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Tetra-O-methyl Nordihydroguaiaretic Acid Induces G₂ Arrest in Mammalian Cells and Exhibits Tumoricidal Activity in Vivo¹

Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218 [J. D. H., J. K., R. C. C. H.]; Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland 21205 [T. C. W.]; and Cancer Immunology Program, Cardinal Bernardin Cancer Center, Loyola University, Chicago, Illinois 60626 [W. M. K.]

The transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M₄N) was found to arrest the proliferation of C3, C33a, CEM-T4, and TC-1 cells in culture at the G₂ stage of the cell cycle. Investigation into the mechanism of arrest revealed that M₄N reduces mRNA levels and subsequent protein production of the cyclin-dependent kinase CDC2, resulting in the inactivation of the CDC2/cyclin B complex (maturation promoting factor). When injected intratumorally in a C3-cell induced C57bl/6 mouse tumor model system, M₄N demonstrated substantial tumoricidal activity that correlated with a reduction in tumor cell CDC2 protein levels. These findings suggest that M₄N may be a useful chemotherapeutic agent for the control of unregulated cellular proliferation.

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