Abstract
Electrochemotherapy is an efficient local treatment of tumors that combines administration of a chemotherapeutic drug with the subsequent application of electric pulses to the tumor. Although no difference in clinical response of the treated tumors to the electrochemotherapy when using 1 Hz or 5 kHz repetition frequency was observed, it is mandatory to be aware of possible differences in the effectiveness of electrochemotherapy when using suboptimal doses of the drugs. Therefore, this study compares the antitumor effectiveness of electrochemotherapy using electric pulse trains with repetition frequencies of 1 Hz and 5 kHz at suboptimal drug doses of bleomycin or cisplatin. Electrochemotherapy of fibrosarcoma SA-1 subcutaneous tumors transplanted in A/J mice resulted in good antitumor effectiveness, but antitumor effectiveness was significantly better at 1 Hz repetition frequency than at 5 kHz. The platinum content was higher in tumors treated with a 1 Hz repetition frequency. The application of electric pulses to the tumors at a 5 kHz repetition frequency induced an immediate reduction in tumor perfusion, comparable to the reduction at 1 Hz but with faster reperfusion. The greater effectiveness of electrochemotherapy using electric pulse trains of 1 Hz compared to 5 kHz is due to the greater electroporative effect and longer time in which electroporated tumors are exposed to the two chemotherapeutic drugs. These differences are observed at suboptimal drug doses, whereas at optimal drug doses of bleomycin or cisplatin the antitumor effectiveness is the same, as demonstrated in clinical trials.
Similar content being viewed by others
References
Belehradek JJ, Orlowski S, Ramirez LH et al (1994) Electropermeabilization of cells and tissues assessed by the quantitative and qualitative electroloading of bleomycin. Biochim Biophys Acta 1190:155–163
Byrne CM, Thompson JF (2006) Role of electrochemotherapy in the treatment of metastatic melanoma and other metastatic and primary skin tumors. Expert Rev Anticancer Ther 6:671–678
Campana LG, Mocellin S, Basso M et al (2009) Bleomycin-based electrochemotherapy: clinical outcome from a single institution’s experience with 52 patients. Ann Surg Oncol 16:191–199
Cemazar M, Milacic R, Miklavcic D et al (1998) Intratumoral cisplatin administration in electrochemotherapy: antitumor effectiveness, sequence dependence and platinum content. Anticancer Drugs 9:525–530
Cemazar M, Miklavcic D, Scancar J et al (1999) Increased platinum accumulation in SA-1 tumour cells after in vivo electrochemotherapy with cisplatin. Br J Cancer 79:1386–1391
Engstrom PE, Persson BR, Salford LG (1999) Studies of in vivo electropermeabilization by gamma camera measurements of (99 m)Tc-DTPA. Biochim Biophys Acta 1473:321–328
Gehl J (2003) Electroporation: theory and methods, perspectives for drug delivery, gene therapy and research. Acta Physiol Scand 177:437–447
Gehl J, Skovsgaard T, Mir LM (2002) Vascular reactions to in vivo electroporation: characterization and consequences for drug and gene delivery. Biochim Biophys Acta 1569:51–58
Gilbert RA, Jaroszeski MJ, Heller R (1997) Novel electrode design for electrochemotherapy. Biochim Biophys Acta 1334:9–14
Larkin JO, Collins CG, Aarons S et al (2007) Electrochemotherapy. Aspects of preclinical development and early clinical experience. Ann Surg 245:469–479
Macek Lebar A, Sersa G, Kranjc S et al (2002) Optimization of pulse parameters in vitro for in vivo electrochemotherapy. Anticancer Res 22:1731–1736
Marty M, Sersa G, Garbay JR et al (2006) Electrochemotherapy—an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: results of ESOPE (European Standard Operating Procedures of Electrochemotherapy) study. EJC Suppl 4:3–13
Miklavcic D, Beravs K, Semrov D et al (1998) The importance of electric field distribution for effective in vivo electroporation of tissues. Biophys J 74:2152–2158
