Histological Evaluation of the Effects of Electropermeabilization after Administration of Bleomycin on Bladder Cancer in the Rat

Kubota, Yōko; Nakada, Teruhiro; Yanai, Hiroshi; Itoh, Keiichi; Sasagawa, Isoji; Kawai, Kioko

doi:10.1159/000019743

Cited by 5 publications

(4 citation statements)

References 20 publications

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“…The cytotoxicity of bleomycin and cisplatin is potentiated by increased drug delivery into tumor cells by EP that results in up to 80% of complete responses in different tumor types [5]. Reversible permeabilization of cell membrane due to EP is the basic mechanism of the antitumor effectiveness of ECT [5][6][7][8][9][10]. Nowadays, EP is also increasingly used for the delivery of different nucleic acids (plasmid DNA, siRNA, miRNA, and shRNA) into cells in vitro and also into different tissues in vivo, including muscle, skin and tumors.…”

Section: Introductionmentioning

confidence: 99%

Intravital microscopy at the single vessel level brings new insights of vascular modification mechanisms induced by electropermeabilization

Bellard

Markelc

Pelofy

et al. 2012

Journal of Controlled Release

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Section: Introductionmentioning

confidence: 99%

Intravital microscopy at the single vessel level brings new insights of vascular modification mechanisms induced by electropermeabilization

Bellard

Markelc

Pelofy

et al. 2012

Journal of Controlled Release

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“…We reported previously that levels of bleomycin in bladder cancer cells and in normal bladder tissues could be augmented by EP [5]. Moreover, the cytotoxic effect of bleomycin on bladder cancer tissue was enhanced by EP [8]. Adriamycin is frequently used to treat bladder cancer; if EP were to enhance the cytotoxicity of both adriamycin and bleomycin, better clinical results would be expected with electrotreatment.…”

Section: Discussionmentioning

confidence: 99%

Effects of electropermeabilization after the administration of anticancer drugs on transitional cell carcinoma

2002

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Objective To assess in vitro and in vivo the potential utility of electropermeabilization (EP) as an anticancer drug delivery system for the treatment of transitional cell carcinoma (TCC). Materials and methods To analyse the effects of EP on the internalization of adriamycin and bleomycin by cells, aliquots of a suspension of YTS‐1 carcinoma cells (derived from a human TCC line) were mixed with a solution of adriamycin or bleomycin and then exposed immediately to an electric field (1000 V/cm, 1 Hz, 100‐µs square wave, eight pulses). After a 2‐h incubation the concentration of each drug in the cells was measured by high‐performance liquid chromatography (for adriamycin) and by bioassay (for bleomycin). The concentrations of drugs in the cells were compared with untreated cells. To analyse the effects of EP on cytotoxicity, the same treatments were applied to a suspension of cells plus adriamycin or bleomycin and then the cells incubated for 6 h with tritiated thymidine ([3H]‐TdR), monitoring the incorporation of [3H]‐TdR into the cells. Cells with no electrotreatment acted as controls. To assess the effects on tumours in vivo, YTS‐1 cells were transplanted subcutaneously into nude mice; when the tumours had reached 7 mm in diameter, EP was applied (using electrical pulses as before, 10 min after the direct injection of bleomycin into the tumour). Tumours were then measured regularly and compared with sham‐treated tumours, tumours treated with electric pulses alone, and tumours treated with bleomycin alone. Survival was also compared. Results There were no significant differences in the levels of adriamycin between cells with and with no EP, whereas there was a marked difference for bleomycin. Growth inhibition by adriamycin with and with no EP was similar, while the growth‐inhibitory effects of bleomycin were almost doubled. There was a reduction in tumour size only in the group treated with bleomycin plus electric pulses and two of five tumours disappeared completely. Survival in this group was also significantly better than in the other groups. Conclusion EP after administering bleomycin might be an effective treatment for TCC.

