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PubMed1985

Enhanced bleomycin-induced DNA damage and cytotoxicity with calmodulin antagonists.

A wide variety of structurally different calmodulin antagonists enhanced the cytotoxicity of bleomycin A2 to leukemic L1210 cells. This potentiation occurred with nontoxic concentrations of calmodulin antagonists. The most potent blockers of L1210 calmodulin activity, melittin and mastoparan, were the most potent potentiators of bleomycin A2 cytotoxicity. Less potent agents such as pimozide, a diphenylbutylpiperidine, trifluoperazine and chlorpromazine, phenothiazines, and W-7, a naphthalene sulfonamide, required higher concentrations for potentiation of bleomycin A2-induced cytotoxicity, while homologs that lack anticalmodulin activity failed to increase the cytotoxicity seen with bleomycin A2. The potentiation of bleomycin A2 cytotoxicity was not due to an elevated cellular content of bleomycin A2 or to inhibition of bleomycin A2 inactivation. Using alkaline elution techniques, we found that pimozide increased bleomycin A2-induced DNA damage in intact L1210 cells. Pimozide did not, however, directly increase the formation of reactive species by bleomycin as measured by single or double strand breakage of covalently closed circular DNA. Thus, the potentiation of bleomycin cytotoxicity by these agents appears to be mediated by an increased damage to cellular DNA; this may be due to inhibition of DNA repair. The hypothesized calmodulin-dependent mechanism was not shared by all agents that caused breaks in DNA because no potentiation in cytotoxicity was observed when calmodulin antagonists were combined with either etoposide or X-irradiation.

Animals↗
PubMed1976

Molecular interactions of the combined effects of bleomycin and x-rays on mammalian cell survival.

The interactions between bleomycin and X-ray damage and repair have been examined in rat and human tumor cells. Bleomycin itself indices extensive DNA single-strand breaks but does not appear to inhibit the repair of X-ray-induced DNA single-strand breaks. Quantitative analysis of these interactions is complicated by the retention of active bleomycin within cells that remains capable of further DNA degradation even under the conditions of alkaline sucrose gradient cell lysis. DNA double-strand breaks and/or disruptions of DNA-lipid complexes also occur following bleomycin exposure. X-ray-induced excision repair replication is only minimally influenced by even high concentrations of bleomycin. A small amount of excision repair is demonstrable in nonirradiated cells treated with high concentrations of bleomycin consistent with repair of bleomycin-induced nucleotide damage in cellular DNA by a "cut and patch" repair mechanism. Repair of bleomycin-induced DNA single-strand breaks also occurs. The data indicate that bleomycin and X-ray damage are quite similar both in their induction and repair, but that lesions occur and are repaired independently. The enzymatic mechanisms appear similar in the two cell types despite substantial differences in their sensitivity to bleomycin.

Animals↗
PubMed1976

Effect of bleomycin on [3H]Thymidine 5'-Triphosphate incorporation into host liver and hepatoma nuclei.

The effect of bleomycin on [3H]thymidine 5'-triphosphate ([3H]TTP) incorporation into isolated sucrose nuclei from host liver and Morris hepatomas has been compared. Bleomycin stimulates [3H]TTP incorporation 13-fold in host liver and hepatoma 16 nuclei, 8-fold in hepatoma 7800 nuclei, and 3-fold in hepatoma 7777 nuclei. Differences in the nuclear membranes are not responsible for the different response of the nuclei. Nuclei, denuded of their membranes by Triton X-100 treatment, give similar results to sucrose nuclei. Analysis of DNA extracted from liver or hepatoma nuclei incubated with bleomycin indicates that bleomycin produces scissions in the nuclear DNA and that some repair synthesis takes place. Incubation of nuclei with 111indium-labeled bleomycin shows an equal binding capacity of liver and hepatoma nuclei for bleomycin. Bleomycin also stimulates incorporation of [3H]TTP in a system using chromatin or calf thymus DNA as primer. Host liver or hepatoma chromatin incubated with a DNA polymerase extracted from normal rat liver nuclei is stimulated approximately to the same extent by bleomycin. When DNA polymerase extracts from host liver and hepatoma nuclei are assayed with calf thymus DNA as primer, bleomycin has a greater stimulatory effect on [3H]TTP incorporation with host liver DNA polymerase than with hepatoma DNA polymerase in the system. We suggest that a defect in the repair system in hepatoma nuclei is responsible for the relatively lower response to bleomycin.

