Exploring the "sweet spot": in vitro efficacy of tumor treating fields and potential for synergy with cytotoxic therapy in bone and soft tissue sarcomas

<title>Abstract</title> <p>Background Soft tissue and bone sarcomas (STS) are a heterogeneous group of malignancies whose systemic treatment remains constrained by the cumulative toxicity of standard cytotoxic agents, particularly anthracycline-related cardiotoxicity. Tumor Treating Fields (TTFields) are a non-invasive, anti-mitotic therapy that delivers low-intensity, intermediate-frequency alternating electric fields, with growing evidence of activity in several solid tumors. Data on TTFields in sarcoma, and on their potential to interact with cytotoxic and targeted therapy, remain sparse. Methods Five sarcoma cell lines (GCT, HT1080, ISO-HAS-B, SJSA-1, SW982) were exposed to 200 kHz TTFields at high (1.62 V/cm) or low (0.76 V/cm) intensity for 72 hours using the inovitro™ system. Cell cycle distribution was assessed by flow cytometry. Doxorubicin, gemcitabine, and pazopanib were each tested concurrently with TTFields, at the field intensity most likely to reveal an added drug effect, and viability was compared with each agent alone. Results TTFields alone produced growth inhibition in all five cell lines at high intensity (43–90% reduction relative to control), with reduced and more variable inhibition at low intensity. Cell cycle analysis showed an increased sub-G1 (apoptotic) fraction after TTFields exposure. At high intensity, TTFields alone reduced viability so substantially that concurrent gemcitabine added no detectable further effect. At low intensity, concurrent doxorubicin reduced viability beyond either agent alone in SW982 (an additive-appearing pattern) and SJSA-1 (a pattern more suggestive of synergy) cells, and concurrent high-intensity TTFields enhanced pazopanib activity in ISO-HAS-B cells. Conclusions TTFields show variable but consistent monotherapy activity across sarcoma subtypes in vitro, and field intensity determines whether a concurrent cytotoxic or targeted-therapy effect can be detected experimentally. These exploratory findings suggest TTFields may lower the drug concentration needed for comparable sarcoma cell kill in some subtypes, a relationship that warrants formal synergy analysis and in vivo confirmation before clinical translation.</p>