Miklavcic D, Pucihar G, Pavlovec M et al (2005) The effect of high frequency electric pulses on muscle contractions and antitumor efficiency in vivo for a potential use in clinical electrochemotherapy. Bioelectrochemistry 65:121–128
Miklavcic D, Corovic S, Pucihar G et al (2006) Importance of tumour coverage by sufficiently high local electric field for effective electrochemotherapy. EJC Suppl 4:45–51
Milacic R, Cemazar M, Sersa G (1997) Determination of platinum in tumor tissue after cisplatin therapy by electrothermal atomic absorption spectrometry. J Pharm Biomed Anal 16:343–348
Mir LM (2006) Bases and rationale of the electrochemotherapy. EJC Suppl 4:38–44
Mir LM, Orlowski S, Belehradek JJ et al (1991) Electrochemotherapy potentiation of antitumour effect of bleomycin by local electric pulses. Eur J Cancer 27:68–72
Neumann E, Schaefer-Riddler M, Wang Y et al (1982) Gene transfer into mouse myeloma cells by electroporation in high electric fields. EMBO J 1:841–845
Pucihar G, Mir LM, Miklavcic D (2002) The effect of pulse repetition frequency on the uptake into electropermeabilized cells in vitro with possible applications in electrochemotherapy. Bioelectrochemistry 57:167–172
Quaglino P, Mortera C, Osella-Abate S et al (2008) Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases. Ann Surg Oncol 15:2215–2222
Ramirez LH, Orlowski S, An D et al (1998) Electrochemotherapy on liver tumours in rabbits. Br J Cancer 77:2104–2111
Satkauskas S, Batiuskaite D, Salomskaite-Davalgiene S et al (2005) Effectiveness of tumor electrochemotherapy as a function of electric pulse strength and duration. Bioelectrochemistry 65:105–111
Sersa G (2006) The state-of-the-art of electrochemotherapy before the ESOPE study; advantages and clinical uses. EJC Suppl 4:52–59
Sersa G, Cemazar M, Miklavcic D (1995) Antitumor effectiveness of electrochemotherapy with cis-diamminedichloroplatinum(II) in mice. Cancer Res 55:3450–3455
Sersa G, Cemazar M, Miklavcic D et al (1999a) Tumor blood flow modifying effect of electrochemotherapy with bleomycin. Anticancer Res 19:4017–4022
Sersa G, Cemazar M, Parkins CS et al (1999b) Tumor blood flow changes induced by application of electric pulses. Eur J Cancer 35:672–677
Sersa G, Jarm T, Kotnik T et al (2008a) Vascular disrupting action of electroporation and electrochemotherapy with bleomycin in murine sarcoma. Br J Cancer 98:388–398
Sersa G, Miklavcic D, Cemazar M et al (2008b) Electrochemotherapy in treatment of tumours. Eur J Surg Oncol 34:232–240
Snoj M, Cemazar M, Slekovec Kolar B et al (2007) Effective treatment of multiple unresectable skin melanoma metastases by electrochemotherapy. Croat Med J 48:91–95
Teissie J, Escoffre JM, Pierre Rols M et al (2008) Time dependent field effects on cell membranes. A review for critical selection of pulse duration for therapeutic applications. Radiol Oncol 42:196–206
Vernhes MC, Cabanes PA, Teissie J (1999) Chinese hamster ovary cells sensitive to localized electric stress. Bioelectrochem Bioenerg 48:17–25
Zupanic A, Ribaric S, Miklavcic D (2007) Increasing the repetition frequency of electric pulse delivery reduces unpleasant sensations that occur in electrochemotherapy. Neoplasma 54:246–250
Acknowledgments
The authors acknowledge the financial support from the state budget of the Slovenian Research Agency (programme P3-0003, project J3-7044) and the EU-funded project ESOPE (QLK-2002-02003). We thank Prof. Damijan Miklavcic and Prof. Eberhard Neumann for their useful comments and criticism of the manuscript during its preparation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sersa, G., Kranjc, S., Scancar, J. et al. Electrochemotherapy of Mouse Sarcoma Tumors Using Electric Pulse Trains with Repetition Frequencies of 1 Hz and 5 kHz. J Membrane Biol 236, 155–162 (2010). https://doi.org/10.1007/s00232-010-9268-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00232-010-9268-z