The anticancer activity of the transcription inhibitor terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid) formulated for systemic administration.
Terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid, formerly known as EM-1421 and M4N) is a semi-synthetic small molecule with antitumor activity occurring via selective targeting of Sp1-regulated proteins, including survivin and cdc2 that control cell cycle and apoptosis. Terameprocol is in clinical development as a site-specific transcription inhibitor in solid refractory tumors. The present studies were designed to investigate the in-vitro and in-vivo anticancer activity of terameprocol in a novel hydroxypropyl beta-cyclodextrin and polyethylene glycol solvent formulation (designated CPE) designed for safe parenteral administration. Terameprocol powder was dissolved in CPE (20% hydroxypropyl beta-cyclodextrin and 50% polyethylene glycol 300 or 30% hydroxypropyl beta-cyclodextrin and 25% polyethylene glycol 300) or dimethyl sulfoxide and used for in-vitro cell proliferation assays, and in human carcinoma xenograft studies using female athymic nude mice injected with SW-780 human bladder cells. Terameprocol (50 and 100 mg/kg), paclitaxel (5 mg/kg), terameprocol and paclitaxel or vehicle was administered intraperitoneally daily for 21 days. Stock solutions of the CPE formulation were stable for up to 12 months. Terameprocol CPE formulation showed concentration-dependent inhibition of HeLa and C33A cell proliferation, and was less toxic than terameprocol dimethyl sulfoxide formulation. The terameprocol CPE formulation showed no overt toxicities in tumor-bearing mice. Terameprocol alone reduced the rate of tumor growth, and a combination of terameprocol/paclitaxel reduced both the rate and extent of tumor growth. These preclinical results confirm the tumoricidal activity of terameprocol formulated in a solvent suitable for parenteral administration and suggest that terameprocol has improved efficacy when coadministered with paclitaxel.
Erimos Pharmaceuticals, Raleigh, North Carolina 27606, USA. ralopez@erimos.com
Rocio A
RA
Lopez
Amanda B
AB
Goodman
Melissa
M
Rhodes
Jessica A L
JA
Blomberg
Jonathan
J
Heller
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004121:Dimethyl Sulfoxide; D005079:Excipients; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D009637:Masoprocol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D011092:Polyethylene Glycols; D016019:Survival Analysis; D047392:beta-Cyclodextrins
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; C076852:terameprocol; D009637:Masoprocol; D017239:Paclitaxel; D004121:Dimethyl Sulfoxide