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 Terameprocol

Description of Terameprocol: Terameprocol is a semi-synthetic tetra-methylated derivative of nordihydroguaiaretic acid (NDGA) and transcriptional inhibitor with potential antiviral, antiangiogenic, and antineoplastic activities. Terameprocol competes with the transcription factor Sp1 for specific Sp1 DNA binding domains within gene promoter regions during DNA synthesis. In virally-infected cells, blocking of the Sp1 binding site suppresses Sp1-regulated viral promoter activity and gene expression, thereby inhibiting viral transcription and replication. In tumor cells, blockage of Sp1 binding sites by this agent interferes with the transcription of the Sp1-dependant genes cyclin-dependant kinase (Cdc2), survivin, and vascular endothelial growth factor (VEGF), which are overexpressed in a variety of cancers. By suppressing Sp1-regulated transcription of these genes, terameprocol may reduce tumor angiogenesis and tumor cell proliferation and induce tumor cell apoptosis. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:   Erimos Pharmaceuticals.

New phase I study of terameprocol.  Grossman et al recently reported the Phase I study of terameprocol in patients with recurrent high-grade glioma.   Terameprocol was administered intravenously for 5 consecutive days each month and discontinued for toxicity or progression. Patients taking enzyme-inducing antiseizure drugs (EIASDs) were escalated independently. Thirty-five patients with a median Karnofsky performance status of 80, median age of 46 years, and median of 2 prior treatment regimens were accrued. Doses of 750, 1100, 1700, and 2200 mg/day were administered. Terameprocol was reformulated to avoid acidosis related to the excipient and was well tolerated at 1700 mg/day. Hypoxia and interstitial nephritis were noted at 2200 mg/day. Concurrent administration of EIASD did not significantly affect the serum pharmacokinetics of the terameprocol. Although no responses were seen, stable disease was noted in 9 (28%) of 32 evaluable patients, with 5 (13%) continuing treatment for >6 months (≥6, 8, 10, 10, and ≥21 months). The overall median survival was 5.9 months. This phase I study defined the toxicity of terameprocol, determined that EIASDs do not affect its pharmacokinetics, and identified 1700 mg/day as the dose for future studies. Preclinical and human data suggest that this novel transcription inhibitor is worthy of further study. The long-term stability noted in some patients and the lack of associated myelosuppression suggest that terameprocol could be safely combined with radiation and temozolomide in newly diagnosed high-grade gliomas. (source: Neuro Oncol. 2012 Feb 8. [Epub ahead of print])

Terameprocol induces radiosensitization in non-small cell lung carcinoma.  Terameprocol significantly enhances the sensitivity of non-small cell lung carcinoma cell lines to radiation therapy, although the mechanism of action remains unclear. Further study is warranted to assess the potential of terameprocol as an agent that may enhance the therapeutic ratio of radiotherapy in lung cancer. [source: J Thorac Oncol. 2011 Jan;6(1):8-14]

Terameprocol forumulation and pre-clinical studies: Terameprocol is currently in clinical development as a site-specific transcription inhibitor in solid refractory tumors, in which trials terameprocol was formulated 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. (source: Anticancer Drugs. 2007 Sep;18(8):933-9).

Terameprocol  in CIN trials: Terameprocol (vaginal ointment) Phase I/II clinical studies: Terameprocol in 1% and 2% vaginal ointment use in Phase I/II trials with women with HPV-linked cervical intraepithelial neoplasia has an excellent safety profile, no SAEs reported and mild, self-limiting treatment-related AEs. There was no detectable absorption of terameprocol. These data support the continued evaluation of terameprocol in in vitro and animal efficacy models followed by definitive human Phase II clinical trials in CIN. (source: Gynecol Oncol. 2007 Dec;107(3):554-62).

