Drug resistance is one of the major problems associated with cancer treatments that use cytotoxic drugs such as Doxorubicin (Dox), vinblastine, paclitaxel, vincristine and others.Long term use of Dox, for example, causes drug resistance to occur in primary and in metastatic tumors resulting from high MDR-1 gene expression and accumulation of the cellular ATPase drug transporter protein Pgp.Pgp acts to expel drugs from the tumor cells resulting in less of the drug being situated where it is able to inhibit tumor growth.A synthetic derivative of the naturally occurring plant Lignan, tetra-o-methyl nordihydroguiaretic acid, NDGA (M4N, Terameprocol), was found to possess antiviral and anticancer activities by blocking the over expression of a variety of the Sp1 regulated genes in a mutation insensitive manner.In addition, M4N was found to be able to inhibit Dox induced MDR gene expression, synthesis of Pgp protein and prevent the "pump-out" of Dox from drug treated cells.In vivo, it was discovered that M4N was extremely effective in elimination of human ovarian cancer xenografts of NCI/ADR-RES cells, a cell line that has already acquired strong resistance to Dox.M4N was equally effective in preventing cancer cells to acquire resistance after chemotherapy.It blocks the induction of MDR gene expression when used in combination with doxorubicin.Results on slowing down Dox efflux are consistent with the reduction of Pgp levels in these cells following M4N/Dox treatment.Thus, in addition to being an effective cancer agent in its own right (US Pat Nos.6,214,874;6,417,234 and 6,608,108) M4N may be able to solve some of the drug resistance problems associated with many cytotoxic drugs commonly used in clinics.Several phase Ⅱ M4N combination trials will be initiated in the Fall of 2012.