Electrochemotherapy: An Alternative Strategy for Improving Therapy in Drug-Resistant SOLID Tumors

Abstract

Electrochemotherapy (ECT) is one of the innovative strategies to overcome the multi drug resistance (MDR) that often occurs in cancer. Resistance to anticancer drugs results from a variety of factors, such as genetic or epigenetic changes, an up-regulated outflow of drugs, and various cellular and molecular mechanisms. This technology combines the administration of chemotherapy with the application of electrical pulses, with waveforms capable of increasing drug uptake in a non-toxic and well tolerated mechanical system. ECT is used as a first-line adjuvant therapy in veterinary oncology, where it improves the efficacy of many chemotherapeutic agents by increasing their uptake into cancer cells. The chemotherapeutic agents that have been enhanced by this technique are bleomycin, cisplatin, mitomycin C, and 5-fluorouracil. After their use, a better localized control of the neoplasm has been observed. In humans, the use of ECT was initially limited to local palliative therapy for cutaneous metastases of melanoma, but phase I/II studies are currently ongoing for several histotypes of cancer, with promising results. In this review, we described the preclinical and clinical use of ECT on drug-resistant solid tumors, such as head and neck squamous cell carcinoma, breast cancer, gynecological cancer and, finally, colorectal cancer.

Keywords: breast cancer; colorectal cancer; electroporation; gynecological cancer; head/neck squamous carcinoma; multidrug resistance.

Figure 1

Schematic representation of the main mechanisms in MDR tumor.

Figure 2

Different electroporation modes: (A) square waveforms delivered in a sequence of single pulses; (B) application of a series of 8 biphasic pulses, with voltage of 1300 V/cm and duration of 50 + 50 μs (time, t) each.

Figure 3

Principle of electrochemotherapy. After drug injection and application of intense and short electrical pulses, the cell membrane becomes more permeable. Most drug molecules enter the cells inducing cell death.

Figure 4

Reversible and irreversible electroporation. In both cases, the cells are exposed to an electric field. In RE, the pulse width varies from 300 to 1300 V/cm, and the number of pulses is 8; in IRE, the amplitude is up to 3000 V/cm, and the number of pulses is up to 40. In RE, after membrane permeabilization, cells recover and survive. In IRE, disruption of cellular homeostasis occurs; cell damage induces different types of cell death (apoptosis; necrosis; necroptosis; pyroptosis).

Figure 5

The main types of devices: (A) device for in vitro experiments; (B) pulse generator and needle electrodes for clinical use.