RITA (NSC 652287) induces both DNA-protein and DNA-DNA cross-links with no detectable DNA single-strand breaks, and also inhibits MDM2-p53 interaction by targeting p53. RITA binds full-length p53 but not glutathione S-transferase (GST) protein or HDM-2. RITA blocks p53−HDM-2 interaction and p53 ubiquitination. RITA substantially decreases the amount of HDM-2 that coprecipitated with p53, although both proteins were upregulated. RITA induces activation of p53 in conjunction with up-regulation of phosphorylated ASK-1, MKK-4 and c-Jun. RITA also induces the activation of JNK signaling. RITA is well tolerated in mice after intraperitoneal administration, with no observable weight loss at doses up to 10 mg/kg during 1 month. After five injections of 0.1 mg/kg of RITA, the growth of the HCT116 tumors is suppressed by 40%, without apparent effects on the HCT116 TP53-/- tumors. At a dose of 1 or 10 mg/kg, RITA shows strong antitumor activity. HCT116 tumors are 90% smaller in mice treated with 10 mg/kg of RITA than in control untreated mice. RITA inhibits the tumor growth in a wild-type p53−dependent manner.
|Source||Oncotarget (2017). Figure 1. RITA|
|Cell Lines||HD-MB03 and DAOY cell|
|Incubation Time||48 h|
|Results||RITA treatment raised the apoptotic fraction in ONS-76 (P = 0.01) and DAOY (P = 0.03) cultures by 5-fold compared to controls, but had no significant effect on UW-228-2 apoptosis|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 50 mg/mL|
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