ABSTRACT
tetra-O-methylnordihydroguaiaretic acid is a derivative of a naturally-occurring lignan, nordihydroguaiaretic acid, that has previously been shown to inhibit various cancer types in vitro and in vivo. Additionally, nordihydroguaiaretic acid has been shown to have nephrotoxic effects in the rat. Here we show that tetra-O-methylnordihydroguaiaretic acid inhibits the growth of a number of tumor cell lines in vitro by inducing apoptosis in a non-schedule-dependent manner. Further, this compound inhibits the synthesis of DNA by melanoma cells and causes cell cycle arrest in G0/G1 and G2/M phases of the cell cycle. tetra-O-Methylnordihydroguaiaretic acid also inhibits the growth of both murine and human melanomas and human colon cancer in vivo without apparent hepatic or renal toxicity.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents, Phytogenic/therapeutic use , Colonic Neoplasms/drug therapy , Masoprocol/therapeutic use , Melanoma, Experimental/drug therapy , Adenocarcinoma/pathology , Animals , Antineoplastic Agents, Phytogenic/toxicity , Apoptosis/drug effects , Breast Neoplasms/pathology , Cell Cycle/drug effects , Colonic Neoplasms/pathology , DNA Replication/drug effects , Female , Intracellular Membranes/drug effects , Kidney/drug effects , Liver/drug effects , Lung Neoplasms/pathology , Male , Masoprocol/analogs & derivatives , Masoprocol/toxicity , Melanoma/pathology , Membrane Potentials/drug effects , Mice , Mice, Inbred C57BL , Mice, SCID , Mitochondria/drug effects , Neoplasm Transplantation , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/transplantation , Xenograft Model Antitumor AssaysABSTRACT
Nordihydroguaiaretic acid (NDGA) has been shown to inhibit both 5-lipoxygenase and ornithine decarboxylase and is active against several cancer cell lines and at least one mouse tumor model. Despite these findings, there have been no reports on the pharmacokinetics of NDGA. A reverse-phase high-performance liquid chromatography (HPLC) method was developed to detect NDGA in mouse plasma. The limit of detection of this method was 0.5 microg/ml. Administration of NDGA (50 mg/kg, i.v.) to mice resulted in a peak plasma concentration of 14.7 microg/ml. The terminal half-life of NDGA was 135.0 min with a clearance of 201.9 ml/min x kg.