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PubMed1980

Copper chelator enhancement of bleomycin cytotoxicity.

Bleomycin's effects on DNA strand scission are inhibited by low concentration of some metal ions (including copper), greatly stimulated by ferrous (Fe+2) ions, and increased and probably mediated by the production of superoxide radicals (O2-), hydroxyl radicals (OH), and hydrogen peroxide (H2O2). However, the role of these mechanisms in overall bleomycin cytotoxicity is not known. For this reason, we have treated the Chinese hamster cell line (V79) cells with a copper chelator, diethyldithiocarbamate (DDC) and bleomycin in vitro DDC is known to inhibit superoxide dismutase (SOD), an enzyme responsible for the scavenging of O2-. The cytotoxicity is determined by the standard clonogenic survival method, which shows that DDC treated cells are more susceptible to bleomycin either as a function of bleomycin dose or as a function of bleomycin treatment time. These results support the notion that reducing Cu2+ levels and/or increasing O2- concentrations can modify the cytotoxicity of bleomycin.

Animals↗
PubMed1982

Cytokinetic evaluation of the four-drug combination of bleomycin, vincristine, mitomycin C, and methotrexate (BOMM) in cultured Burkitt's lymphoma cells and human bone marrow.

The four-drug combination of bleomycin, vincristine, mitomycin C and methotrexate produces a high response rate in patients with squamous cell carcinoma. In this study we have examined the cytokinetic effects of this drug combination in vitro and in human bone marrow in vivo. The in vitro analysis revealed that mitomycin C produces a concentration dependent slowing of S-phase transit with partial G2/M and G1/S blocks in cell cycle progression. A partially synchronized S-wave occurs 4-8 and 16-20 hours following a two-hour drug exposure. Bleomycin produces a dose dependent G2/M block during a 14-hour drug exposure. Drug removal did not result in appreciable cell cycle synchrony. In vitro exposure to the two drug combination resulted in loss of both the marked G2/M accumulation seen with bleomycin, and the partially synchronized S-phase waves seen following mitomycin C exposure. The sequential changes in bone marrow cytokinetics were determined in eight patients during and following administration of vincristine, mitomycin C and a continuous four-day infusion of bleomycin. The major cytokinetic changes observed were an increase in G2/M phase cells 18 hours following vincristine, and an increase in thymidine incorporation and S-phase cells 24 and 48 hours following the end of the bleomycin infusion. The clinical course of 24 patients was reviewed. Eleven patients who received methotrexate 36 to 42 hours following bleomycin had a subsequent median leukocyte nadir of 1.8 x 10(3)/mm3. Thirteen patients receiving methotrexate 60 to 72 hours after bleomycin had median leukocyte nadir of 3.9 x 10(3)/mm3. The objective response rates in the two groups was 75% and 80%, respectively. This study demonstrates that bone marrow cytokinetic analysis may allow schedule modification to avoid myelosuppression without loss of therapeutic activity.

Antineoplastic Agents↗
PubMed1983

Sequential cyclophosphamide-prednisone and vincristine-bleomycin (CPOB). An effective, schedule-dependent treatment for advanced diffuse histiocytic lymphoma.

