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PubMed1986

Increased lethality of calmodulin antagonists and bleomycin to human bone marrow and bleomycin-resistant malignant cells.

The effect of bleomycin and calmodulin antagonists on human cells was studied using a clonogenic assay. A 1-h exposure to nontoxic concentrations of the calmodulin antagonists melittin (0.5 microM), pimozide (5 microM), and chlorpromazine (20 microM) increased the lethality of bleomycin to human ovarian carcinoma cells (SK-OV). No increase was seen with chlorpromazine sulfoxide, which lacks calmodulin antagonistic activity. Maximum enhancement of bleomycin lethality by calmodulin antagonists was seen when the antagonist was present simultaneously with bleomycin rather than before or after bleomycin. The cytotoxicity of bleomycin to A-253 head and neck squamous carcinoma cells, which were 10-fold more sensitive to bleomycin alone compared to SK-OV cells, was not markedly altered by the presence of 20 microM chlorpromazine. Chlorpromazine, melittin, or pimozide also increased the toxicity of bleomycin to human granulocyte/macrophage and erythroid stem cell colonies. These results demonstrate that calmodulin antagonists can significantly increase the lethality of bleomycin to some but not all human tumor cells and that nonmalignant hematological human cells may also be affected by this combination.

Bleomycin↗
PubMed1996

Heparin attenuates bleomycin but not silica-induced pulmonary fibrosis in mice: possible relationship with involvement of myofibroblasts in bleomycin, and fibroblasts in silica-induced fibrosis.

Pulmonary fibrosis was elicited in mice or rats by the intratracheal instillation of bleomycin or silica. Daily injections of heparin significantly reduced the collagen deposition in bleomycin, but not in silica, injected mice, as evaluated by the lung hydroxyproline content on day 15 after instillation. Heparin also reduced the bleomycin-induced morbidity and mortality. Study of the broncho-alveolar lavage fluid (BAL) detected no significant change in the number of leucocytes or the amount of protein in heparin treated mice. Histologies of bleomycin instilled mice suggested that heparin did reduce the alveolar remodelling but not the alveolitis, evidenced by leucocytic infiltration. As detected by electron microscopy (EM), bleomycin increased the number of leucocytes and platelets within the alveolar capillaries but this was not significant ly reduced by heparin. The phenotype of the interstitial cell involved in these two types of pulmonary fibrosis was investigated by immunohistochemistry and EM. While in bleomycin injected animals the interstitial cells had the phenotype of an actin (alpha-actin in the rat) and lipid containing interstitial cell, with a poorly developed RE, in silica injected animals in contrast, the interstitial cells were without cytoplasmic actin or lipid but with a markedly developed endoplasmic reticulum (ER). Thus bleomycin and silica induced the growth of two different types of interstitial cells, the myofibroblast and the regular fibroblast, which might be a reason why heparin selectively inhibits bleomycin but not silica-induced fibrosis.

Animals↗
PubMedDate not supplied

Lymphokines in bleomycin-induced lung injury in bleomycin-sensitive C57BL/6 and -resistant BALB/c mice.

To study the pattern of lymphokines in bleomycin-induced lung injury, T cells were isolated from lung interstitial tissue (LIL), peribronchial lymphatic tissue (PBLT), and bronchoalveolar lavage (BAL) fluid of bleomycin-"sensitive" C57Bl/6 and bleomycin-"resistant" BALB/c mice at 3, 6, and 14 days following intratracheal instillation of bleomycin or saline. After 48 hours in culture, conditioned media were collected and assayed with specific enzyme-linked immunosorbent assay (ELISA) for interferon (IFN)-gamma, interleukin (IL)-2, IL-4 and IL-5. In bleomycin-treated C57B1/6 mice, IFN-gamma production was increased up to 20-fold at 3 and 6 days in LIL, and at 3 days in PBLT lymphocytes. IL-4 production was slightly decreased in LIL and PBLT lymphocytes at 14 days. IL-2 and IL-5 were not changed by bleomycin. In BALB/c mice, IFN-gamma production was increased 5-fold at 14 days, and IL-2 production at 6 days, in LIL but not PBLT. IL-4 and IL-5 were not significantly changed. The increase in IFN-gamma may play a role in the pathogenesis of bleomycin-induced lung injury. Differences in the cytokine pattern between the strains of mice may contribute to the variable strain susceptibility in bleomycin-induced lung injury.

