A novel retinoid, 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), induces apoptosis of human ovarian carcinoma cells and shows potential as a new antitumor agent for clear cell adenocarcinoma.

Abstract

OBJECTIVES:

A novel retinobenzoic acid derivative, 4-[3,5-bis (trimethylsilyl) benzamido] benzoic acid (TAC-101), was reported to suppress the growth and invasion of human gastric cancer or hepatocellular carcinoma by induction of apoptosis. We examined the antitumor activity of TAC-101 against human ovarian carcinoma cell lines.

METHODS:

Apoptosis of human epithelial ovarian carcinoma-derived cell lines (RMG-I, RMG-II, RTSG, RMUG-S, RMUG-L, and KF) was investigated by detecting DNA laddering and was quantified by an enzyme-linked immunosorbent assay. Inhibition of apoptosis was also examined using a caspase inhibitor. Furthermore, TAC-101 (8 mg kg(-1) day(-1) orally for 30 days) was investigated in nude mice with subcutaneous RMG-II tumors. A prominent apoptotic response to TAC-101 was observed. The antitumor effects of cisplatin (7 mg/kg intravenously on day 1) and paclitaxel (36 mg/kg intravenously on days 1 and 5) were also assessed for comparison.

RESULTS:

Apoptosis occurred in all of the cell lines (except KF) in a concentration-dependent manner after exposure to TAC-101 and was markedly induced in RMG-I and RMG-II cells (derived from ovarian clear cell adenocarcinomas). A caspase inhibitor blocked the induction of apoptosis by TAC-101. The maximum inhibition of RMG-II tumor growth in nude mice by TAC-101, cisplatin, and paclitaxel was 45%, 34%, and 47%, respectively.

CONCLUSION:

Oral TAC-101 shows potential as a novel antitumor agent for ovarian carcinoma, especially ovarian clear cell adenocarcinoma.

• Authors: Nao Suzuki, Daisuke Aoki, Shinji Oie, Miwa Horiuchi, Yuko Hasegawa, Sachiko Ezawa, Atsushi Suzuki, Nobuyuki Susumu, Fumihito Hosoi, Kenji Kitazato, Shiro Nozawa
• Journal: Gynecologic oncology (Gynecol Oncol) Vol. 94 Issue 3 Pg. 643-9 (Sep 2004) ISSN: 0090-8258 [Print] United States
• PMID: 15350353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzoates
• RARA protein, human
• RNA, Messenger
• Rara protein, mouse
• Receptors, Retinoic Acid
• Retinoic Acid Receptor alpha
• TAC 101
• Trimethylsilyl Compounds
• retinoic acid receptor beta
• retinoic acid receptor gamma

Topics

• Adenocarcinoma, Clear Cell (drug therapy, genetics, metabolism, pathology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Benzoates (pharmacology)
• Cell Line, Tumor
• Female
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Ovarian Neoplasms (drug therapy, genetics, metabolism, pathology)
• RNA, Messenger (biosynthesis, genetics)
• Receptors, Retinoic Acid (biosynthesis, genetics)
• Retinoic Acid Receptor alpha
• Trimethylsilyl Compounds (pharmacology)
• Xenograft Model Antitumor Assays