Juan Luis Vásquez1, Per Ibsen1, Henriette Lindberg1, Julie Gehl2. 1. Center for Experimental Drug and Gene Electrotransfer, Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark; Department of Pathology, Copenhagen University Hospital Hvidovre (PI), Hvidovre, Denmark. 2. Center for Experimental Drug and Gene Electrotransfer, Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark; Department of Pathology, Copenhagen University Hospital Hvidovre (PI), Hvidovre, Denmark. Electronic address: Julie.Gehl@regionh.dk.
Abstract
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 alone CONCLUSIONS: 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.
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 humanbladder 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 Ccytotoxicity 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 alone CONCLUSIONS: 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.
Authors: Emilie Louise Hansen; Esin Bengisu Sozer; Stefania Romeo; Stine Krog Frandsen; P Thomas Vernier; Julie Gehl Journal: PLoS One Date: 2015-04-08 Impact factor: 3.240
Authors: Olga Michel; Julita Kulbacka; Jolanta Saczko; Justyna Mączyńska; Piotr Błasiak; Joanna Rossowska; Adam Rzechonek Journal: Biomed Res Int Date: 2018-03-19 Impact factor: 3.411