Systemic Antitumor Effects of Electrochemotherapy Combined with Histoincompatible Cells Secreting Interleukin-2

Mir, Lluis M.; Roth, Claude; Orlowski, Stéphane; Quintin-Colonna, Françoise; Fradelizi, D; Belehradek, Jean; Kourilsky, Philippe

doi:10.1097/00002371-199501000-00004

Cited by 88 publications

(69 citation statements)

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“…Treatment of a murine sarcoma by a combination of high-voltage (1,350 V/cm) electrochemotherapy (ECT) with IL-2-secreting histoincompatible cells resulted in a long-term tumor resistance in cured mice. 21 In a similar study, it was observed that rabbits bearing VX2 carcinoma, implanted in the liver, demonstrated a significant decrease in the number of visceral metastases and lung micro metastases after treatment with electrochemotherapy (850 V/cm) and IL-2-secreting cells. However, ECT alone failed to protect the animals from metastases development.…”

Section: Discussionmentioning

confidence: 84%

Involvement of the immune response in the cure of metastatic murine CT‐26 colon carcinoma by low electric field‐enhanced chemotherapy

Plotnikov

Tichler

Korenstein

et al. 2005

Intl Journal of Cancer

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Low electric field cancer treatment-enhanced chemotherapy (LEFCT-EC) is a new treatment modality that combines chemotherapeutic agents and low electric field stimulation. LEFCT-EC was found to destroy malignant mouse tumors and cause massive death of tumor cells. This may enable the immune system cells to efficiently recognize and eliminate tumor cells at the primary tumor site and at metastatic foci. Mice with 15 mm diameter intracutaneous colon carcinomas (CT-26) were injected with BCNU (35 mg/kg), and 2 min later the tumors were exposed to low electric fields (intensity 40 V/cm, pulse duration 180 s, frequency 500 Hz) for 12 min (LEFCT-EC). We found that treatment with LEFCT-EC achieved complete cure of 93% of the animals. In comparison, electric fields alone (13% cure), chemotherapy alone (0%), surgery (15%) or a combination of surgery and bischloroethyl-nitrosurea, carmustine (BCNU; 84%) treatments resulted in lower cure rates. After treatment and cure with LEFCT-EC, 50% of the cured mice developed resistance to a tumor challenge (surgery 1 BCNU only 15%). Furthermore, splenocytes from cured animals protected naive animals from a tumorigenic dose of tumor cells. Separation of spleen cells into lymphocyte subpopulations indicated a major role for CD4 and CD8 T cells in this protection. FACS analysis revealed restoration of normal splenocyte subpopulation proportions impaired by cytotoxic chemotherapy. Our results suggest that LEFCT-EC can directly destroy primary tumors and facilitate the destruction of metastatic disease by enforcement of antitumor immune responses. ' 2005 Wiley-Liss, Inc.Key words: electrostimulation; metastases; colon cancer; chemotherapy; antitumor immune response About 11% of all new cancer cases in the USA in 2004 are colorectal cancer (CRC), making it the third most common malignancy in both sexes in developed countries. 1 Surgical resection remains the primary treatment modality for localized disease with a relapse-free rate of approx. 50%. 2 Although 15-20% of initially diagnosed patients with CRC have distant metastases, most patients develop metastasis at some point during the disease cycle, and the 5-year survival rate with metastasis has been reported as <5%. 3 We report here a recently developed method for the treatment of metastatic malignancies, which takes advantage of the specific synergistic effects of low electric fields and chemotherapy. This approach is based on the phenomenon of electrically enhanced endocytosis (electroendocytosis) of macromolecules (molecular weight of 1-2,000 kD) after exposure of cells to low unipolarpulsed electric fields (2.5-80V/cm). [4][5][6] It should be stressed that this process differs fundamentally from that of electroporation. Electroporation, which was initially discovered more than 2 decades ago, is characterized by induction of very short-lived (in the microsecond time domain) permeability changes in the plasma membrane by high electric fields (250-5,000 V/cm). The typical exposure to fields inducing electroporation consists of a sing...

