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

Abstract

Lung neoplasia is a major cause of death in cancer patients throughout the world. Diagnostic techniques and therapeutic modalities for lung cancer patients have been improved over the past decade; however, the overall death rate is still high. 1) Despite undergoing curative surgical treatment, many patients develop recurrent disease and most of such recurrent disease includes distant metastasis.2, 3) Therefore, controlling metastatic disease is one of the important problems that must be addressed in order to conquer lung neoplasia.Among the various clinicopathological factors, lymphatic metastasis is one of the most critical factors for the prognosis of lung cancer patients. [4][5][6] Although experimental models for lung cancer have been reported by several investigators, these models have included some important drawbacks, such as ectopic implantations and complicated procedures.7-9) Recently, we established a model of spontaneous lymphatic metastasis produced by orthotopic implantation of lung cancer cells.10) Direct implantation of Lewis lung carcinoma (LLC) admixed with "MATRIGEL" into the left lobe of the lung caused the formation of a solitary tumor followed by metastasis to the mediastinal lymph node. This model should be useful for investigating therapeutic approaches for lung cancer disease in preclinical studies.We have reported that 4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid, TAC-101, abolished activating protein-1 (AP-1) binding to consensus DNA and inhibited the experimental liver metastasis of gastrointestinal tract cancer in animal models.11) AP-1 has been reported to be a major transcriptional enhancer for the expression of urokinase-type plasminogen activator, overexpression of which has been reported to be correlated with lymphatic metastasis of lung cancer. [12][13][14][15][16] In the present study, we investigated the effects of TAC-101 on the growth at the implantation site and the spontaneous lymphatic metastasis caused by the orthotopic implantation of LLC, and we examined its anti-metastatic mechanism of action in vitro. Since platinum agents have been used as standard treatment modalities for lung cancer, 1,17,18) combination therapy of TAC-101 and CDDP in the LLC model was also examined.

Contribution of AP-1 Interference Induced by TAC-101 to Tumor Growth Suppression in a Hepatocellular Carcinoma Model

“…These activities were associated with a reduction in angiogenic factors, e.g. urokinase-type plasminogen activator, matrix metalloproteinases or vascular endothelial growth factor expression, via decreased AP-1 activity [12,[21][22][23][24] .…”

“…The abundant level of RAR ␣ in HCC tissue is one major therapeutic target for TAC-101 in the clinical setting. TAC-101 affects the transcriptional activity of activator protein-1 (AP-1) [12] and suppresses liver metastases by inducing apoptopic mechanisms in cancer cells and possibly by controlling the transcriptional activity of AP-1. AP-1, which comprises jun and fos oncoprotein families, is one of the representative transcription factors which play a critical role in the induction of inflammatory responses and malignancy of HCC [13,14] .…”

A phase I/II trial of TAC-101, an oral synthetic retinoid, in patients with advanced hepatocellular carcinoma

“…TAC-101 inhibits both the interaction of AP-1 with consensus DNA sequence and the transcriptional activity of AP-1 possibly via the retinoid signal (Murakami et al 1999;Lin et al 2000). AP-1 plays a pivotal role in the progression of cancer by inducing transcription of several factors that have a consensus binding site on its promoter region (Matthews et al 2007).…”

Multifunctional anti‐angiogenic activity of the cyclic peroxide ano‐2 with antitumor activity

“…[12][13][14][15][16][17][18] However, these u-PA-targeting compounds have not yet been used clinically. Although promising, this approach is thought to have several drawbacks.…”