In an Eastern Cooperative Oncology Group non-Hodgkin's lymphoma clinical trial, 90 patients with Stage III or IV diffuse histiocytic lymphoma (DHL) were treated with one of four chemotherapy regimens. All patients were previously untreated with chemotherapy, and careful restaging was required to document responses. Each treatment included cyclophosphamide, vincristine and prednisone (COP) plus Adriamycin (COPA), BCNU (BCVP) or bleomycin (COPB and CPOB). The two bleomycin-containing regimens differed only in the schedule of drug administration. CPOB-treated patients received cyclophosphamide on day 1, prednisone on days 1 to 5 and vincristine and bleomycin on day 15 of each 21-day cycle. COPB-treated patients received the same four drugs in the same dosage; however, the schedule was changed so that vincristine and bleomycin were given on day 1. Treatment of responders was continued for 8 cycles. Those with a complete response (CR) were randomized to maintenance therapy with BCVP or no treatment. Treatment with CPOB yielded a CR rate of 55% compared to 25% for COPB (P = 0.07). In contrast to COPB, treatment with CPOB was associated with a significantly longer median duration of CR (26.5 versus 5.7 months; P less than 0.05) and median survival (27.7 versus 11.2 months; P less than 0.02). The CR rate was 31% for BCVP and 45% for COPA, and the median survivals were 10.7 months and 14.4 months, respectively. One half of the CPOB-treated patients who achieved CR remained alive in continuous CR after 30 to 72 months. No advantage for maintenance therapy was observed. Myelotoxicity was greater with CPOB than COPB, but comparable to COPA. This trial demonstrated that the results of treatment of DHL with COP plus bleomycin were strikingly dependent upon the schedule of administration of bleomycin and vincristine. Bleomycin effectively combined with COP, as in CPOB, yielded results comparable to those obtained when Adriamycin was added to COP. CPOB appears to be an effective treatment for DHL that should be considered as an alternative to other regimens, particularly for patients who cannot receive Adriamycin.

Antineoplastic Agents↗
PubMed1988

Mutagenesis of bleomycin-damaged lambda phage in SOS-deficient and repair endonuclease-deficient Escherichia coli.

Previous DNA sequence analysis of bleomycin-induced forward mutations in repackaged lambda phage has suggested SOS-dependent replicative bypass of oxidized apyrimidinic sites as a possible mechanism of mutagenesis. In order to evaluate this hypothesis further, frequencies of mutation to a clear-plaque phenotype were compared for bleomycin-damaged phage grown in various repair-deficient strains of Escherichia coli. Survival of bleomycin-damaged phage was virtually identical in all host strains. Studies in SOS-deficient strains indicated specific requirements for functional recA+ and umuC+ alleles in the generation of the majority of bleomycin-induced mutations, as well as a less stringent requirement for induction of the SOS response by ultraviolet irradiation of the host cells. These results are expected for mutagenesis resulting from apyrimidinic sites. However, the mutation frequency for bleomycin-damaged phage was the same whether the phage were grown in a wild-type strain or in strains deficient in apurinic/apyrimidinic repair endonucleases; this was true even for an nth-nfo-xth- strain lacking all three major apurinic/apyrimidinic endonucleases (endonuclease III, endonuclease IV, and exonuclease III). Likewise, phage grown in an endonuclease IV-overproducing strain showed the same mutation frequency as those grown in wild-type cells. These data suggest that either i) bleomycin-induced mutagenesis results from SOS-dependent bypass of lesions other than apyrimidinic sites or ii) the number of apyrimidinic sites available for SOS processing is virtually independent of the level of apurinic/apyrimidinic endonuclease activity in the cell. It is possible that a fraction of the apyrimidinic sites induced by bleomycin either are intrinsically resistant to repair or undergo secondary reactions that render them resistant.

Bacterial Proteins↗
PubMed1985

Effects of bleomycin on 14C-proline uptake, its incorporation into proteins and hydroxylation in collagenous proteins of hamster lung slices.

The uptake of 14C-proline by lung slices and its incorporation into trichloroacetic-acid (TCA)-insoluble proteins and hydroxylation in collagenous proteins were studied. They were found to be linearly increased with the incubation time for as long as 8 h. The effects of different concentrations of bleomycin on these parameters were subsequently investigated. Bleomycin at 10(-3) M significantly reduced the uptake of 14C-proline to 75% of the control value. The incorporation of 14C-proline into TCA-insoluble proteins was reduced to 84%, 78% and 75% of the control at 2.5 X 10(-4) M, 5 X 10(-4) M and 10(-3) M concentrations of bleomycin, respectively. Bleomycin failed to alter the proline pool size of the lung slices at any of these concentrations. In addition, bleomycin also inhibited the hydroxylation of 14C-proline into collagen to 72% and 69% of the control at 5 X 10(-4) M and 10(-3) M, respectively. These findings show that bleomycin-induced increases in collagen synthesis in vivo is probably secondary to inflammatory reactions of the lung and bleomycin per se has little effect on increased collagen synthesis responsible for lung fibrosis.