Animals↗
PubMed1976

Radioimmunoassay of bleomycin.

A radioimmunoassay for bleomycin has been produced using 125l-labeled bleomycin and antisera raised in rabbits against a carbodiimide-catalyzed bleomycin-bovine serum albumin conjugate. 125l-Labeled bleomycin was synthesized by direct iodination of the drug using the chloramine-T technique. The standard curve of the assay was linear on a logit-log plot and the lower limit of sensitivity was 250 pg bleomycin sulfate. A mean recovery of 102.6% (+/- 3.3% S.E.) was obtained using bleomycin added to normal sera. No significant decrease in bleomycin immunoreactivity was observed following 24 hr incubation of the drug in serum at 37 degrees. The radioimmunoassay was also suitable for measuring bleomycin in the presence of other drugs since the assay was not significantly affected by the other antineoplastic agents tested. The sensitivity and specificity of the radioimmunoassay for bleomycin should provide a new means for pharmacokinetic and toxicity studies of bleomycin.

Animals↗
PubMed1983

Mössbauer study of iron bleomycin and its activation intermediates.

Using Mössbauer spectroscopy, we have examined iron-bleomycin in various oxidation states and in complexes with dioxygen or carbon monoxide. Ferrous bleomycin is a high spin ferrous complex. Addition of O2 converts it into an EPR-silent oxygenated complex. Mössbauer studies in strong applied magnetic fields show that oxygenated bleomycin is diamagnetic. At 4.2 K, the quadrupole splitting delta EQ = -2.96 mm/s and the isomer shift delta = 0.16 mm/s suggest that its electronic structure is best described as low spin ferric iron bound to superoxide anion. A single electron reduction yields activated bleomycin, an EPR-active form that still retains oxygen and which is kinetically competent to initiate DNA cleavage. We have produced this complex by exposing ferrous bleomycin to O2 or by reacting ferric bleomycin with H2O2. The Mössbauer spectra give convincing evidence that the iron of activated bleomycin is low spin ferric. The decay of activated bleomycin yields low spin ferric bleomycin, a complex with Mössbauer parameters nearly identical with those reported for ferric cytochrome P-450. Although iron bleomycin does not have a polyaromatic structure like heme, many features of its electronic structure at the iron are very similar to those produced by the sulfur-coordinated heme iron of ferric cytochrome P-450, a protein that catalyzes a similar oxygen-dependent reaction.

Bleomycin↗
PubMed1976

Structure and action of bleomycin.

The structures of bleomycins and of other bleomycin-phleomycin group of antibiotics were described. The activity of bleomycins and their derivatives in causing strand scission of SV40 viral DNA suggests that the beta-aminoalanine amide moiety and the carbamoyl group are involved in this reaction. More than one guanido group in the terminal amine of bleomycin-phleomycin group antibiotics caused irreversible renal toxicity in dogs. Pulmonary toxicity varied depending on the terminal amines. A bleomycin-inactivating enzyme which distributes widely in animal cells was shown to be a new aminopeptidase B which hydrolyzes beta-aminoalanine amide group. At least one of the reasons for activity against squamous cell carcinoma was shown to be due to the lower content of this enzyme. The inhibitor of this enzyme was synergistic to bleomycin in inhibiting growth of cells, thus suggesting the intracellular action of this enzyme. Selected for further study from the bleomycins containing various terminal amines, bleomycin 5033 which showed the same activity against squamous cell carcinoma in mouse skin as the bleomycin used at present and lower toxicity than the latter, and bleomycin A5196 which showed stronger activity and stronger toxicity but lower lung toxicity than the latter.