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Section: Discussionmentioning

confidence: 84%

Involvement of the immune response in the cure of metastatic murine CT‐26 colon carcinoma by low electric field‐enhanced chemotherapy

Plotnikov

Tichler

Korenstein

et al. 2005

Intl Journal of Cancer

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“…Therefore, in preclinical trials, ECT has been combined with immunotherapy. Systemic effect demonstrated by responses of distant tumours was obtained by combining local ECT with the local administration of histoincompatible interleukin 2 (IL-2)-secreting cells in a murine model (Mir et al, 1995). In addition, local anti-tumour effect was enhanced by the local administration of IL-2 (Mir et al, 1992).…”

Section: Discussionmentioning

confidence: 99%

Effective treatment of cutaneous and subcutaneous malignant tumours by electrochemotherapy

Mir

Glass²,

Serša³

et al. 1998

Br J Cancer

414

233

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Effective treatment of cutaneous and subcutaneous malignant tumours by electrochemotherapy LM Mir', LF Glass23, G Sersa4, J Teissi65, C Domenge6, D Miklavdid7, MJ Jaroszeski38, S Orlowski9, DS Reintgen38, Z Rudolf4, M Belehradek6, R Gilbertl0, M-P Rols5, J Belehradek Jr', JM Bachaud", R DeConti23, B Stabuc4, M Cemazar4, P Coninx'2 and R Heller38 The application of electric pulses to the patients was safe and well tolerated. An instantaneous contraction of the underlying muscles was noticed. Minimal adverse side-effects were observed. ECT was shown to be an effective local treatment. ECT was effective regardless of the histological type of the tumour. Therefore, ECT offers an approach to the treatment of cutaneous and subcutaneous tumours in patients with minimal adverse side-effects and with a high response rate.

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“…However, several other mechanisms have been demonstrated to be involved in tumour response to electrochemotherapy, e.g. involvement of immune system and changes in tumour blood flow (Mir et al, 1995;Sersa et al, 1997a,b). The vascular targeting action of electrochemotherapy was only speculated.…”

mentioning

confidence: 99%

“…The vascular targeting action of electrochemotherapy was only speculated. The immune status of experimental mice was shown to be positively correlated with the incidence of complete responses of tumours treated with electrochemotherapy (Sersa et al, 1997a) and potentiation of tumour response to electrochemotherapy was achieved by adjuvant immunotherapy, either with IL-2 or TNF-α (Mir et al, 1995;Sersa et al, 1997b). We have previously shown that the application of electric pulses alone result in substantial, but transient, reduction of tumour perfusion (Sersa et al, 1999a) and furthermore that electrochemotherapy with bleomycin causes rapid cessation of tumour perfusion (Sersa et al, 1999b).…”

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confidence: 99%

Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy

et al. 2001

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Recent studies have indicated that the antitumour effectiveness of electrochemotherapy, a combination of chemotherapeutic drugs with application of high voltage electric pulses applied to the tumour nodule (electroporation), result in a significant reduction in tumour blood flow and may therefore be mediated by an anti-vascular mechanism. The aim of this study was to evaluate the cytotoxicity of electroporation with bleomycin or cisplatin on cultured human microvascular endothelial cells (HMEC-1). The sensitivity of HMEC-1 cells to a 5 min treatment by electroporation with bleomycin or cisplatin (8 electric pulses, pulse duration 100 μs, frequency 1 Hz, electric field intensity 1400 V cm –1 ) was compared to the sensitivity of cells treated continuously for 3 days with drugs alone. HMEC-1 cells were moderately sensitive to continuous exposure to cisplatin, but showed greater sensitivity to bleomycin. Combination of a 5 min drug exposure with electric pulses increased cytotoxicity of cisplatin by ∼10-fold for cisplatin and ∼5000-fold for bleomycin. The electroporation of HMEC-1 cells with bleomycin for a 5 min exposure was ∼250-fold better than a continuous exposure to the drug alone. The results of this study indicate that the anti-tumour action of electrochemotherapy is likely to be due, in part, to the highly sensitive response of vascular endothelial cells. Further studies are necessary to identify the determinants of endothelial response and its relationship to the anti-vascular action of electrochemotherapy in vivo. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Systemic Antitumor Effects of Electrochemotherapy Combined with Histoincompatible Cells Secreting Interleukin-2

Cited by 88 publications

References 0 publications

Involvement of the immune response in the cure of metastatic murine CT‐26 colon carcinoma by low electric field‐enhanced chemotherapy

Involvement of the immune response in the cure of metastatic murine CT‐26 colon carcinoma by low electric field‐enhanced chemotherapy

Effective treatment of cutaneous and subcutaneous malignant tumours by electrochemotherapy

Electroporation of human microvascular endothelial cells: evidence for an anti-vascular mechanism of electrochemotherapy

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