Animals↗
PubMed1994

Dietary supplementation with taurine and niacin prevents the increase in lung collagen cross-links in the multidose bleomycin hamster model of pulmonary fibrosis.

Taurine and niacin have been previously found to block the accumulation of collagen in lung in the multidose bleomycin hamster model of pulmonary fibrosis. Previous studies have found an increase in the pulmonary collagen cross-links dihydroxylysinonoroleucine (DHLNL) and hydroxypyridinium (OHP) in the single dose bleomycin rat model. In this study, we asked if taurine and niacin would block the increase in DHLNL and OHP in the multidose bleomycin hamster model of lung fibrosis. Hamsters were intratracheally instilled with three consecutive doses of saline or bleomycin sulfate 1 week apart (2.5, 2.0, 1.5 units/5 mL/kg). Animals were fed diet containing either 2.5% niacin and 2.5% taurine or control diet throughout the experiment. The four groups were saline-instilled with control diet (SCD), bleomycin instilled with control diet (BCD), bleomycin-instilled with taurine-niacin in diet (BTN), and saline-instilled with taurine-niacin in diet (STN). Animals were sacrificed at 1, 4, and 8 weeks after the last bleomycin instillation. Hydroxyproline per lung in the BCD group was significantly elevated by 38, 56, and 60% over the SCD group at 1, 4, and 8 weeks, respectively. There were no statistically significant differences among the four groups in DHLNL (mmole) per mole collagen at the 1 or 8 week time point. At four weeks, DHLNL was significantly elevated by 46.4% in the BCD group over the SCD group. The OHP (mmole) per mole of collagen at 1 and 4 weeks in the BCD group was not statistically different from the SCD group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Inhibition of bleomycin-induced pulmonary fibrosis in mice by the matrix metalloproteinase inhibitor batimastat.

Bleomycin-induced pulmonary fibrosis is known to be associated with the increased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, in bronchoalveolar lavage (BAL). This study has investigated the effect of a synthetic inhibitor of MMP, batimastat, on the development of pulmonary fibrosis induced by bleomycin administration in mice. Animals were intranasally instilled with saline or bleomycin (0.5 mg in 100 microl per mouse). Batimastat (30 mg/kg) or vehicle alone was administered by intraperitoneal injection 24 h and 1 h before saline or bleomycin instillation, and then daily at the same dosage until the end of the study. Fifteen days after bleomycin administration, BAL was performed and the lung was removed. Treatment of mice with batimastat significantly reduced bleomycin-induced lung fibrosis, as shown in the lung by histopathological examination and by a decrease in hydroxyproline levels. Batimastat also prevented the increase in BAL macrophage and lymphocyte numbers, whereas it did not show any effect on the increased expression of active transforming growth factor-beta (TGF-beta) in BAL. Batimastat treatment was effective in reducing MMP-2 and MMP-9 activity as well as the tissue inhibitor of metalloproteinase-1 (TIMP-1) level in BAL. These results suggest that administration of the MMP inhibitor batimastat is useful in preventing experimental pulmonary fibrosis induced by bleomycin and raises the possibility of a therapeutic approach to human pulmonary fibrotic disease.

Animals↗
PubMedDate not supplied

Effect of endothelin receptor antagonists (BQ-485, Ro 47-0203) on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats.