Animals↗
PubMed1987

Enhanced bleomycin-mediated damage of DNA opposite charged nicks. A model for bleomycin-directed double strand scission of DNA.

The anticancer drug, bleomycin, causes both single and double strand scission of duplex DNA in vitro, with double strand scission occurring in excess of that expected from the random accumulation of single strand nicks. The mechanism of the preferential double strand scission of DNA by bleomycin has been investigated through the synthesis of a series of double hairpin and linear oligonucleotides designed to contain a single nick-like structure at a defined site to serve as models of bleomycin-damaged duplex DNA. The 3' and/or 5' hydroxyls flanking the nick have been phosphorylated to model the increased negative charge at a bleomycin-generated nick. The ability of bleomycin to cleave the intact strand opposite the nick was then determined by autoradiography. The results demonstrate that phosphorylation at either the 3' or 5' hydroxyl, and especially when both sites are phosphorylated, strongly enhances selective cleavage by bleomycin of the opposite strand. These experiments indicate that bleomycin-mediated double strand scission is a form of self-potentiation in which the high affinity of bleomycin for the initially generated nicked sites leads to a greatly enhanced probability of scission of the strand opposite those sites.

Base Sequence↗
PubMed1975

Binding of bleomycin to DNA in bleomycin-sensitive and -resistant rat ascites hepatoma cells.

The 14C activity of [14C]bleomycin bound to DNA in bleomycin-sensitive rat ascites hepatoma cells (AH-66) was 8.7 times higher than in resistant cells (AH-66F) when the cells were incubated with [14C]bleomycin. The difference in permeability to bleomycin was not significant; uptake of [14C]bleomycin by the sensitive cells was only 1.2 times larger than that by the resistant cells, and the radioactivity incorporated into the nuclei of sensitive cells was only 1.3-fold greater. The bleomycin-inactivating enzyme level in the resistant cells was 3.5 times higher than in the sensitive cells, indicating that the antibiotic incorporated into the resistent cells was reduced in DNA-binding activity to a large extent. The level of protein-free thiol compound in the sensitive cells was 1.8-fold higher than in the resistant cells, suggesting a possible enhancement of bleomycin action by intracellular thiol compound as is found in vitro. These factors probably affect the DNA strand scission and the sensitivity of cells to this antibiotic. Binding of [14C]bleomycin to DNA in vitro was studied in the presence and the absence of dithiothreitol. A large portion of the radioactivity bound in the presence of dithiothreitol was unstable to acid, but the acid-resistant binding was also enhanced by this thiol compound.

Animals↗
PubMed2005

Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients.

OBJECTIVE: Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A>G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP). METHODS: From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype. RESULTS: BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes. CONCLUSIONS: The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype.

Adolescent↗
PubMed1982

Studies on the interaction of bleomycin A2 with rat lung microsomes. II. Involvement of adventitious iron and reactive oxygen in bleomycin-mediated DNA chain breakage.