Aminopeptidases↗
PubMed1977

Comparison of radiolabeled bleomycins and gallium citrate in tumor-bearing mice.

Radioiodinated bleomycin is a chemically stable radiopharmaceutical that can be prepared with high specific activity using 123I. Its pharmacokinetics were compared with those of 99mTc,- 111In-, and 57Co-bleomycin, and 67Ga citrate in mice bearing a transplanted KHJJ tumor. The in vivo kinetics and stability of 123I- and 57Co-bleomycin were similar: both were acceptable, although not equivalent, tags for bleomycin and, along with 67Ga citrate, both had biologic properties suitable for tumor detection. Both 99mTc- and 111In-bleomycin dissociated rapidly in vivo and hence do not represent legitimate tags for bleomycin. However, 111In-bleomycin may have tumor-localizing properties related to its biochemical properties after the indium and chelate separate in vivo. Iodine-123 is superior to either 57Co or 55Co. Tumor-to-blood and tumor-to-liver ratios were higher for I-bleomycin than for 67Ga or Co-bleomycin. The nearly ideal nuclear properties of 123I should complement the biologic properties of bleomycin and lead to a useful tumor radiodiagnostic agent.

Adenocarcinoma↗
PubMed1989

The concentration of bleomycin labeled with Co-57 in primary and metastatic tumors.

The concentration over time of bleomycin labeled with Co-57 was measured in 39 primary and metastatic tumor sites in 16 patients using a newly developed and validated single photon emission computed tomography (SPECT) method. There were nine primary tumors, 15 metastatic tumors, and five multifocal lymphomas. Co-bleomycin concentrations also were measured in primary and metastatic B-16 melanoma tumors in mice. In humans, metastases to lymph nodes (1.58 +/- 0.51 %ID/ml X minutes) showed significantly higher (P less than 0.01) tumor cumulative concentrations of Co-bleomycin than metastases to liver, bone, lung, and brain (0.76 +/- 0.20 %ID/ml X minutes). The cumulative concentrations of Co-bleomycin in human lymphomas (1.1 +/- 0.25 %ID/ml X minutes) also were significantly higher (P less than 0.01) than the concentrations in human metastases other than lymph nodes. The cumulative concentration in cerebral metastases (0.65 +/- 0.18 %ID/ml X minutes) was significantly lower (P less than 0.05) than in noncerebral metastases (1.22 +/- 0.53 %ID/ml X minutes). Primary tumors in humans showed higher concentrations of Co-bleomycin than metastases, except for lymph nodes. In contrast with humans, murine metastases showed higher concentrations of Co-bleomycin (6.20 +/- 2.65 %ID/g) than primary tumors (2.94 +/- 0.90 %ID/g) (P less than 0.001). The concentrations of Co-bleomycin in murine tumors that were affected by bleomycin were about three orders of magnitude higher than in human tumors. The results of this in vivo study document the differences in drug delivery of Co-57-labeled bleomycin to human primary and metastatic tumors and show differences in drug delivery between human and murine tumors.

Adolescent↗
PubMed1999

Inhibition of antioxidants and hyperthermia enhance bleomycin-induced cytotoxicity and lipid peroxidation in Chinese hamster ovary cells.