Previous evidence suggests a role for endothelin-1 (ET-1) in the pathogenesis of pulmonary fibrosis. To determine if ET-1 regulates collagen deposition in pulmonary fibrosis, we examined the effect of the non-selective ETA and ETB receptor antagonist bosentan (Ro 47-0203), and a selective ETA receptor antagonist, BQ-485, on collagen deposition during the development of bleomycin-induced pulmonary fibrosis in rats. Lung collagen content, derived from measurements of hydroxyproline and expressed as mg collagen/lung, was increased in the bleomycin-treated animals by day 7 (bleomycin, 22.88+/-1.46; control 18.50+/-0.98; P<0.05), continued to increase up to day 14 (bleomycin, 38.80+/-2.17; control 22.57+/-0.77; P<0.001) and then remained constant to 21 days. Daily treatment by gavage with bosentan (100 mg/kg) did not prevent the increase in collagen deposition induced by instillation of bleomycin at any of the times measured. Continuous administration of BQ-485, by subcutaneously implanted minipump (7.5 mg/day), also failed to prevent the bleomycin-induced collagen deposition at 14 days. These findings suggest that ET-1 does not modulate collagen deposition during the development of bleomycin-induced pulmonary fibrosis. Further studies are required to assess whether endothelin receptor antagonists modulate other components of the fibrotic response or play a role in man.

Animals↗
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↗
PubMedDate not supplied

Quantification of metastatic tumor growth in bleomycin-injured lungs.

The lung is a common target organ in experimental models of tumor metastasis in which quantification usually involves counting labeled tumor cells shortly after injection, or enumeration of grossly visible pleural tumors. In this study, these approaches were used in addition to autoradiographic and morphometric methods to analyse the effect of bleomycin-mediated injury on the development, distribution and quantification of pulmonary metastases. One day after intravenous injection of 2 X 10(5) fibrosarcoma cells, the lungs of C57 bl/6 mice, pretreated with bleomycin (120 mg/kg i.v., 5 days before) contained about nine times as many [131I] iododeoxyuridine-labeled cells as the lungs of control animals given saline injections. At this time, autoradiographic counts of [3H]thymidine-labeled tumor cells in lung sections showed a similar increase in tumor cell localization after bleomycin, with labeled cells distributed equally between parenchymal and pleural areas. However, subsequent tumor growth was demonstrated microscopically to be predominantly in pleural and peribronchial areas, especially at sites of lung injury induced by bleomycin. Counts of grossly visible pleural tumors failed to demonstrate a difference between bleomycin groups and controls at 7 days whereas counts of nodules in lung sections, and quantification of lung area occupied by tumor both showed significantly greater tumor involvement in bleomycin-treated animals. As tumors became confluent, morphometric measurements demonstrated tumor growth in the lung more accurately than did nodule counts. We conclude that bleomycin-induced injury greatly enhances metastatic tumor growth and that morphometric methods are more sensitive than lung colony counts in their ability to quantify pulmonary metastases. Morphometry and autoradiography have also demonstrated that while there is a uniform distribution of arrested tumor cells in the lung initially, there is preferential development of metastatic tumors at sites of pulmonary damage, in particular at the pleura.

Animals↗
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↗
PubMed2004

Localization of endothelin receptors in bleomycin-induced pulmonary fibrosis in the rat.

Pulmonary fibrosis is characterized by excessive extracellular matrix deposition with concomitant loss of gas exchange units, and endothelin-1 (ET-1) has been implicated in its pathogenesis. Increased levels of ET-1 from tissues and bronchoalveolar lavage have been reported in patients with pulmonary fibrosis and in animal models after intratracheal bleomycin. We characterized the cellular distribution of alveolar ET receptors by immunohistochemistry in bleomycin-induced pulmonary fibrosis in the rat and determined the regulation by bleomycin of ET receptor mRNA expression in isolated alveolar macrophages and rat lung fibroblasts. We found significant increases in the numbers of fibroblasts and macrophages at day 7 compared to day 28 and control animals. ET(B) receptor immunoreactivity was observed on fibroblasts and invading monocytes. Isolated fibroblasts expressed both ET(A) and ET(B) receptor mRNA, and ET(A) receptor mRNA was upregulated by bleomycin. Isolated resident alveolar macrophages expressed neither ET(A) nor ET(B) receptor mRNA which were also not induced by bleomycin. We conclude that, while ET(B) receptor stimulation of fibroblasts and monocytes recruited during bleomycin-induced lung injury exerts antagonistic effects on fibroblast collagen synthesis, the observed increase in the number of fibroblasts in vivo and upregulation of fibroblast ET(A) receptor mRNA by bleomycin in vitro point to a predominance of the profibrotic effects of ET receptor engagement.

