sulindac and Carcinoma--Lewis-Lung

The purpose of the study was to evaluate the metabolism, pharmacokinetics and efficacy of phospho-NSAIDs in Ces1c-knockout mice.. Hydrolysis of phospho-NSAIDs by Ces1c was investigated using Ces1c-overexpressing cells. The rate of phospho-NSAID hydrolysis was compared between wild-type, Ces1c+/- and Ces1c-/- mouse plasma in vitro, and the effect of plasma Ces1c on the cytotoxicity of phospho-NSAIDs was evaluated. Pharmacokinetics of phospho-sulindac was examined in wild-type and Ces1c-/- mice. The impact of Ces1c on the efficacy of phospho-sulindac was investigated using lung and pancreatic cancer models in vivo.. Phospho-NSAIDs were extensively hydrolyzed in Ces1c-overexpressing cells. Phospho-NSAID hydrolysis in wild-type mouse plasma was 6-530-fold higher than that in the plasma of Ces1c-/- mice. Ces1c-expressing wild-type mouse serum attenuated the in vitro cytotoxicity of phospho-NSAIDs towards cancer cells. Pharmacokinetic studies of phospho-sulindac using wild-type and Ces1c-/- mice demonstrated 2-fold less inactivation of phospho-sulindac in the latter. Phospho-sulindac was 2-fold more efficacious in inhibiting the growth of lung and pancreatic carcinoma in Ces1c -/- mice, as compared to wild-type mice.. Our results indicate that intact phospho-NSAIDs are the pharmacologically active entities and phospho-NSAIDs are expected to be more efficacious in humans than in rodents due to their differential expression of carboxylesterases.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Aspirin; Carboxylic Ester Hydrolases; Carcinoma, Lewis Lung; Ibuprofen; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organophosphates; Organophosphorus Compounds; Sulindac

To examine whether a sulindac derivative (C-18) with previously reported anti-angiogenic properties limits malignant pleural effusion (MPE) formation in mice.. MPE was generated by intrapleural injection of murine adenocarcinoma cells in C57BL/6 mice. Animals were divided into three groups, a control group and two treatment groups receiving intraperitoneally a daily dose of either 1 mg or 2 mg of C-18 for a total of 12 doses. Mice were sacrificed on day 14.. Pleural fluid volume and the number of pleural tumor implantations were measured. Tumor angiogenesis, pleural vascular permeability and the host inflammatory response were also assessed. C-18 significantly limited pleural fluid formation and inhibited intrapleural tumor dissemination. The mean±SEM pleural fluid volume was 758±63 μl for the control group, compared to 492±120 μl (p=0.042) and 279±77 μl (p<0.001) for the low dose and high dose group of C-18, respectively. Control group animals had 6.2±1 intrapleural tumors, while C-18 treated animals had 3.1±0.8 (p=0.014) and 3±0.7 (p=0.009) for the low and high dose respectively. In addition C-18 significantly suppressed pleural vascular permeability. No significant difference in tumor angiogenesis and inflammatory response was observed, while there was also no measurable effect in tumor cell apoptosis and proliferation in vitro and in vivo.. C-18 halted experimental MPE formation and intrapleural tumor dissemination, through down-regulation of pleural vascular permeability.

Topics: Animals; Capillary Permeability; Carcinoma, Lewis Lung; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cytokines; Evans Blue; Inflammation Mediators; Mice; Mice, Inbred C57BL; Pleural Effusion, Malignant; Pleural Neoplasms; Sulindac; Tumor Burden; Xenograft Model Antitumor Assays