Tetraiodothyroacetic acid and tetraiodothyroacetic acid nanoparticle effectively inhibit the growth of human follicular thyroid cell carcinoma

Abstract

Background: Tetraiodothyroacetic acid (tetrac) is a deaminated analogue of L-thyroxine that blocks the actions of L-thyroxine and 3,5,3'-triiodo-L-thyronine at the cell surface receptor for thyroid hormone on integrin alpha v beta 3. Tetrac blocks the proliferative effects of thyroid hormone on tumor cells and the proangiogenesis actions of the hormone. In the absence of thyroid hormone, tetrac also blocks angiogenesis induced by various growth factors. Covalently linked to poly(lactide-co-glycolide), tetrac nanoparticles (tetrac NP) do not gain access to the cell interior and act exclusively at the integrin receptor. Here, the activity of tetrac and tetrac NP against follicular thyroid carcinoma (FTC)-236 cells was studied in two models: (1) tumor cell implants in the chick chorioallantoic membrane (CAM) system and (2) xenografts in the nude mouse.

Methods: FTC-236 cells (10(6)) were implanted in the CAM (n = 8 each for control, and for tetrac and tetrac NP, both at 1 mu g/CAM) and the actions of tetrac and tetrac NP were determined after 8 days on tumor-related angiogenesis and tumor growth. Xenografts of 10(7) FTC-236 cells were implanted in nude mice (n = 8 per group). Tetrac or tetrac NP was administered intraperitoneal (1 mg/kg and 1 mg tetrac equivalent/kg, respectively) every other day for 32 days beginning on day 10, when tumor volume was 200-250 mm(3). Animals were monitored after discontinuation of treatment up to day 40.

Results: In the CAM paradigm, tetrac and tetrac NP arrested tumor-related angiogenesis and tumor growth. In the xenograft model, tetrac and tetrac NP promptly and progressively reduced tumor volume (p < 0.01) over 32 days. There was some regrowth of tumor after interruption of tetrac treatment, but at day 40, tumor volume and tumor weight at sacrifice were 45-55% below those of controls (p < 0.01). Animal weight gain was comparable in the control and treatment groups of animals.

Conclusions: Tetrac and tetrac NP effectively arrest FTC-236 cell tumor growth in the CAM and xenograft models, suggesting its potential utility against FTC.