Animals↗
PubMed2006

Effects of erdosteine on bleomycin-induced lung fibrosis in rats.

This study was designed to examine the effects of erdosteine on bleomycin (BLM)-induced lung fibrosis in rats. Thirty-three Sprague-Dawley rats were divided randomly into three groups, bleomycin alone (BLM), bleomycin + erdosteine (BLM + ERD), and saline alone (control). The BLM and BLM + ERD groups, were given 2.5 mg/kg BLM intratracheally. The first dose of oral erdosteine (10 mg/kg/day) in the BLM + ERD group was started 2 days before BLM administration and continued until animals were sacrificed. Animals were sacrificed 14 days after intratracheal instillation of BLM. The effect of erdosteine on pulmonary fibrosis was studied by analysis of bronchoalveolar lavage (BAL) fluid, histopathology, and biochemical measurements of lung tissue superoxide dismutase (SOD) and glutathione (GSH) as antioxidants, malondialdehyde (MDA) as an index for lipid peroxidation, and nitrite/nitrate levels. Bleomycin-induced lung fibrosis as determined by lung histology was prevented with erdosteine (grades of fibrosis were 4.9, 2.3, and 0.2 in BLM, BLM + ERD, and control groups, respectively). Erdosteine also prevented bleomycin-induced increase in MDA (MDA levels were 0.50 +/- 0.15, 0.11 +/- 0.02, and 0.087+/- 0.03 nmol/mg protein in BLM, BLM + ERD, and control groups, respectively) and nitrite/nitrate (nitrite/nitrate levels were 0.92 +/- 0.06, 0.60 +/- 0.09, and 0.56+/- 0.1 micromol/mg protein in BLM, BLM + ERD, and control groups respectively) levels. Bleomycin-induced decrease in GSH and SOD levels in the lung tissue also prevented by erdosteine [(GSH levels were 213.5 +/- 12.4, 253.2+/- 25.2, and 287.9+/- 34.4 nmol/mg protein) (SOD levels were 1.42+/- 0.12, 1.75+/- 0.17, and 1.89+/- 0.09 U/mg protein) in BLM, BLM + ERD, and control groups respectively]. Erdosteine prevented bleomycin-induced increases in total cell number and neutrophil content of the BAL fluid. In conclusion, oral erdosteine is effective in prevention of BLM-induced lung fibrosis in rats possibly via the repression of neutrophil accumulation, inhibition of lipid peroxidation, and maintenance of antioxidant and free radical scavenger properties.

Acute Lung Injury↗
PubMed1995

Beneficial effects of a novel anti-hypoxemic agent, TEI-7322, on bleomycin-induced experimental hypoxemia in rats.

