Intravesical Thalidomide boosts bacillus Calmette-Guérin (BCG) in non-muscle invasive bladder cancer treatment.

Abstract

The aim of this study was to explore the efficacy of intravesical Thalidomide (immunomodulatory, anti-inflammatory and anti-angiogenic) added to BCG using an immune competent autochthonous orthotopic NMIBC animal model. Female Fischer 344 rats, 7weeks of age, received every 2weeks for four times, a dose of 1.5mg/kg of N-methyl-N-nitrosourea (MNU) intravesically. The rats were randomized into four groups (n=10 per group) to receive intravesical treatment once a week for 6weeks as follows: control (0.2ml vehicle), BCG (2×106 CFU of Connaught strain in 0.2ml), Thalidomide (20mg/kg in 0.2ml) and BCG-Thalidomide in 0.2ml. At week 15, bladders were collected for histopathology, cell turnover index by immunohistochemistry and immunoblotting quantification of 4E-BP1 and p70S6K1 for downstream mTOR proliferation signaling and HIF and VEGF for angiogenesis pathway. Thalidomide-BCG association showed a trend for normal histopathology and down-regulation of cell turnover, p70S6K1, HIF-1 and VEGF. 4E-BP1 was up-regulated by treatment, especially in the Thalidomide groups, supporting that its regulation occurs independently of p70S6K1 on mTOR pathway in NMIBC. Intravesical BCG-Thalidomide might represent a significant increment in NMIBC treatment, suggesting p70S6K1, HIF-1 and VEGF as potential molecular target candidates in a clinically relevant immune competent NMIBC model.