Terameprocol in solid refractory tumors: Several preclinical studies have demonstrated the potent anticancer activity of terameprocol in tumor cell lines and animal models. In addition, terameprocol prevented the proliferation of HIV, HSV and HPV by a deactivation of viral Sp1-dependent promoters in preclinical studies. In a phase I clinical trial in patients (25 evaluable) with solid tumors administered intravenous terameprocol, 8 patients exhibited stable disease and 17 had progressive disease; the drug was generally well tolerated. A good safety and efficacy profile has also been observed with the intratumoral and intravaginal administration of terameprocol in patients with head and neck or squamous cell carcinoma and in patients with cervical dysplasia, respectively. At the time of publication, terameprocol was in phase I or I/II clinical development for the treatment of glioma, treatment-refractory solid tumors and cervical dysplasia; a phase I clinical trial was also planned in patients with hematological cancers. Thus, the favorable tolerability and efficacy profile demonstrated for terameprocol to date suggests that the further investigation of this drug is warranted (source: IDrugs. 2008 Mar;11(3):204-14).

1: Grossman SA, Ye X, Peereboom D, Rosenfeld MR, Mikkelsen T, Supko JG, Desideri S; for the Adult Brain Tumor Consortium, Baltimore, MD. Phase I study of terameprocol in patients with recurrent high-grade glioma. Neuro Oncol. 2012 Feb 8. [Epub ahead of print] PubMed PMID: 22323663.

2: Oyegunwa AO, Sikes ML, Wilson JR, Scholle F, Laster SM. Tetra-O-methyl nordihydroguaiaretic acid (Terameprocol) inhibits the NF-κB-dependent transcription of TNF-α and MCP-1/CCL2 genes by preventing RelA from binding its cognate sites on DNA. J Inflamm (Lond). 2010 Dec 7;7:59. PubMed PMID: 21138578; PubMed Central PMCID: PMC3002343.

3: Sun Y, Giacalone NJ, Lu B. Terameprocol (tetra-O-methyl nordihydroguaiaretic acid), an inhibitor of Sp1-mediated survivin transcription, induces radiosensitization in non-small cell lung carcinoma. J Thorac Oncol. 2011 Jan;6(1):8-14. PubMed PMID: 21107289; PubMed Central PMCID: PMC3010256.

4: Pollara JJ, Laster SM, Petty IT. Inhibition of poxvirus growth by Terameprocol, a methylated derivative of nordihydroguaiaretic acid. Antiviral Res. 2010 Dec;88(3):287-95. Epub 2010 Oct 1. PubMed PMID: 20888364.

5: Eads D, Hansen R, Oyegunwa A, Cecil C, Culver C, Scholle F, Petty I, Laster S. Terameprocol, a methylated derivative of nordihydroguaiaretic acid, inhibits production of prostaglandins and several key inflammatory cytokines and chemokines. J Inflamm (Lond). 2009 Jan 8;6:2. PubMed PMID: 19133137; PubMed Central PMCID: PMC2631502.

6: Khanna N, Dalby R, Connor A, Church A, Stern J, Frazer N. Phase I clinical trial of repeat dose terameprocol vaginal ointment in healthy female volunteers. Sex Transm Dis. 2008 Jun;35(6):577-82. PubMed PMID: 18418294.

7: Smolewski P. Terameprocol, a novel site-specific transcription inhibitor with anticancer activity. IDrugs. 2008 Mar;11(3):204-14. Review. PubMed PMID: 18311658.

8: Khanna N, Dalby R, Tan M, Arnold S, Stern J, Frazer N. Phase I/II clinical safety studies of terameprocol vaginal ointment. Gynecol Oncol. 2007 Dec;107(3):554-62. Epub 2007 Oct 1. PubMed PMID: 17905420.

9: Lopez RA, Goodman AB, Rhodes M, Blomberg JA, Heller J. The anticancer activity of the transcription inhibitor terameprocol (meso-tetra-O-methyl nordihydroguaiaretic acid) formulated for systemic administration. Anticancer Drugs. 2007 Sep;18(8):933-9. PubMed PMID: 17667599.