Tetrahydrouridine dihydrate (THU dihydrate) is a potent cytidine deaminase (CDA) inhibitor that competitively blocks the enzyme's active site more effectively than intrinsic cytidine.

Tetrahydrouridine (THU), a specific cytidine deaminase (CDA) inhibitor, effectively prevents the deamination process in the metabolism of cytotoxic deoxycytidine analogues, such as ara-C and Gemcitabine. Research involving combination therapy demonstrates that THU enhances Gemcitabine's anti-cancer efficacy against pancreatic and lung carcinoma cells. Notably, BxPC-3 and H441 cells, with high CDA expression, exhibit significantly increased sensitivity to Gemcitabine following a 100 μM THU treatment, with sensitivity augmenting by approximately 2.1 and 4.4 fold, respectively. Conversely, MIAPaCa-2 and H1299 cells, characterized by low CDA expression, also show unexpected sensitivity increases to Gemcitabine, with a 2.2 and 2.3 fold enhancement in IC 50 respectively. However, Panc-1 and H322 cells display no notable change in drug responsiveness. These findings indicate that THU is capable of sensitizing certain pancreatic and lung carcinoma cells to Gemcitabine, leading to cell death, independently of CDA expression levels, and does so by halting the S-phase of the cell cycle without inducing apoptosis [1].

Administration of 167 mg/kg Tetrahydrouridine (THU) followed by 1.0 mg/kg DAC resulted in the death of one male and eight females. Surviving animals scheduled for termination appeared mostly asymptomatic, showing no treatment-related effects on body weights, food consumption, clinical chemistry, and urinalysis with up to 1.0 mg/kg DAC combined with 167 mg/kg Tetrahydrouridine [2].