Low-Voltage Electrochemotherapy with Low-Dose Methotrexate Enhances Survival in Mice with Osteosarcoma

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Abstract
Methotrexate plays a key role in adjuvant chemotherapy for treatment of osteosarcoma, but is used at a high dose because it can pass through a cell membrane only with difficulty. Therefore, if the drug delivery of methotrexate to the tumor could be enhanced, antitumor effect and survival would improve. We examined whether enhancement of the antitumor effect of electrochemotherapy was feasible by using low-dose methotrexate in mice with osteosarcoma. The tumor-bearing mice were divided into four groups: no treatment, methotrexate treatment alone, electroporation alone, and methotrexate treatment followed by electroporation. In single-treatment series, the size of the tumors in mice treated with electrochemotherapy decreased substantially 6 days after treatment, whereas continuous growth was observed in the other groups. In the series of treatments repeated three times at 6-day intervals, the original tumors in the electrochemotherapy group decreased consistently and the tumors disappeared in four of seven animals within 16 days. In the other groups, the tumors continued to grow and all host animals died within 58 days. These results show the usefulness of electroporation to enhance the effects of low-dose methotrexate and the potential benefits of electrochemotherapy for the treatment of human osteosarcoma.