TY - JOUR

T1 - In Vitro and In Vivo Experiments on Electrochemotherapy for Bladder Cancer

AU - Vásquez, Juan Luis

AU - Ibsen, Per

AU - Lindberg, Henriette

AU - Gehl, Julie

N1 - Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

PY - 2015/3

Y1 - 2015/3

N2 - PURPOSE: Electrochemotherapy is widely performed to treat solid tumors but experience with bladder cancer is limited. We investigated mitomycin C and cisplatin administered with electrochemotherapy for bladder cancer in vitro and in vivo.MATERIALS AND METHODS: The human bladder cancer cell line SW780 was used. Cells were treated with electroporation, drug alone or electroporation plus increasing concentrations of drug (mitomycin C 0.001 to 2,000 μM or cisplatin 1.56 to 300 μM). Electrochemotherapy parameters were 8 pulses of 1.2 kV/cm for 99 microseconds at 1 Hz. We investigated survival and apoptosis, the latter evaluated by caspase activity. NMRI-Fox1nu nude mice were inoculated subcutaneously and randomized to 1) electrochemotherapy plus NaCl, 2) NaCl alone, 3) electrochemotherapy plus drug or 4) drug alone (mitomycin C 5 mM or cisplatin 250 μM). Tumors were measured 3 times per week. A similar experiment was done to assess necrosis by histology at days 2 and 6.RESULTS: In vitro mitomycin C cytotoxicity and caspase activity was unaffected by electrochemotherapy (p = 0.9057 and 0.53, respectively). However, electrochemotherapy with cisplatin caused 6.6-fold increased cytotoxicity and higher caspase activity (p <0.0001 and <0.001, respectively). In vivo electrochemotherapy plus mitomycin C resulted in tumor volume reduction (p <0.0005). The survival rate in mice that received electrochemotherapy plus mitomycin C and mitomycin C alone was greater than in controls (p = 0.0004). The tumor response rate was 100% for electrochemotherapy plus mitomycin C, 53% for mitomycin C alone, 14% for electrochemotherapy plus NaCl and 0% for NaCl alone. In vivo electrochemotherapy plus cisplatin was associated with slower tumor growth over other combinations as well as significantly higher survival (p = 0.0005 and 0.0003, respectively). The tumor response rate was 47% for electrochemotherapy plus cisplatin, 0% for cisplatin alone, 0% for electrochemotherapy plus NaCl and 8% for NaCl aloneCONCLUSIONS: In vivo electrochemotherapy with mitomycin C or cisplatin was more effective than chemotherapy alone in a bladder cancer tumor model, opening new perspectives in bladder cancer therapy.

AB - PURPOSE: Electrochemotherapy is widely performed to treat solid tumors but experience with bladder cancer is limited. We investigated mitomycin C and cisplatin administered with electrochemotherapy for bladder cancer in vitro and in vivo.MATERIALS AND METHODS: The human bladder cancer cell line SW780 was used. Cells were treated with electroporation, drug alone or electroporation plus increasing concentrations of drug (mitomycin C 0.001 to 2,000 μM or cisplatin 1.56 to 300 μM). Electrochemotherapy parameters were 8 pulses of 1.2 kV/cm for 99 microseconds at 1 Hz. We investigated survival and apoptosis, the latter evaluated by caspase activity. NMRI-Fox1nu nude mice were inoculated subcutaneously and randomized to 1) electrochemotherapy plus NaCl, 2) NaCl alone, 3) electrochemotherapy plus drug or 4) drug alone (mitomycin C 5 mM or cisplatin 250 μM). Tumors were measured 3 times per week. A similar experiment was done to assess necrosis by histology at days 2 and 6.RESULTS: In vitro mitomycin C cytotoxicity and caspase activity was unaffected by electrochemotherapy (p = 0.9057 and 0.53, respectively). However, electrochemotherapy with cisplatin caused 6.6-fold increased cytotoxicity and higher caspase activity (p <0.0001 and <0.001, respectively). In vivo electrochemotherapy plus mitomycin C resulted in tumor volume reduction (p <0.0005). The survival rate in mice that received electrochemotherapy plus mitomycin C and mitomycin C alone was greater than in controls (p = 0.0004). The tumor response rate was 100% for electrochemotherapy plus mitomycin C, 53% for mitomycin C alone, 14% for electrochemotherapy plus NaCl and 0% for NaCl alone. In vivo electrochemotherapy plus cisplatin was associated with slower tumor growth over other combinations as well as significantly higher survival (p = 0.0005 and 0.0003, respectively). The tumor response rate was 47% for electrochemotherapy plus cisplatin, 0% for cisplatin alone, 0% for electrochemotherapy plus NaCl and 8% for NaCl aloneCONCLUSIONS: In vivo electrochemotherapy with mitomycin C or cisplatin was more effective than chemotherapy alone in a bladder cancer tumor model, opening new perspectives in bladder cancer therapy.

U2 - 10.1016/j.juro.2014.09.039

DO - 10.1016/j.juro.2014.09.039

M3 - Journal article

C2 - 25245485

VL - 193

SP - 1009

EP - 1015

JO - Journal of Urology

JF - Journal of Urology

SN - 0022-5347

IS - 3

ER -