In vivo and in vitro study on potential combination therapy of COL-3 and tamoxifen in breast cancer: a pilot study

Abstract

This thesis project is a preclinical study on the potential combination therapy of tamoxifen with COL-3, a matrix metalloproteinases inhibitor in breast cancer therapy. Pharmacokinetic (PK) study was performed on female rats to examine the pharmacokinetic profile of COL-3 alone, or in combination of low-dose/high-dose tamoxifen in fed/fasted rats. When fed rats were pretreated with high-dose tamoxifen before COL-3a??s oral administration, absorption of COL-3 was found extensively inhibited. In order to find evidence to support our hypothesis that food may play a role in this unexpected phenomenon in COL-3 PK profile, in vitro dissolution/diffusion study was carried out to mimic the physiological environment in gastrointestinal tract. Anti-proliferative effects of COL-3, when given alone and in the combination with tamoxifen, were evaluated in estrogen-receptor-positive (MCF-7) and estrogen-receptor-negative (MDA-MB-231) breast cancer cell lines. Four different PK models were proposed and compared to characterize the PK aspect of COL-3 under various conditions.