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

Abstract

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...

Effective treatment of mouse metastatic prostate cancer by low electric field enhanced chemotherapy

“…In previous studies we observed that animals treated by LEFCT and LEFCT-EC developed an anti-tumor immune response in experimental models of melanoma [7] and colon carcinoma [8,9]. In the present study we examined the immune status of the treated animals and their anti-TRAMP immune reactivity.…”

“…cancer treatment method was designed as LEFCT-EC and was successfully applied in curing mice bearing B-16 melanoma and CT-26 colon carcinoma [7][8][9].…”

“…Our previous results clearly demonstrated the ability of LEFCT-EC to initiate immune responses against B16 melanoma, and CT-26 colon carcinoma and completely cure mice from both the primary tumor and metastases. Following the cure, these animals became resistant to the tumor challenge and their splenocytes delayed tumor growth in a Winn assay [7][8][9].…”

“…Low Electric Field Cancer Treatment-Enhanced Chemotherapy was tested previously by us in-vivo in several experimental models of murine tumors with different chemotherapeutic drugs and was found to be effective against DA-3 breast carcinoma, SQ-2 squamous cell carcinoma (unpublished results), B-16 melanoma [7], and CT-26 colon carcinoma [8,9].…”

Herpes Simplex Virus Type 1 Preferentially Targets Human Colon Carcinoma: Role of Extracellular Matrix

“…Local tumor growth was determined by measuring three mutually orthogonal tumor diameters with a caliper. The volume (V) of the tumors was calculated using the formula V ϭ D1 ϫ D2 ϫ D3 ϫ /6, where D1, D2, and D3 represent the three mutually orthogonal tumor diameters (35).…”