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The anticancer activity of the transcription inhibitor terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid) formulated for systemic administration.

Abstract
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.
AuthorsRocio A Lopez, Amanda B Goodman, Melissa Rhodes, Jessica A L Blomberg, Jonathan Heller
JournalAnti-cancer drugs (Anticancer Drugs) Vol. 18 Issue 8 Pg. 933-9 (Sep 2007) ISSN: 0959-4973 [Print] England
PMID17667599 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents
  • Antineoplastic Agents, Phytogenic
  • Excipients
  • beta-Cyclodextrins
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Polyethylene Glycols
  • terameprocol
  • Masoprocol
  • Paclitaxel
  • Dimethyl Sulfoxide
Topics
  • 2-Hydroxypropyl-beta-cyclodextrin
  • Animals
  • Antineoplastic Agents (administration & dosage, chemistry, pharmacology)
  • Antineoplastic Agents, Phytogenic (pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Chemistry, Pharmaceutical
  • Dimethyl Sulfoxide
  • Excipients
  • Female
  • Humans
  • Infusions, Intravenous
  • Injections, Intraperitoneal
  • Masoprocol (administration & dosage, analogs & derivatives, chemistry, pharmacology)
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Paclitaxel (pharmacology)
  • Polyethylene Glycols
  • Survival Analysis
  • beta-Cyclodextrins

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