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“…[28][29][30] The antitumor effects of the compound are also highly increased in vivo by electric pulses delivered locally to the tumor site. [30][31][32][33] The plasma membrane is known to limit BLM uptake 29) and electropermeabilization 34) is an efficient means of circumventing this barrier, thus allowing the direct internalization of BLM molecules into the cytoplasm. 29) Although electrochemotherapy on human skin tumors has shown good results, [35][36][37] direct application of electric current to cancerous tissue deep inside the human body can cause unacceptable side effects.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Anti‐tumor Effect of Combination of Bleomycin and Shock Waves

Kato¹,

Ioritani²,

Suzuki

et al. 2000

Japanese Journal of Cancer Research

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We have previously reported marked enhancement of the cytocidal effect of bleomycin (BLM) on cancer cell suspensions in vitro by the combination with shock waves. In this study, we evaluated the synergistic effects on cancer cell proliferation and apoptosis in solid tumors. A spherical piezoceramic element was used as the shock wave source, with a pressure peak of 40 MPa. A human colon cancer cell line, SW480 was implanted onto the back of nude mice. Two thousand shock waves were administered to the tumor immediately following an intravenous injection of BLM at a dose of one-tenth of the LD 50 . The tumor was extirpated at 3, 6, 12, 24, 72 h and 1 week following shock exposure. Cell proliferation and apoptosis were detected by Ki-67 using antibody MIB-1 and by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick-end labeling (TUNEL) method. The lowest percentage (35.7%) of Ki-67-positive cells appeared 24 h following the treatment. The maximum apoptotic index was detected within 6 h following the treatment. Moreover, numerous large cells with enlarged nuclei were detected histologically. These results suggest that shock waves may enhance chemotherapeutic effects by increasing apoptosis and decreasing cell proliferation in the tumor tissue. Key words: Shock wave -Bleomycin -SW480 -TUNEL -Mitotic deathA focused underwater shock wave can exert a high acoustic intensity in deep portions of the body without causing damage to adjacent tissues because of its high permeability through the tissues.1-3) The apparent feasibility of exposing a spatially limited region of the body to a potentially destructive form of mechanical energy has led to the idea of applying shock waves in tumor therapy. 4)Previous results have not necessarily been promising, in cases of shock wave therapy alone, [4][5][6][7][8] or in combination with various anti-cancer agents, for example, cisplatinum, 9-13) mitomycin C (MMC), 12, 13) actinomycin D, 12) methotrexete 13) and adriamycin (ADR). 11, 13, 14) However, we have reported that the combination of focused shock waves and bleomycin (BLM) reduced the IC 50 of BLM to 1/10 000-1/100 000 in various human cancer cell lines, when compared to BLM alone. 15,16) This effect was detected even with a weak shock wave energy, which alone had almost no cytotoxic effect, and the degree of cytotoxicity enhancement was proportional to the amount of shock wave energy applied. 15,16) Immediately after shock wave exposure, cancer cells were examined under scanning and transmission electron microscopes. Numerous dimples (diameters distributed from 0.05 to 0.5 µm) became apparent on the cell surface.15, 16) These dimples were concluded to be pores penetrating through the cell membrane, because reagents such as propidium iodide and 5(6)-carboxyfluorescein could enter the cytoplasm of the cells treated with shock waves. The mechanism of this enhancement of chemotherapeutic effect was considered to be the entry of BLM molecules into cells through pores opened by the shock waves, but the details rem...

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Histological Evaluation of the Effects of Electropermeabilization after Administration of Bleomycin on Bladder Cancer in the Rat

Cited by 5 publications

References 20 publications

Intravital microscopy at the single vessel level brings new insights of vascular modification mechanisms induced by electropermeabilization

Intravital microscopy at the single vessel level brings new insights of vascular modification mechanisms induced by electropermeabilization

Effects of electropermeabilization after the administration of anticancer drugs on transitional cell carcinoma

Mechanism of Anti‐tumor Effect of Combination of Bleomycin and Shock Waves

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