Synergism between chemotherapy and alternating electric fields in the inhibition of cancer cell proliferation in-vitro Free

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Currently the mainstay of cancer therapy is based on combinations of several chemotherapeutic protocols with the aim to increase efficacy while maintaining tolerable toxicity. The present study explores the in-vitro efficacy of combining chemotherapeutic treatment together with a new, non-toxic, anticancer modality (Kirson et al, Cancer Research, 2004;64:3288-3295); termed Tumor Treating Fields (TTFields). TTFields are specially tuned, low intensity, intermediate frequency alternating electric fields. TTFields, when generated by insulated external electrodes, have been shown to effectively inhibit cancer cell proliferation in tissue culture, animal tumor models and patients with brain tumors (glioblastoma multiforme) as well as skin metastases from breast carcinoma.

The inhibition of cancer cell proliferation, in human breast carcinoma cells (MDA-MB-231) in culture, was studied by applying TTFields of different intensities alone and in combination with different concentrations of the following chemotherapeutic agents: paclitaxel, doxorubicin and cyclophosphamide. The effects of chemo-TTField combinations were compared to the effect of each treatment modality alone. Similarly, the inhibitory efficacy of the TTFields - paclitaxel combinations was evaluated in human non-small cell lung cancer cells (H1299). Analysis of the results was performed by calculating Combination Index values, as derived from the median effect plots and by isobologram analysis.

It wasfound that the exposure of breast carcinoma and non-small cell lung carcinoma cell cultures to TTFields and paclitaxel, together, had the same inhibitory efficacy as exposure to paclitaxel alone at a concentration two orders of magnitude higher. Qualitatively similar results were obtained for cyclophosphamide and doxorubicin as well. Analysis of these results indicates that, depending on the field intensity and drug concentration, the efficacy of TTField-chemotherapy combinations varies between simple additivity for doxorubicin to overt synergism for cyclophosphamide and paclitaxel.We conclude that, since TTFields are not expected to contribute to systemic toxicity, treatment of cancer with TTFields - Chemotherapy combinations can cause significant potentiation of the efficacy of chemotherapeutic agents, while maintaining relatively low toxicity.