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Systemic Treatment with Tetra-O-Methyl Nordihydroguaiaretic Acid Suppresses the Growth of Human Xenograft Tumors

Authors' Affiliation: Department of Biology, Johns Hopkins University, Baltimore, Maryland

Requests for reprints: Ru Chih C. Huang, Biology Department, Johns Hopkins University, 249 Mudd Hall, 3400 North Charles Street, Baltimore, MD 21218-2685. Phone: 410-516-5181; Fax: 410-516-5213; E-mail: rhuang{at}jhu.edu.

Purpose: We have previously shown that the transcriptional inhibitor tetra-O-methyl nordihydroguaiaretic acid (M₄N) induces growth arrest in tumor cells and exhibits tumoricidal activity when injected intratumorally into tumor cell explants in mice. The experiments reported here were designed to determine whether M₄N can be given systemically and inhibit the growth of five different human xenograft tumors.

Experimental Design: Nude (nu/nu) mice bearing xenografts of each of five human tumor types (i.e., hepatocellular carcinoma, Hep 3B; prostate carcinoma, LNCaP; colorectal carcinoma, HT-29; breast carcinoma, MCF7; and erythroleukemia, K-562) were treated with M₄N given i.v. or i.p. in a Cremophor EL–based solvent system or orally in a corn oil based diet. Tumors from the treated animals were measured weekly and analyzed for the expression of the Cdc2 and survivin genes, both previously shown to be down-regulated by M₄N.

Results: Systemic M₄N treatment suppressed the in vivo growth of xenografts in each of the five human tumor types. Four of the five tumor models were particularly sensitive to M₄N with tumor growth inhibitions (T/C values) of 42%, whereas the fifth, HT-29, responded to a lesser extent (48.3%). Growth arrest and apoptosis in both the xenograft tumors and in the tumor cells grown in culture were accompanied by reductions in both Cdc2 and tumor-specific survivin gene expression. Pharmacokinetic analysis following oral and i.v. administration to ICR mice indicated an absolute bioavailability for oral M₄N of 88%. Minimal drug-related toxicity was observed.

Conclusion: These preclinical studies establish that when given systemically, M₄N can safely and effectively inhibit the growth of human tumors in nude mice.

Key Words: M₄N • CDC2 • survivin • Cremophor EL

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