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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

Percentage of necrosis in tumours 24 h after different treatments. (A) Increased percentage of necrotic tumour area was observed 24 h after treatment with combination of TNF-α and electrochemotherapy. (B–E) Haematoxylin and eosin staining of tumour sections in tumours 24 h after different treatments at 4× magnification. (B) – CDDP; (C) – electrochemotherapy; (D) – TNF-α and CDDP; (E) – TNF-α and electrochemotherapy. Scale bar 1 mm. Bars represent mean ± SEM. * p<0.05 vs. CDDP, ECT, and TNF + CDDP.
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f5-rado-49-01-32: Percentage of necrosis in tumours 24 h after different treatments. (A) Increased percentage of necrotic tumour area was observed 24 h after treatment with combination of TNF-α and electrochemotherapy. (B–E) Haematoxylin and eosin staining of tumour sections in tumours 24 h after different treatments at 4× magnification. (B) – CDDP; (C) – electrochemotherapy; (D) – TNF-α and CDDP; (E) – TNF-α and electrochemotherapy. Scale bar 1 mm. Bars represent mean ± SEM. * p<0.05 vs. CDDP, ECT, and TNF + CDDP.

Mentions: Necrosis of tumour tissue was evaluated histologically in all samples 24 h after different treatments (Figure 5). Cisplatin treatment did not result in significantly increased necrosis compared with control untreated tumours.19 The degree of necrosis was significantly increased in tumours treated with adjuvant TNF-α and electrochemotherapy in comparison to tumours treated with CDDP, electrochemotherapy or combination of TNF-α and CDDP.


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)

Percentage of necrosis in tumours 24 h after different treatments. (A) Increased percentage of necrotic tumour area was observed 24 h after treatment with combination of TNF-α and electrochemotherapy. (B–E) Haematoxylin and eosin staining of tumour sections in tumours 24 h after different treatments at 4× magnification. (B) – CDDP; (C) – electrochemotherapy; (D) – TNF-α and CDDP; (E) – TNF-α and electrochemotherapy. Scale bar 1 mm. Bars represent mean ± SEM. * 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

f5-rado-49-01-32: Percentage of necrosis in tumours 24 h after different treatments. (A) Increased percentage of necrotic tumour area was observed 24 h after treatment with combination of TNF-α and electrochemotherapy. (B–E) Haematoxylin and eosin staining of tumour sections in tumours 24 h after different treatments at 4× magnification. (B) – CDDP; (C) – electrochemotherapy; (D) – TNF-α and CDDP; (E) – TNF-α and electrochemotherapy. Scale bar 1 mm. Bars represent mean ± SEM. * p<0.05 vs. CDDP, ECT, and TNF + CDDP.
Mentions: Necrosis of tumour tissue was evaluated histologically in all samples 24 h after different treatments (Figure 5). Cisplatin treatment did not result in significantly increased necrosis compared with control untreated tumours.19 The degree of necrosis was significantly increased in tumours treated with adjuvant TNF-α and electrochemotherapy in comparison to tumours treated with CDDP, electrochemotherapy or combination of TNF-α and CDDP.

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