Bleomycin-dependent DNA chain breakage catalyzed by rat lung microsomes and NADPH was significantly inhibited by the reactive oxygen scavengers superoxide dismutase and dimethylurea and by the metal chelator EDTA. Cytochrome c and nitro blue tetrazolium, compounds which interfere with microsomal electron transport, also inhibited bleomycin-mediated DNA chain breakage. In contrast to these agents, ascorbic acid significantly enhanced this bleomycin-mediated reaction. In addition to ascorbic acid, the redox cycling compounds paraquat, nitrofurantoin and mitomycin C also significantly increased the DNA damage by bleomycin. The stimulatory action of these redox cycling compounds was significantly inhibited by superoxide dismutase, demonstrating that reactive oxygen generated by the redox cycling of these compounds was diverted to the bleomycin-DNA complex. These collective observations support the concept that oxidation/reduction of adventitious iron bound by bleomycin and accompanying reactive oxygen generation participate in the microsome-catalyzed DNA damage mediated by bleomycin.

Animals↗
PubMed1977

Comparison of oncophilic radiopharmaceuticals, *I-fibrinogen, 67Ga-citrate, 111In-bleomycin, and *I-bleomycin in tumor-bearing mice.

The pharmacokinetics of 67Ga-citrate, 111In-bleomycin, *I-bleomycin, and *I-fibrinogen were compared in a murine KHJJ tumor model in order to assess their relative potential as agents for in vivo detection of cancer. Although all four agents have been reported to be clinically efficacious, in this tumor model, *I-fibrinogen and 67Ga-citrate had the greatest tumor accumulation with maximum concentrations of 11.7% and 10.5% respectively. However, both these radiopharmaceuticals cleared slowly from the blood and animal. The maximum tumor concentrations of 111In-bleomycin and *I-bleomycin were 2.9% and 2.6% respectively, but *I-bleomycin had the advantage of rapid clearance from the blood and animal. 67Ga-citrate did not achieve its maximum tumor concentration until 24 hours after administration, whereas the other radiopharmaceuticals achieved maximum tumor concentration within several hours of administration. From these observations 123I-bleomycin seems to deserve clinical trials in patients. 123I-fibrinogen appears to have significant oncophilic potential if its clearance from the animal can be accelerated without altering its accumulation in the tumor.

Animals↗
PubMed1984

A comparison of the pulmonary toxicity and chemotherapeutic activity of bleomycin-BAPP to bleomycin and pepleomycin.

The pulmonary toxicity and antitumor activity of a new bleomycin analog butylamino-3-propylamino-3-propylamine (Blm-BAPP) was investigated and compared with bleomycin and pepleomycin. Blm-BAPP was significantly more pulmonary toxic than bleomycin and had no greater activity against B16 melanoma than either bleomycin or pepleomycin. Although pepleomycin was as equitoxic as bleomycin in producing pulmonary fibrosis, doses of pepleomycin greater than 5 mg/kg were more lethal than bleomycin. Not only did the three drugs function similarly in vivo, but they behaved similarly in two in vitro test systems: microsome-catalyzed drug-mediated DNA deoxyribose cleavage and binding to DNA.

Animals↗
PubMed1980

Metal binding to modified bleomycins. Zinc and ferrous complexes with an acetylated bleomycin.

We have studied the DNA- and metal-binding properties of a bleomycin A2 derivative in which the alpha-amino group of the beta-aminoalanine moiety has been N-acetylated. The modified antibiotic has been shown to be without activity in mediating the in vitro release of [3H]thymine from Pm-2 DNA. Fluorescence experiments indicate that the degree of quenching by DNA of the bithiazole fluorescence is unaffected by N-acetylation of bleomycin. Furthermore, 1H NMR experiments demonstrate that N-acetylation does not alter the stoichiometry of metal binding. The Fe(II)--Ac-bleomycin A2 complex, however, has been found to be stable in the presence of both O2 and CO, and thus inactivation appears to be accounted for by the loss of the ability to bind and/or reduce O2. Comparison of the 1H NMR spectra of the Fe(II)--bleomycin and Fe(II)--Ac-bleomycin A2 complexes indicates that either a drastic reorganization of the ligands with respect to the central iron atom has occurred or that an altered spin state is stabilized. These experiments establish that the ability of bleomycin to cause DNA damage is sensitive to even minor structural alterations within the antibiotic.

Animals↗