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In vitro and in vivo experiments on electrochemotherapy for bladder cancer
Juan Luis Vásquez1, Per Ibsen1, Henriette Lindberg1
1Center 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.
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.
