC) or alpha-tocopherol-containing liposomes (8 mg alpha-tocopherol/kg body weight) and 30 min later, were exposed to bleomycin sulphate (4 units/kg body weight) by intratracheal instillation; treated animals were killed 21 days later. Results of this study showed that lungs of animals treated with bleomycin were seriously damaged, as evidenced by significant histological changes and increases in lung weight, lipid peroxidation, myeloperoxidase activity and hydroxyproline content as well as decreases in lung angiotensin converting enzyme (ACE) and alkaline phosphatase (AKP) activities. Pretreatment of rats with plain liposomes alone did not alter significantly the bleomycin-induced changes of all parameters examined. In contrast, pretreatment of rats with alpha-tocopherol liposomes 30 min prior to bleomycin administration resulted in little or no histological changes and conferred a significant protection against bleomycin-induced changes in edema, lipid peroxidation, hydroxyproline content, and ACE, AKP and myeloperoxidase activities. Results of this study suggested that pretreatment of rats with alpha-tocopherol liposomes can provide a significant protection against bleomycin-induced lung injury.

1,2-Dipalmitoylphosphatidylcholine↗
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↗
PubMed1987

Purification of bleomycin hydrolase with a monoclonal antibody and its characterization.

We established a hybridoma clone that produced anti-bleomycin hydrolase antibody. The subclass of the monoclonal antibody was immunoglobulin M. The antibody significantly reacted with bleomycin hydrolase from rabbit tissues, mouse livers, sarcoma 180, and adenocarcinoma 755 but not significantly with that from MH 134 and Ehrlich carcinoma. The enzyme from L5178Y cells showed an intermediate reactivity. Bleomycin hydrolase was purified from rabbit liver by immunoaffinity with the monoclonal antibody and DEAE gel chromatography. Approximately 1300-fold-purified bleomycin hydrolase was obtained. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and isoelectric focusing on a polyacrylamide slab gel of purified bleomycin hydrolase showed a single band with an apparent Mr of 48K and an isoelectric pH of 5.2. The molecular weight of bleomycin hydrolase determined on gel filtration high-performance liquid chromatography was ca. 300K, suggesting a hexameric enzyme. The enzyme showed an optimum pH of 6.8-7.8 and gave a Vmax value of 6.72 mg min-1 mg-1 for peplomycin and 9.24 mg min-1 mg-1 for bleomycin B2 and a Km value of 0.79 mM for both substrates. The enzyme was inhibited by E-64, leupeptin, p-tosyl-L-lysine chloromethyl ketone, N-ethylmaleimide, Fe2+, Cu2+, and Zn2+ but was enhanced by dithiothreitol. The results suggest that bleomycin hydrolase is a thiol enzyme.

Animals↗
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↗