TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) Inhibits Spontaneous Mediastinal Lymph Node Metastasis Produced by Orthotopic Implantation of Lewis Lung Carcinoma

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Abstract
The anti‐tumor and anti‐metastatic effects of 4‐[3,5‐bis(trimethylsilyl)benzamido]benzoic acid (TAC‐101) were investigated using our established lung cancer model. Orthotopic implantation of Lewis lung carcinoma (LLC) cells into the lung parenchyma produced a solitary tumor nodule in the lung followed by mediastinal lymph node metastasis. Daily oral administration of TAC‐101 at doses ranging from 4 to 16 mg/kg resulted in a significant inhibition of lymphatic metastasis (inhibition rate=57 to 76%), while only the dose of 16 mg/kg significantly inhibited tumor growth at the implanted sites (inhibition rate=46%). Combined treatment with cis‐diamminedichloroplatinum (CDDP) and TAC‐101 (8 mg/kg, p.o., daily) enhanced the anti‐tumor effect of CDDP (7 mg/ kg, i.v., bolus) against both the growth of implanted tumor and lymphatic metastasis. In addition, this combined treatment significantly prolonged the survival time of LLC tumor‐bearing mice as compared to treatment with each agent alone. The anti‐activating protein‐1 (AP‐1) activity of TAC‐101 caused inhibition of LLC cell invasion through the repression of expression of urokinase‐type plasminogen activator and its receptor. The anti‐invasive activity of TAC‐101 may be involved in its in vivo anti‐metastatic activity. These findings suggest that TAC‐101 is a novel anti‐cancer agent that may improve the therapeutic modalities for lung cancer patients with metastatic disease.

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