Regional hyperthermia has potential for human cancer treatment, particularly in combination with systemic chemotherapy or radiotherapy. Heat enhances the cytotoxic effect of certain anticancer agents such as bleomycin, but the mechanisms involved in cell killing are currently unknown. Bleomycin generates reactive oxygen species. It is likely that hyperthermia itself also increases oxidative stress in cells. We evaluate whether oxidative stress has a role in the mechanism of cell death caused by bleomycin and heat in Chinese hamster ovary cells. Heat (41 to 44 degrees C) increased cytotoxicity of bleomycin, evaluated by clonogenic cell survival. Decreased levels of cellular antioxidants should create an imbalance between prooxidant and antioxidant systems, thus enhancing cytotoxic responses to heat and to oxidant-generating drugs. We determine the involvement of four major cellular antioxidant defenses, superoxide dismutase (SOD), the glutathione redox cycle (GSH cycle), catalase, and glutathione S-transferase (GST), in cellular sensitivity to bleomycin, alone or combined with hyperthermia. These cellular defenses were inhibited by diethyldithiocarbamate, l-buthionine sulfoximine, aminotriazole, and ethacrynic acid, respectively. We show that levels of antioxidants (SOD, GSH cycle, and GST) affect cellular cytotoxic responses to bleomycin, at normal and elevated temperatures (41 to 44 degrees C), suggesting the involvement of oxidative stress. Bleomycin and iron caused oxidative damage to membrane lipids in intact cells, at 37 and 43 degrees C. Lipid peroxidation was evaluated by fluorescence detection of thiobarbituric acid-reactive products. There was an increase in damage to membrane lipids when the antioxidant defenses, SOD and catalase, were inhibited. The differing effects of antioxidant inhibitors on bleomycin-induced cytotoxicity and membrane lipid damage suggest that different mechanisms are involved in these two processes. However, free radicals appear to be involved in both cases. The marked sensitization of cells by diethyldithiocarbamate, to both bleomycin-induced cytotoxicity and lipid peroxidation, suggests that superoxide could be involved in both of these processes.

Animals↗
PubMed2002

Animal model of sclerotic skin. V: Increased expression of alpha-smooth muscle actin in fibroblastic cells in bleomycin-induced scleroderma.

Scleroderma is a connective tissue disorder with unknown etiology. Myofibroblasts appear during fibrotic processes such as scleroderma, hypertrophic scarring, and wound healing. We previously established a mouse model for scleroderma by local injections of bleomycin. To determine the phenotype of the fibroblasts in sclerotic skin after bleomycin treatment, we examined the expression of alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblasts, in lesional skin as well as in fibrous lung in this model. Dermal sclerosis was induced by daily local injections of bleomycin (100 microg/ml) for 3 weeks in C3H mice. Immunohistochemical examination showed that alpha-SMA-reactive cells were detectable on fibroblastic cells in bleomycin-injected skin at 1 week. There was a significant increase in the immunoreactive fibroblastic cells for alpha-SMA in lesional skin in parallel with the induction of dermal sclerosis. After 3 weeks' treatment with bleomycin, the number of alpha-SMA-reactive fibroblasts showed an 11-fold increase compared with that in control PBS-treated mice. alpha-SMA-positive cells were also detected in lung parenchyma after bleomycin treatment. Following concomitant treatment with anti-transforming growth factor-beta (TGF-beta) antibody with bleomycin, the number of alpha-SMA-positive fibroblastic cells was significantly reduced up to 50%, along with the reduction of dermal sclerosis. To confirm the protein level of alpha-SMA, immunoblotting was carried out. Results showed an increase of alpha-SMA expression in lesional skin at 3 weeks of bleomycin treatment, which was reduced following anti-TGF-beta antibody treatment. These data suggest that fibroblastic cells are phenotypically altered into myofibroblasts during the fibrotic process in the experimental model of bleomycin-induced scleroderma, which was considered mediated, for the most part, by TGF-beta. Blockade of TGF-beta may be a therapeutic intervention for scleroderma.

Actins↗
PubMed1986

Effect of Fluosol-DA/O2 on the antitumor activity and pulmonary toxicity of bleomycin.

