RITA

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.