Electroporation is a physical event that temporarily reduces cell membrane barrier properties. Diminished membrane barrier properties are achieved by exposing cells to pulsed electric fields. When a cell has been treated with electric fields it is possible for extracellular agents to gain access to the cell interior. This process has been used in vivo to increase the uptake of chemotherapeutic agents by tumor cells which results in dramatically higher response rates than when drug is used alone. This type of treatment is called electrochemotherapy (ECT); bleomycin is most often used as the drug for this type of treatment. It was hypothesized that electroporation could be used to augment the cytotoxicity of other anticancer agents. Therefore, this study was performed in order to screen 44 different combinations of drug and cell type in vitro to identify drugs that may have higher cytotoxicity when combined with electroporation. Results from seven cell types indicate that the IC50 of bleomycin can be reduced by a factor of 100-5000 when electroporation is used to facilitate internalization. The IC50 values of cisplatin and carboplatin could be reduced by factors ranging from 3 to 13 in six different cell lines as a result of electroporation. These IC50 reductions in multiple cell lines suggest that cisplatin and carboplatin may be effective in vivo as part of ECT treatment.
BACKGROUND Pulsed electric fields have been shown to increase the effectiveness of antineoplastic agents by temporarily increasing the permeability of cell membranes. This type of drug delivery is called electrochemotherapy, and it has been successful in the treatment of patients with cutaneous malignancies in clinical trials. This study focused on determining the applicability of electrochemotherapy to the treatment of soft tissue sarcoma, using an animal model bearing human sarcomas. The antitumor effects of single and multiple electrochemotherapy treatments were investigated using small (250 mm3) and large (4000 mm3) tumors. METHODS Established tumors were injected with bleomycin, then electric pulses were administered to the tumor site. Animals were followed based on periodic tumor volume determinations, which were used to categorize treatment of each tumor as a complete response, a partial response, stable disease, or progressive disease. Histologic analysis was used to confirm response data. RESULTS Animals were randomly assigned to one of four different treatment groups. These groups received no treatment, drug only, electric pulses only, or drug combined with electric pulses. A single electrochemotherapy treatment protocol for small tumors resulted in a 100% complete response rate and a 41.7% cure rate. Multiple treatments of small and large tumors resulted in complete response rates of 83.3% and 100%, respectively. These responses were identical to the cure rates. In contrast, tumors in the groups that received no treatment, electric pulses only, and drug only progressed for both single treatment and multiple treatment scenarios, regardless of tumor size. CONCLUSIONS In this study, a single electrochemotherapy treatment had a strong cytoreductive effect on small tumors that lasted approximately 35 days, until recurrences began. Multiple treatment of small and large tumors resulted in high complete response rates that lasted at least 100 days after treatment. This indicates the feasibility of electrochemotherapy as a modality of limb‐preserving treatment for patients with sarcoma of the extremities. Cancer 1999;85:409–17. © 1999 American Cancer Society.
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