Anticancer Activity of the Combination of Cabozantinib and Temozolomide in Uterine Sarcoma
Clinical Cancer Research, July 2022
Joseph J. Noh, Young-Jae Cho, Ji-Yoon Ryu, Jung-Joo Choi, Jae Ryoung Hwang, Ju-Yeon Choi, Jeong-Won Lee
To evaluate the anti-cancer effects of cabozantinib, temozolomide, and their combination in uterine sarcoma cell lines and mouse xenograft models. Human uterine sarcoma cell lines (SK-LMS-1, SK-UT-1, MES-SA, and SKN) were used to evaluate the anti-cancer activity of cabozantinib, temozolomide, and their combination. The optimal dose of each drug was determined by MTT assay. Cell proliferation and apoptosis were assessed 48 hours and 72 hours after the drug treatments. The tumor weights were measured in an SK-LMS-1 xenograft mouse model and a patient-derived xenograft (PDX) model of leiomyosarcoma treated with cabozantinib, temozolomide, or both. Given individually, cabozantinib and temozolomide each significantly decreased the growth and viability of cells. This inhibitory effect was more pronounced when cabozantinib (0.50 µM) and temozolomide (0.25 mM or 0.50 mM) were co-administered (p-value < 0.05). The combination of the drugs also significantly increased apoptosis in all cells. Moreover, this effect was consistently observed in patient-derived leiomyosarcoma cells. In vivo studies with SK-LMS-1 cell xenografts and the PDX model with leiomyosarcoma demonstrated that combined treatment with cabozantinib (5 mg/kg/day, per os administration) and temozolomide (5 mg/kg/day, per os administration) synergistically decreased tumor growth (both p-values < 0.05). The addition of cabozantinib to temozolomide offers synergistic anti-cancer effects in uterine sarcoma cell lines and xenograft mouse models, including PDX. These results warrant further investigation in a clinical trial.
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