Preclinical antitumor activity of CI-994.
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.
LoRusso
P M
PM
Department of Internal Medicine, Wayne State University, Harper Hospital, Detroit, MI 48201, USA.
Demchik
L
L
Foster
B
B
Knight
J
J
Bissery
M C
MC
Polin
L M
LM
Leopold
W R
WR
Corbett
T H
TH
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D001549:Benzamides; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D010655:Phenylenediamines / Q000008:administration & dosage* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D001549:Benzamides; D010655:Phenylenediamines; C081895:tacedinaline