The effect of an oxygen-carrying perfluorochemical emulsion on bleomycin antitumor activity and pulmonary toxicity was examined. Fluosol-DA (0.3 ml/mouse, i.v.), combined with bleomycin (10 or 15 mg/kg, i.p.) and a 2 h exposure to 95% oxygen (BFO) increased by five- to six-fold the tumor growth delay of FSaIIC fibrosarcoma compared to bleomycin alone (B). Only a slight increase in tumor growth delay was noted with the incomplete combinations of bleomycin and O2 (BO) and bleomycin and Fluosol-DA (BF). When bleomycin (10 mg/kg) was co-administered with 0.3 ml Fluosol-DA and 95% O2, cell survival was reduced ten-fold compared to that seen with bleomycin alone. In contrast, the surviving fraction of cells obtained from FSaIIC tumors treated in vivo indicated that 0.3 ml Fluosol-DA per mouse or a 2 h exposure to 95% O2 did not markedly alter the effects of bleomycin alone. The pulmonary effects of the BFO combination were assessed during the course of the therapy by bronchoalveolar lavage (BAL) analysis and pulmonary hydroxyproline (OH-Pro) content. Mice treated with this combination had a 20-fold increase in total numbers of cells obtained in the BAL compared to control animals. An increased cellularity in the lungs was also seen morphologically. The composition of the cells in the lavage fluid was altered after BFO but not BO treatment and reflected a neutrophilic influx. Furthermore, total protein recovered in the BAL fluid was increased 5-fold in the BFO treatment group compared to that in the control mice. Pulmonary OH-Pro, an index of collagen and fibrosis, was unaffected acutely after three treatments of either BFO or BO compared to control mice. Thus, Fluosol-DA and O2 can enhance the antitumor activity of bleomycin. The increased pulmonary cellularity suggests that this combination may also have adverse effects on lung tissue.

Animals↗
PubMed1983

Increases in lung prolyl hydroxylase and superoxide dismutase activities during bleomycin-induced lung fibrosis in hamsters.

Intratracheal administration of bleomycin causes pulmonary fibrosis in hamsters. Using this model the activities of lung prolyl hydroxylase and superoxide dismutase and the accumulation of neutral salt soluble and insoluble collagens have been determined. One unit of bleomycin was injected intratracheally to hamsters, whereas control animals received an equivalent volume of sterile saline by the same route. Total lung prolyl hydroxylase activity was significantly elevated at all times following bleomycin treatment. The activity was increased as early as 2 days, peaked to a maximum value of 400% of the control at 14 days, followed by a sharp decline to 235% and 180% of the control activity at 21 and 28 days after bleomycin treatment, respectively. Except for the earliest time (2 days), lung prolyl hydroxylase specific activity was also significantly elevated at all times after bleomycin treatment. A significant increase in both total and specific activities of lung superoxide dismutase was also observed at all times after bleomycin treatment. Total activity peaked to a maximum value of 315% of the control activity at 14 days and the specific activity to a maximum value of 190% of the control at 21 days after bleomycin treatment. Thereafter, both activities declined, but were still significantly elevated over the control at 28 days after the treatment. Lung proline pool size was significantly increased at all times and attained a maximum value of 372% of the control at 14 days after bleomycin treatment. Increases in the lung prolyl hydroxylase and superoxide dismutase activities and in the proline pool size preceded the significant increases in neutral salt soluble and insoluble collagens which occurred at 7 days after bleomycin treatment and continued to be significantly elevated for the remaining period of the study.

Animals↗
PubMed1983

Fibrogenic structure-activity study of the bleomycin molecule.

In the present study the fibrogenic potential of intact bleomycins as well as their acetyldipeptide and terminal polyamine constituents have been assessed. Administration of Blenoxane, bleomycin A2, or bleomycin B2 to rats produced histopathologic evidence of pulmonary fibrosis when tissues were examined 28 days following a single intratracheal dose. These compounds also produced a readily detectable increase in pulmonary collagen synthesis as evidenced by an approximate twofold increase over control values in the formation of [3H]hydroxyproline in an in vitro lung mince system. Lung collagen synthetic activity remained significantly elevated over control values for up to 2 weeks. However, neither the acetyldipeptides nor the polyamine constituents of bleomycin A2 and B2 produced detectable increases in lung collagen synthesis or in histopathologic evidence of pulmonary injury. Spermine and spermidine, the terminal amine components associated with bleomycin-A6 and with tallysomycin A, tallysomycin B, and bleomycin-A5, respectively, did produce significant pulmonary fibrotic injury in rats following intratracheal administration. Out of an extensive series of polyamines, bleomycin acetyldipeptides and intact bleomycin and tallysomycin analogs, only spermine and spermidine were found to produce hydrogen peroxide and acrolein upon incubation in vitro with amine oxidase, a common pulmonary enzyme. Conclusions regarding the relative toxicity of different bleomycin analogs based solely on the toxicity produced by administration of their terminal amine constituent must therefore be made with caution.

