生物活性

• 描述Tumor suppressor p53 is a powerful growth suppressive and pro-apoptotic protein that plays a central role in protectionfrom tumor development. The overproduction of MDM2, the primary negative regulator of p53, effectively disables p53 function. RG7388, a potent and selective MDM2 antagonist, inhibits p53-MDM2 interaction with an IC₅₀ value of 6 nM. RG7388 induced dose-dependent p53 stabilization, cell cycle arrest, and apoptosis in cancer cells expressing wild-type p53, consistent with a nongenotoxic p53 activation mechanism^[2]. In the MDM2-amplified SJSA1 osteosarcoma cell line, a significant apoptotic response over the control was induced with both the single 300 nmol/L and 1.8 μmol/L concentrations of RG7388 for 16 hours (P < 0.005), with the 1.8 μmol/L concentration providing optimal response. In SJSA osteosarcoma xenograft-bearing mice, the once-daily dose of 30 mg/kg of RG7388 (total 210 mg/kg/wk) seemed to be the most effective dose at inhibiting tumor growth (>100% TGI with 9 partial regressions), the 50 mg/kg of RG7388 given twice a week (total 100 mg/kg/wk) was equivalent by statistical analysis (96% TGI with 3 partial regressions; P > 0.05) ^[1]. It also achieved 88% tumor growth inhibition against established human SJSA1 osterosarcoma xenografts in nude mice at a dose of 12.5 mg/kg^[2].