Anti-tumor Activity And Safety Evaluation Of Hydroxyurea Derivatives

Objective:to detect the anti-tumor activity of Hydroxylthiourea derivatives in vito and screen out the compounds with cytotony against tumor cell;observe the cell apoptosis effects of Hydroxylthiourea derivatives; observe the toxic reaction and general situation of HY-D11 and HY-D10 to NIH mice by single tramsotal dosing. Determine the maximum tolerated dose (MTD), provide the reference for long-term toxicity tests and clinical drug safety.Method:Hydroxylthiourea derivatives were screened in vitro antitumor activities against L1210 cells and K562 cells through MTT assay, and screened out the effected compounds, the IC50 value for 48h treatment on L1210 and K562 were calculated.The anti-tumor action mechanism of Hydroxylthiourea derivatives on L1210 cells and K562 cells were investigates. The morphologic changes of K562 cells and L1210 cells were observed in microscopy by Wight-Giemsa. Annexin V-FITC/PI staining was performed to confirm the apoptosis of L1210 cells and K562 cells incubates with Hydroxylthiourea derivatives for different time.Mice were used applied as experimental animals, and HY-D11 or HY-D10 poisoning model was replicated, toxic symptoms, general symptoms, body weight,consumption of food intake and histopathological aspects were observed. For a more systematic study, the toxicity and rough circumstances of death were observed, which can provide the reference for long-term toxicity tests and clinical drug safety.Results:We found that 19 kinds of compounds showed inhibition against LI21 Ocells, and 5 kinds of compounds showed inhibition against K562 cells. The IC50 value on L1210 cells and K562 cells were calculated, these compounds possess certain antitumor activity in vitro. The results of AnnexinV^ FITC/PI double staining FCM assay showed YL3 treated for 24 hours can induce apoptosis of LI 210 cell compared with HU, HY-11 treated for 24 hours and 48 hours can induce apoptosis of K562 cell compared with HU。 Acute toxicology experiment showed:①Maximal tolerance does (MTD 8g/kg-bw)about HY-11 to mice was 8g/kg-bw.2 mice in 20 died by Oral administration,3 animals appeared tail necrosis and blood callus formation,1 animal appeared foot necrosis and blood callus formation.②Maximal tolerance does (MTD 8g/kg-bw)about HY-D10 to mice was 5.6g/kg-bw,with any obvious toxicity.