Animals↗
PubMed1988

Modulation of the development of bleomycin-induced fibrosis by deferoxamine.

Bleomycin is an antineoplastic compound which produces a time- and dose-dependent pulmonary fibrosis. The mechanisms which cause this fibrosis are not known. The ability of bleomycin to produce oxygen radicals in the presence of iron and molecular oxygen appears to be related to the fibrosis. Previous studies, which have examined single time points utilizing the ferric ion chelator deferoxamine and iron-deficient diets, suggest that iron plays a central role in bleomycin-induced pulmonary fibrosis. Therefore, the present study was designed to determine the effects of deferoxamine on the development of bleomycin-induced pulmonary fibrosis. Deferoxamine pretreatment and daily injections resulted in a significant reduction in lung collagen content and lung lipid peroxidation 21 days after intratracheal bleomycin compared with bleomycin treatment alone. In addition deferoxamine treatment significantly inhibited lung DNA increases at 4, 7, and 14 days after bleomycin treatment compared with bleomycin treatment alone. These data indicate that deferoxamine treatment reduces the development of bleomycin-induced pulmonary fibrosis in the later phase. The mechanism might be by the prevention of iron-catalyzed, free-radical formation and modulation of some cellular functions.

Animals↗
PubMed1989

Intracellular degradation of bleomycin hydrolase in two Chinese hamster cell lines in relation to their peplomycin susceptibility.

The Chinese hamster lung (V79) cell was intrinsically 10-times more resistant to peplomycin, a bleomycin-related antitumor antibiotic, than the Chinese hamster ovary (CHO) cell. This may be associated with the 3-times higher levels of recovery of bleomycin hydrolase activity of the V79 cell. The degradation of bleomycin hydrolase molecules in both V79 and CHO cells was examined using a monoclonal antibody specific for the enzyme. Labelling experiments showed that the bleomycin hydrolase in CHO cells was less stable than the comparable enzyme in V79 cells, and that 48 kDa subunits comprising bleomycin hydrolase (a homohexameric enzyme) molecules were degraded into 31 kDa forms in both cell lines. The 105,000 X g pellet (microsomes) fraction obtained after subcellular fractionation of CHO cells contained both 48 kDa subunit and 31 kDa forms of bleomycin hydrolase, while the 105,000 X g supernatant cytosol fraction yielded only 48 kDa subunit forms of the enzyme. Moreover, bleomycin hydrolase activity of both V79 and CHO cells was almost entirely recovered from the cytosol fraction. These results suggest that degradation of the 48 kDa subunit form of bleomycin hydrolase in these two lines of cultured cells into the 31 kDa form occurs on the plasma membrane or the endoplasmic reticulum, with which the resulting large number of bleomycin hydrolase molecules or degraded forms of the enzyme that have lost enzymatic activity are associated.

Animals↗
PubMed1984

Alteration of bleomycin cytotoxicity by glutathione depletion or elevation.

