title: Electrochemotherapy on liver tumours in rabbits.
abstract: Electrochemotherapy (ECT) is a new therapeutic approach combining the effects of a low-permeant cytotoxic drug, bleomycin (BLM), administered i.v. and cell-permeabilizing electric pulses (EPs) locally delivered to tumours. The transient permeabilization of the cell membrane by the EPs allows free access of BLM to its intracellular targets, largely enhancing BLM's cytotoxic effects. ECT efficacy has been proved so far on transplanted subcutaneous murine tumours and on subcutaneous metastases in humans. Here, we present the first study of the effects of ECT on tumours transplanted to livers in rabbits. We used a recently developed EP applicator consisting of an array of parallel and equidistant needles to be inserted in tissues. Effects of EPs alone or of ECT were assessed by histological analysis, tumour growth rates and survival of the treated animals. A transient blood hypoperfusion was seen in the electropulsed areas, with or without BLM, related to EP-dependent vasoconstriction but this had no major effects on cell survival. Long-term effects depended on the presence of BLM at the time of EP delivery. Almost complete tumour necrosis was observed after ECT, resulting from both BLM direct cytotoxic effects on electropermeabilized tumour cells and indirect effects on the tumour vessels. A large reduction in tumour growth rate and significantly longer survival times were scored in comparison with control rabbits. Moreover, ECT of liver tumours was well tolerated and devoid of systemic side-effects. When ECT was associated with a local interleukin 2-based immunotherapy, increased local anti-tumour effectiveness as well as a large decrease in the number of metastases were observed. Thus, ECT could become a novel treatment modality for liver tumours and other solid internal malignancies.
authors.affiliation: UMR 1772 CNRS, Institut Gustave-Roussy, Villejuif, France.
authors.forename: L H
authors.initials: LH
authors.lastname: Ramirez
authors.forename: S
authors.initials: S
authors.lastname: Orlowski
authors.forename: D
authors.initials: D
authors.lastname: An
authors.forename: G
authors.initials: G
authors.lastname: Bindoula
authors.forename: R
authors.initials: R
authors.lastname: Dzodic
authors.forename: P
authors.initials: P
authors.lastname: Ardouin
authors.forename: C
authors.initials: C
authors.lastname: Bognel
authors.forename: J
authors.initials: J
authors.lastname: Belehradek
authors.forename: J N
authors.initials: JN
authors.lastname: Munck
authors.forename: L M
authors.initials: LM
authors.lastname: Mir
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001761:Bleomycin / Q000008:administration & dosage*; D016466:CHO Cells / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D003131:Combined Modality Therapy; D006224:Cricetinae; D004599:Electric Stimulation Therapy; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics / Q000627:therapeutic use; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000628:therapy*; D011817:Rabbits; D012039:Regional Blood Flow / Q000502:physiology; D014162:Transfection
chemical_list: D000964:Antimetabolites, Antineoplastic; D007376:Interleukin-2; D001761:Bleomycin