Almitrine bismesylate is known to be an anti-hypoxemic agent that acts via the enhancement of hypoxic pulmonary vasoconstriction. However, screening for this class of compounds has been minimal, owing, in part, to a lack of convenient hypoxemic models in small animals. The present study was designed to establish a convenient model of hypoxemia induced by bleomycin and to evaluate anti-hypoxemic agents including a newly synthesized compound. TEI-7322, 2-allylamino-4-tert-butyl-amino-7-methyl-7H-pyrrolo[2,3- d]pyrimidine hydrochloride by using this model. Bleomycin was intratracheally instilled into rats. After 3 weeks, the arterial blood gas pressures were monitored in the animals in the conscious state. Then, prednisolone, doxapram, almitrine or TEI-7322 was administered to the bleomycin-treated rats to monitor changes in arterial blood gas pressures. Bleomycin-treated rats showed a decrease in the arterial blood O2 pressure (PaO2). The blood CO2 pressure (PaCO2) increased, along with an increase in the alveolar-arterial oxygen difference (AaDO2). These blood gas pressures in bleomycin-treated rats were not affected by treatment with prednisolone. Doxapram decreased the PaCO2 but did not change the PaO2. However, administration of almitrine or TEI-7322 significantly improved the PaO2 of bleomycin-treated rats with a decrease in the PaCO2. In conclusion, (1) bleomycin-induced lung injury causes hypoxemia in rats, probably resulting from ventilation-perfusion inequality; thus this model may be useful for evaluating anti-hypoxemic agents; and (2) TEI-7322, as well as almitrine, showed anti-hypoxemic effects in this model with different properties from those of doxapram, possibly due to improvement of ventilation-perfusion inequality, indicating that TEI-7322 may be a potent candidate for the treatment of hypoxemia.

Almitrine↗
PubMed1987

Bleomycin-induced mutagenesis in repackaged lambda phage: base substitution hotspots at the sequence C-G-C-C.

DNA isolated from lambda phage was treated with bleomycin A2 plus Fe2+. The bleomycin-damaged DNA was added to lambda packaging extracts and the resulting phage were grown in SOS-induced E. coli. Under these conditions, treatment of the DNA with 0.8 microM bleomycin reduced the viability of the repackaged phage to 3% and increased the frequency of clear-plaque mutants in the progeny by a factor of 16. Bleomycin-induced mutations which mapped to the DNA-binding domain of the cI gene were subjected to DNA-sequence analysis. The most frequent events were single-base substitutions at G:C base pairs, nearly all of which occurred at cytosines in the sequence Py-G-C. Cytosines in the third position of the sequence C-G-C-C were particularly susceptible to mutation. At A:T base pairs, mutations were less frequent and were a mixture of single-base substitutions and -1 frameshifts, occurring primarily at G-T and A-T sequences. Thus, the overall specificity of bleomycin-induced mutations matches that of bleomycin-induced DNA lesions (strand breaks and apyrimidinic sites), which are formed at G-C (particularly Py-G-C), G-T and, to a lesser extent, A-T sequences. Furthermore, the frequency of various types of substitutions was consistent with selective incorporation of A and T residues opposite apyrimidinic sites at these sequences. The highly selective nature of bleomycin-induced mutations may explain the lack of mutagenesis by this compound in a number of reversion assays.

Bacteriophage lambda↗
PubMed1993

Polymerase chain reaction-based deletion screening of bleomycin induced 6-thioguanine-resistant mutants in Chinese hamster ovary cells: the effects of an inhibitor and a mimic of superoxide dismutase.

Bleomycin-induced 6-thioguanine-resistant mutants pretreated with or without TRIEN (triethylenetetramine), a superoxide dismutase (SOD) inhibitor, or TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl), an SOD mimic, were analyzed by polymerase chain reaction (PCR)-based deletion screening in a Chinese hamster ovary (CHO) clone K1-BH4 and its derivative AS52 cells. As we proposed earlier, TRIEN would decrease and TEMPOL would increase the intracellular level of hydroxyl radical leading to a higher and lower recovery of deletion mutants. We found that the proportion of the deletion mutants induced by bleomycin at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in K1-BH4 cells was 45.5% (25/55). The proportion of deletion HPRT- mutants induced by bleomycin pretreated with TRIEN was 31.0% (9/29) and with TEMPOL was 50.0% (14/28). The proportion of deletion mutants induced by bleomycin on the xanthine-guanine phosphoribosyltransferase (gpt) gene in AS52 cells was 61.0% (36/59). The proportion of deletion GPT- mutants induced by bleomycin pretreated with TRIEN was 56.8% (21/37) and with TEMPOL was 61.4% (27/44). The trend of the change of the proportion of bleomycin-induced deletion mutants as affected by TRIEN and by TEMPOL provides molecular evidence for the involvement of reactive oxygen species (ROS) in bleomycin mutagenesis in mammalian cells, in which deletion is a major type of induced mutation.

