The Effects of Paclitaxel-Coated Nylon Thread on the Proliferative Cholangitis in a Rat

Choi, Jae Woon; Jin, Guang Bi; Lee, Dong Gyu; Lee, Sang Jeon; Jang, Lee Chan; Sung, Rohyun; Kim, Dong Woon; Park, Seon Mee

Abstract

BACKGROUND/AIMS: Local drug delivery to the bile duct may be effective to prevent proliferative cholangitis (PC) through capability of high dose administeration with minimal systemic side effects. Paclitaxel is an anticancer drug whose side effect on the stabilization of microtubule leads to cell death. The aims of this study were to establish the proliferative cholangitis model in rat, mimicking biliary stricture in human, and to test whether paclitaxel-coated nylon thread prevents biliary stricture in a PC model of rat.
METHODS
PC was induced by introducing a fine nylon thread into the bile duct in a rat from 1 week to 4 week. To evaluate the effects of paclitaxel as a locally-delivered anti-proliferative drug, dog gallbladder epithelial cells were exposed to sequential concentrations of paclitaxel (0.1microM, 1microM, 10microM, and 100microM) for 20 min. in vitro, and inhibition of proliferation was measured by (3)H-thymidine uptake assay. Paclitaxel- coated 5-0 nylon threads (1.8+/-0.5 ug/3 cm thread, measured by HPLC) were made by immersion of ethanolic paclitaxel (50 mg/ml) and evaporation of the solvent. Nylon threads were inserted into the bile duct of male Sprague-Dawley rats weighing 200~50 g. Paclitaxel (n=15) and control (n=15) groups were divided with or without paclitaxel-coating procedure. The paclitaxel effects were assessed by histomorphological examination one week after thread implantation.
RESULTS
The decrease of (3)H-thymidine uptake was observed at 100microM of paclitaxel exposured for 20 minutes in the presence of epidermal growth factor (50 nM/ml) than control. PC model characterized by epithelial-glandular proliferation and fibrous thickening of the bile duct wall through 1~ week. This model was established at 1 week. The effect of paclitaxel-coated nylon thread into the bile duct were evaluated after 1 week. In paclitaxel treated the luminal area, luminal length and the ratio of lumen to bile duct cross sectional area increased by 276% (p=0.044), 87% (p=0.012) and by 330% (p=0.000), respectively, versus control. The total wall area, epithelial-glandular area, and stromal area were similar between paclitaxel treated group and control (p>0.05). The bile duct wall thickness of paclitaxel group decreased by 33% (p=0.011, 273 (90)microM vs 410 (95)microM, paclitaxel vs control).
CONCLUSION
Paclitaxel-coated nylon thread into bile duct was effective for the suppression of luminal stenosis, and may offer a therapeutic option for biliary stricture and biliary stricture associated disease.