Preclinical antitumor activity of CI-994

Abstract

CI-994 [aka: acetyldinaline; PD 123654; 4-acetylamino-N-(2'aminophenyl)-benzamide] (Figure 1) is a novel antitumor agent with a unique mechanism of action. It is the acetylated metabolite of dinaline, a compound previously identified as having cytotoxic and cytostatic activity against several murine and human xenograft tumor models. CI-994 had activity against 8/8 solid tumors tested (log cell kills at the highest non-toxic dose): pancreatic ductal adenocarcinoma #02 (4.7); pancreatic adenocarcinoma #03 (3.0; 1/6 cures); colon adenocarcinoma #38 (1.6); colon adenocarcinoma #51/A (1.1); mammary adenocarcinoma #25 (1.7); mammary adenocarcinoma #17/ADR (0.5); Dunning osteogenic sarcoma (4.0); and the human prostate carcinoma LNCaP (1.2). CI-994 had the same spectrum of activity in vivo as dinaline. It also behaved similarly in schedule comparison/toxicity trials. Prolonged administration with lower drug doses was more effective than short-term therapy at higher individual doses. If doses were kept between 40 and 60 mg/kg/injection, prolonged administration (> 50 days) was tolerated with no gross toxicity. Doses > or = 90 mg/kg/injection caused lethality after 4-5 days of administration. The maximum tolerated total dose was also increased with smaller individual doses administered for prolonged intervals. Clinical Phase I trials are ongoing with this agent.

Mitotic arrest induced by XK469, a novel antitumor agent, is correlated with the inhibition of cyclin B1 ubiquitination

“…1,2 Despite the demonstration of impressive activity in vivo, very little is known about its mechanism of action. A recent study by Gao et al 3 suggests that XK469 may act as a topoisomerase II␤ poison.…”

“…Initially, XK469 was selected through a disk-diffusion soft agar colony-formation assay and was found to have selective antiproliferative activity for solid tumors. 1,2 Despite the demonstration of impressive activity in vivo, very little is known about its molecular targets and mechanism of action. A recent study by Gao et al 3 showed that XK469 might be a selective topoisomerase II␤ poison with functional activity similar to that of the topoisomerase II inhibitor 4Ј-(9-acridinylamino) methanesulfon-m-anisidide (m-AMSA).…”

Histone Deacetylase Inhibitors as Therapeutic Agents for Cancer Therapy: Drug Metabolism and Pharmacokinetic Properties

“…CI994, a small molecule (MW=269.3) and with poor aqueous solubility, was developed as an acetylated analogue of Dinaline (GOE-1734), which, also showed equivalent antitumor activity (LoRusso et al, 1996). CI994 was eventually identified as an active metabolite of Dinaline (LoRusso et al, 1996).…”

Clinical impact of novel treatment strategies

“…CI-994 (N-acetyl dinaline) is a novel substituted benzamide derivative with cytotoxic activity in preclinical models (LoRusso et al, 1996). Although the precise mechanism of action is not completely understood, CI-994 appears to work with increase in acetylation of histones.…”