Animals↗
PubMed1989

A randomized trial of intracavitary bleomycin and Corynebacterium parvum in the control of malignant pleural effusions.

Fifty-eight patients with malignant pleural effusions were entered into a prospectively randomized clinical trial comparing the efficacy of a local instillation of bleomycin or corynebacterium parvum (C. parvum) in controlling fluid reaccumulation after simple needle aspiration (thoracentesis). The response was assessed at 30 days by chest X-ray and clinical examination. There were 44 evaluable patients; 18 of 25 (72%) of those receiving bleomycin and 9/19 (47%) of those who had C. parvum gained a complete or partial response. This difference in response rate was not statistically significant (p = 0.13). The majority of patients had an effusion from a primary breast carcinoma and the response in this group was almost statistically significant (p = 0.06) with 74% of bleomycin patients and 43% of C. parvum patients responding. Fever following instillation was more common with C. parvum (53% of patients compared with 24% after bleomycin, p = 0.02), whereas nausea was more common after bleomycin (28% vs. 10.5%, p = 0.16). Local chest pain after aspiration occurred in 52% of the bleomycin group and 47% of the C. parvum subjects. There was no significant difference between the groups in age, sex, tumour type, presenting symptoms, volume of aspirate, systemic therapy or number of previous aspirations. Both of these agents appeared to be active in the control of malignant pleural effusions although the response rate was higher with bleomycin and overall, both have acceptable levels of toxicity.

Bleomycin↗
PubMed1988

Bleomycin and X-ray-hypersensitive Chinese hamster ovary cell mutants: genetic analysis and cross-resistance to neocarzinostatin.

We have previously reported the isolation of 3 mutants of Chinese hamster ovary cells which exhibit hypersensitivity to bleomycin. 2 mutants were isolated on the basis of bleomycin-sensitivity [designated BLM-1 and BLM-2, Robson et al., Cancer Res., 45 (1985) 5304-5309] and 1 as adriamycin-sensitive [ADR-1, Robson et al., Cancer Res., 47 (1987) 1560-1565]. Because bleomycin generates DNA-strand breaks via a free-radical mechanism, we have studied the survival response of these mutants to a range of drugs which also generate free radicals and consequently DNA-strand breaks. The mutants are all hypersensitive to phleomycin, which differs from bleomycin in being unable to intercalate due to a modified bithiazole moiety. However, BLM-2 cells alone are hypersensitive to pepleomycin, a semi-synthetic bleomycin analogue. In contrast, BLM-1 cells are more sensitive than BLM-2 to streptonigrin (which operates via a hydroquinone intermediate). ADR-1 cells show wild-type resistance to streptonigrin. The results obtained with neocarzinostatin, an antibiotic requiring thiol activation, are unusual in that both BLM-1 and BLM-2 are approximately 3-fold more resistant than parental cells. However, the steady-state intracellular level of the major non-protein thiol, glutathione, is not altered in BLM-1 or BLM-2 cells. ADR-1 cells show essentially wild-type resistance to neocarzinostatin. Analysis of cell hybrids shows that BLM-1 and BLM-2 cells are phenotypically recessive in combination with parental CHO-K1 cells and represent different genetic complementation groups not only from one another, but also from the bleomycin-sensitive mutant xrs-6, isolated on the basis of X-ray sensitivity by Jeggo and Kemp [Mutation Res., 112 (1983) 313-319]. These results indicate that at least 3 gene products are involved in cellular protection against bleomycin toxicity in mammalian cells.

Animals↗