Possible Involvement of Antitumor Immunity in the Eradication of Colon 26 Induced by Low-Voltage Electrochemotherapy with Bleomycin

Miyazaki, Shinichi; Gunji, Yoshio; Matsubara, Hisahiro; Shimada, Hideaki; Uesato, Masaya; Suzuki, Takao; Kouzu, Teruo; Ochiai, Takenori

doi:10.1007/s005950300006

Cited by 21 publications

(16 citation statements)

References 17 publications

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“…22 ECT alone exhibited a certain antimetastatic effect in the model of murine Lewis lung tumor (3LL), an effect that was attributed to the effects of ECT on the primary tumor from which 3LL cells escape to colonize the lungs. 23 Specific anticolon 26 immunity after low-voltage electrochemotherapy (25-150 V/cm) was reported by Miyazaki et al 17 The possible involvement of the immune response in the eradication of residual tumor cells after LEFCT and LEFCT-EC was tested with the aid of the immunosuppressive drug cyclosporin A, which affects mainly T-cell functions. 24 In a previous study, we reported that treatment with cyclosporin A of LEFCT-EC-cured mice abolished their anti-B16 melanoma resistance.…”

Section: Discussionmentioning

confidence: 94%

“…12,13 Alternatively, low-voltage electric fields (<100 V/cm) are given for longer durations. Several studies previously reported in the literature showed that low-electric fields and chemotherapy could inhibit tumor growth 14,15 and even cure [16][17][18] animals possessing small size (5-10 mm in diameter) tumors that are probably at a premetastatic stage. However, the possibility that these low-electric fields enhance the uptake of molecules into living cells has never been established in these studies.…”

Section: Discussionmentioning

confidence: 99%

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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: 94%

Section: Discussionmentioning

confidence: 99%

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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“…According to our previous report with regard to electrochemotherapy in colon 26 tumors, we established eight electric pulses (5 time/s) of 100 ms duration as the electroporation standard using a square electroporator CUY 21 (TR TECH Co Ltd, Tokyo, Japan). 18 The shape of the pulse was a square wave. The nominal applied field strengths (voltage to electrode spacing ratio) of the pulses were experimental variables that ranged from 25 to 100 V/ cm.…”

Section: Intratumoral Dna Injection and Electroporationmentioning

confidence: 99%

“…17 In recent study, we showed that low-voltage electroporation combined with chemotherapy has been effective against antitumor growth and also convenient in clinical use. 18 To our knowledge, there have been no reports that antiangiogenic genes have been delivered successfully using the low-voltage electroporation to inhibit tumor growth.…”

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confidence: 99%

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation

et al. 2004

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Antiangiogenic factors are potent endothelial cell growth inhibitors that have been shown to inhibit angiogenesis in vitro and tumor growth in mice. We have demonstrated the synergistic antitumor effect of antiangiogenic genes (mouse angiostatin: pBLASTmAngio; and mouse endostatin: p-BLAST42-mEndo XV) delivered to tumors by low-voltage electroporation in mouse colon 26 models. A synergistic antitumor effect was strongly suggested by in vivo tumor growth kinetics, as well as in survival studies with the mice. RT-PCR confirmed that the fragments of each gene were transferred by low-voltage electroporation in the tumor. Decreased microvessel density measurements in tumors also confirmed the efficacy of the synergistic antitumor effect of both genes. Significant growth inhibition was observed in mice treated with a 1:1 proportion of angiostatin and endostatin genes, and the order of the both genes transferred (first the endostatin gene, followed 1 week later by the angiostatin gene) had a profound inhibitory effect on tumor growth. These data suggest that in vivo delivery of antiangiogenic genes with low-voltage electroporation could be a possible therapeutic strategy for established solid tumors when both genes were applied in combination.

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“…This method, known as electrochemotherapy (ECT), was developed in order to increase the efficacy of antitumour drugs, and this effect is now drawing considerable attention [6][7][8][9] . To date, there have been a considerable number of experimental studies on ECT [10][11][12][13][14][15][16][17][18][19][20] , but most of these have involved bleomycin and the use of high-voltage (1.3 to 3.0 kV) electrical pulses. The use of high-voltage ECT in experimental and clinical studies poses the problem of thermal injury as a possible adverse reaction 10 .…”

Section: Introductionmentioning

confidence: 99%

Potentiation of the Antitumour Effect of Cisplatin by Administering Local Electrical Pulses to Metastatic Lesions of Hamster Oral Fibrosarcoma

Sugita

Miyamoto

Erkhembaatar

et al. 2012

J. Hard Tissue Biology.

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Electrochemotherapy (ECT) is currently receiving much attention as a method that can enhance the delivery of antitumour drugs into tumour cells by electroporation. In this study, we examined the effect of cisplatin on metastatic lesions of hamster oral fibrosarcoma by administering it in association with low-voltage electrical pulses. Oral fibrosarcoma was transplanted submucosally into the cheek pouches of 80 hamsters. After transplantation, when the diameter of the metastatic lesion in the left submandibular lymph node had reached 100 mm 3 , the hamsters were divided into four groups: D+E+ group (cisplatin treatment followed by electroporation; D+E-group (cisplatin treatment); D-E+ group (electroporation without cisplatin treatment); and D-E-group (no treatment). The antitumour effect of cisplatin was marked in the D+E+ group and the metastatic lesion disappeared in some of the animals. These results showed that when ECT consisting of cisplatin plus low-voltage electroporation was applied to metastatic tumour lesions, the antitumour effect of the drug on the lesions was enhanced. Therefore, ECT would seem to be a highly-safe new method that may be of use in the treatment of metastatic tumours.

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Possible Involvement of Antitumor Immunity in the Eradication of Colon 26 Induced by Low-Voltage Electrochemotherapy with Bleomycin

Abstract: Our results suggest that the generation of T-cell-dependent, tumor-specific protective immunity might be involved in the process of tumor nodule regression in low-voltage electrochemotherapy.

Cited by 21 publications

References 17 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

Synergistic antitumor effect of antiangiogenic factor genes on colon 26 produced by low-voltage electroporation

Potentiation of the Antitumour Effect of Cisplatin by Administering Local Electrical Pulses to Metastatic Lesions of Hamster Oral Fibrosarcoma

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