The ability of tumor cells to become resistant to a variety of chemotherapeutic agents is a major unsolved problem in clinical oncology. Research in this area has provided strong evidence that the overexpression of a single gene (MDRI), which encodes a membrane-bound glycoprotein, contributes to the resistance of a large proportion of drug-resistant tumors present in the clinic. This glycoprotein (Pgp) actively transports a variety of chemotherapeutic agents out of the cell; thereby, this activity conveys resistance. We will regulate the expression of the MDRI gene using antisense oligodeoxynucleotides (later phosphorothioates) targeted to MDRI mRNA. We will initially employ a transgenic cell system wherein the cloned human MDRI gene is overexpressed in NIH3T3 cells. Restoration of drug sensitivity in these cells provides a rapid and effective screen for specific inhibitors of MDRI gene expression and the gene product. We will confirm the effectiveness of anti sense sequences identified using this screen by characterizing their effects on Pgp activity at a functional and molecular level. Lastly, we will determine the ability of antisense sequences to sensitize human tumor cells resistant to chemotherapeutic agents. The results of these studies will contribute to the development of new treatment modalities effective in overcoming multidrug resistance in human cancer.Awardee's statement of the potential commercial applications of the research: There are approximately I ,000,000 new cancer cases in the us each year, half of which are curable by surgery or radiotherapy. Nearly half of the remaining cancers (i. e. 250,000) exhibit resistance to chemotherapeutic agents and high percentage of these over-express the MDRI gene, the product of which contributes to resistance. A selective inhibitor of this gene product will have a significant place in the clinic and, thus, a substantial market.National Institute of General Medical Sciences (NIGMS)