In part, some of the cytotoxicity of bleomycin may be lessened or enhanced by modulation of glutathione (GSH) concentrations. Enhancement of bleomycin cytotoxicity was observed when GSH levels were low and protection was observed when GSH levels were elevated. Since H2O2 is one of the reactive species produced by bleomycin catalyzed oxygen activation, we studied the effects of H2O2 exposure after GSH depletion. H2O2, like bleomycin, shows enhanced cytotoxicity in GSH depleted cells. It has been proposed that bleomycin cytotoxicity requires reducing equivalents from non-protein bound thiols (such as GSH) to activate the bleomycin-metal complex, which in turn reacts with oxygen to generate free radicals and peroxides. Our data suggest that either GSH is not required to cycle reducing equivalents to the oxidized bleomycin-metal complex, or the low levels of depleted GSH attained (less than 5% of control) were still sufficient to effect reduction. Further, our data shows that GSH in fact provides a means of protection and detoxification from the cytotoxic effects of bleomycin. Our data suggest that caution should be exercised clinically when one uses drugs that modulate GSH because there may be either enhancement of normal tissue toxicity or decreases in tumor targeted cytotoxicity resulting from bleomycin treatment.

Animals↗
PubMed2005

The role of intratumour therapy with electroporation and bleomycin in the management of advanced squamous cell carcinoma of the head and neck.

OBJECTIVES: To determine the safety and efficacy of electroporation with bleomycin in patients with advanced squamous cell carcinoma of the head and neck. METHODS: Two open-label, multicenter, single-arm Phase II studies of intratumour electroporation therapy. Sixty-two patients with 86 squamous cell carcinoma tumours of the head and neck were enrolled. Twenty-five patients were treated with bleomycin alone. Fifty-four patients (17 initially treated with bleomycin alone) were treated with electroporation and bleomycin therapy. Local tumour response was measured. RESULTS: In the bleomycin alone group, one tumour showed a partial response and 36 tumours showed no response to treatment. In the bleomycin with electroporation groups, 17 tumours showed complete response, 22 tumours showed partial response and 30 failed to achieve more than a 50% reduction in tumour size (no response). Bleomycin with electroporation had a significantly (p<0.001) greater number of patients showing a partial or complete response to the therapy when compared to bleomycin alone. Thirteen adverse events were reported which included five episodes of local bleeding, six local infections, one local tongue swelling and one cardiac arrhythmia. CONCLUSIONS: Fifty-seven percent of squamous cell carcinomas of the head and neck demonstrated a partial or complete response to intratumour electroporation with bleomycin suggesting that further work investigating its use as a treatment for local control of these lesions should be pursued.

Aged↗
PubMed2005

Ultra-deformable liposomes containing bleomycin: in vitro stability and toxicity on human cutaneous keratinocyte cell lines.

Formulations of ultra-deformable liposomes containing bleomycin (Bleosome) have previously been described and proposed for topical treatment of skin cancer [Lau, K.G., Chopra, S., Maitani, Y., 2003. Entrapment of bleomycin in ultra-deformable liposomes. S. T. P. Pharm. Sci. 13, 237-239]. In this study, the stability of various Bleosome formulations was characterised and a purification process was established to isolate Bleosome for testing on cultures of either human cutaneous keratinocytes (NEB-1) immortalised by human papilloma virus (HPV)-type 16, or a spontaneously immortalised human squamous cell carcinoma (SCC) from a primary tumour. Bleosome facilitated entrapment of high concentrations of active bleomycin and samples purified by gel-filtration chromatography remained stable during 7 days of storage at 4 degrees C or at room temperature. Serially-diluted samples of this purified, high-strength product, 'high dose' were applied onto keratinocyte cell cultures to elucidate Bleosome LD50 profiles. In vitro data revealed that the LD50 of bleomycin encapsulated in Bleosome was approximately three-fold higher than free bleomycin solution for SCC cells, and nearly 30 times higher for NEB-1 cells. However, Bleosome containing 30 microg/ml of active bleomycin killed more than twice as many SCC cells than NEB-1 cells. At that concentration, the potency of liposomal bleomycin on causing cell death of SCC cells was found to be similar to that of free bleomycin solution. This effect was not seen on NEB-1 cells. It seems that SCC cells were particularly susceptible to Bleosome containing high levels of bleomycin. Results from these experiments promote the development of a novel product for the topical treatment of skin cancer.

Bleomycin↗