title: Adjuvant TNF-α therapy to electrochemotherapy with intravenous cisplatin in murine sarcoma exerts synergistic antitumor effectiveness.
abstract: BACKGROUND
  Electrochemotherapy is a tumour ablation modality, based on electroporation of the cell membrane, allowing non-permeant anticancer drugs to enter the cell, thus augmenting their cytotoxicity by orders of magnitude. In preclinical studies, bleomycin and cisplatin proved to be the most suitable for clinical use. Intravenous administration of cisplatin for electrochemotherapy is still not widely accepted in the clinics, presumably due to its lower antitumor effectiveness, but adjuvant therapy by immunomodulatory or vascular-targeting agents could provide a way for its potentiation. Hence, the aim of the present study was to explore the possibility of adjuvant tumour necrosis factor α (TNF-α) therapy to potentiate antitumor effectiveness of electrochemotherapy with intravenous cisplatin administration in murine sarcoma.
  
  
  METHODS
  In vivo study was designed to evaluate the effect of TNF-α applied before or after the electrochemotherapy and to evaluate the effect of adjuvant TNF-α on electrochemotherapy with different cisplatin doses.
  
  
  RESULTS
  A synergistic interaction between TNF-α and electrochemotherapy was observed. Administration of TNF-α before the electrochemotherapy resulted in longer tumour growth delay and increased tumour curability, and was significantly more effective than TNF-α administration after the electrochemotherapy. Tumour analysis revealed increased platinum content in tumours, TNF-α induced blood vessel damage and increased tumour necrosis after combination of TNF-α and electrochemotherapy, indicating an anti-vascular action of TNF-α. In addition, immunomodulatory effect might have contributed to curability rate of the tumours.
  
  
  CONCLUSIONS
  Adjuvant intratumoural TNF-α therapy synergistically contributes to electrochemotherapy with intravenous cisplatin administration. Due to its potentiation at all doses of cisplatin, the combined treatment is predicted to be effective also in tumours, where the drug concentration is suboptimal or in bigger tumours, where electrochemotherapy with intravenous cisplatin is not expected to be sufficiently effective.
authors: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia ; Faculty of Health Sciences, University of Primorska, Izola, Slovenia.
authors: Maja
authors: M
authors: Cemazar
authors: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors: Vesna
authors: V
authors: Todorovic
authors: Jozef Stefan Institute, Ljubljana, Slovenia.
authors: Janez
authors: J
authors: Scancar
authors: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors: Ursa
authors: U
authors: Lampreht
authors: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors: Monika
authors: M
authors: Stimac
authors: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors: Urska
authors: U
authors: Kamensek
authors: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors: Simona
authors: S
authors: Kranjc
authors: Faculty of Health Sciences, University of Primorska, Izola, Slovenia.
authors: Andrej
authors: A
authors: Coer
authors: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors: Gregor
authors: G
authors: Sersa
keywords: TNF-α; adjuvant immunotherapy; cisplatin; electrochemotherapy