TAC-101 (4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid) inhibits spontaneous mediastinal lymph node metastasis produced by orthotopic implantationof Lewis lung carcinoma

The anti-tumor and anti-metastatic effects of 4-[3,5-bis(trimethylsilyl)ben zamido]benzoic acid (TAC-101) were investigated using our established lung cancer model. Orthotopic implantation of Lewis lung carcinoma (LLC) cells i nto the lung parenchyma produced a solitary tumor nodule in the lung follow ed by mediastinal lymph node metastasis, Daily oral administration of TAC-1 01 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 o f 16 mg/kg significantly inhibited tumor growth at the implanted sites (inh ibition rate=46%). Combined treatment with cis-diamminedichloroplatinum (CD DP) and TAC-101 is mg/kg, p.o., daily enhanced the anti-tumor effect of CDD P (7 mg/kg, i.v., bolus) against both the growth Of implanted tumor and lym phatic metastasis, In addition, this combined treatment significantly prolo nged the survival time of LLC tumor-bearing mice as compared to treatment w ith each agent alone. The anti-activating protein-1 (AP-1) activity of TAC- 101 caused inhibition of LLC cell invasion through the repression of expres sion of urokinase-type plasminogen activator and its receptor, The anti-inv asive activity of TAC-101 may be involved in its in vivo anti-metastatic ac tivity. These findings suggest that TAC-101 is a novel anti-cancer agent th at may improve the therapeutic modalities for lung cancer patients with met astatic disease.