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Adjuvant TNF-α therapy to electrochemotherapy with intravenous cisplatin in murine sarcoma exerts synergistic antitumor effectiveness.

Cemazar M, Todorovic V, Scancar J, Lampreht U, Stimac M, Kamensek U, Kranjc S, Coer A, Sersa G - Radiol Oncol (2015)

Bottom Line: 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.Adjuvant intratumoural TNF-α therapy synergistically contributes to electrochemotherapy with intravenous cisplatin administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia ; Faculty of Health Sciences, University of Primorska, Izola, Slovenia.

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.

Materials and 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Platinum content in tumours 24 h after different treatments. Increased platinum uptake was observed after electrochemotherapy and exposure to TNF-α. Bars represent mean ± SEM. * p<0.05 vs. CDDP, # p<0.05 vs. CDDP, ECT and TNF+CDDP.
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f3-rado-49-01-32: Platinum content in tumours 24 h after different treatments. Increased platinum uptake was observed after electrochemotherapy and exposure to TNF-α. Bars represent mean ± SEM. * p<0.05 vs. CDDP, # p<0.05 vs. CDDP, ECT and TNF+CDDP.

Mentions: To determine whether TNF-α treatment affects CDDP uptake in tumours, platinum content in whole tumours was determined 24 h post treatment. Significant differences in platinum concentration in tumours were observed after different treatments (Figure 3). Tumour treatment with electrochemotherapy alone or with TNF-α resulted in significantly higher platinum concentration in the whole tumours (p<0.05). Electrochemotherapy increased platinum content in the tumours, as expected, approximately by factor of 2.19 Furthermore, in the TNF-α with the electrochemotherapy treatment group, platinum content in tumours was further significantly increased compared to tumours treated with either electrochemotherapy or TNF-α in combination with CDDP without EP. Overall 2.2-fold increase in tumour platinum content was observed. The data do not prove the internalisation of the platinum in the cells of tumours, but rather indicate on the overall platinum content in the tumours.


Adjuvant TNF-α therapy to electrochemotherapy with intravenous cisplatin in murine sarcoma exerts synergistic antitumor effectiveness.

Cemazar M, Todorovic V, Scancar J, Lampreht U, Stimac M, Kamensek U, Kranjc S, Coer A, Sersa G - Radiol Oncol (2015)

Platinum content in tumours 24 h after different treatments. Increased platinum uptake was observed after electrochemotherapy and exposure to TNF-α. Bars represent mean ± SEM. * p<0.05 vs. CDDP, # p<0.05 vs. CDDP, ECT and TNF+CDDP.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4362604&req=5

f3-rado-49-01-32: Platinum content in tumours 24 h after different treatments. Increased platinum uptake was observed after electrochemotherapy and exposure to TNF-α. Bars represent mean ± SEM. * p<0.05 vs. CDDP, # p<0.05 vs. CDDP, ECT and TNF+CDDP.
Mentions: To determine whether TNF-α treatment affects CDDP uptake in tumours, platinum content in whole tumours was determined 24 h post treatment. Significant differences in platinum concentration in tumours were observed after different treatments (Figure 3). Tumour treatment with electrochemotherapy alone or with TNF-α resulted in significantly higher platinum concentration in the whole tumours (p<0.05). Electrochemotherapy increased platinum content in the tumours, as expected, approximately by factor of 2.19 Furthermore, in the TNF-α with the electrochemotherapy treatment group, platinum content in tumours was further significantly increased compared to tumours treated with either electrochemotherapy or TNF-α in combination with CDDP without EP. Overall 2.2-fold increase in tumour platinum content was observed. The data do not prove the internalisation of the platinum in the cells of tumours, but rather indicate on the overall platinum content in the tumours.

Bottom Line: 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.Adjuvant intratumoural TNF-α therapy synergistically contributes to electrochemotherapy with intravenous cisplatin administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Experimental Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia ; Faculty of Health Sciences, University of Primorska, Izola, Slovenia.

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.

Materials and 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus