Research Project
2112820
DESCRIPTION: (Adapted from the Applicant's Abstract). Multi-drug resistance (MDR) is a common problem in cancer chemotherapy. One important form of MDR involves overexpression of a gene that codes for a drug transport ATPase, the P-glycoprotein. Inhibition of P- glycoprotein function by suppression of P-glycoprotein expression could have a significant impact on cancer therapy. One important means for selectively modulating the expression of the individual genes involves use of antisense oligonucleotides. These compounds can inhibit gene expression by interfering with several steps in the pathway of mRNA expression, maturation, and translation into protein. The applicants have recently demonstrated that expression of the MDRI drug resistance gene can be blocked using phosphorothioate antisense oligonucleotides in a cell culture model using an oligonucleotide complementary to the region flanking the AUG translation initiation cordon. These observations will be extended to try to develop a practical approach to modulation of MDR in vivo using antisense technology. This effort will have two components. (1) Additional forms of chemically modified oligonucleotides will be used in their tissue culture model to try to identify compounds that have greater potency and efficacy for inhibiting MDR. (2) Antisense strategies will be evaluated for their ability to reduce MDR in an in vivo setting. An MDR overexpressing human breast tumor cell line xenotransplanted into nude mice will be used as a model system. Antisense compounds directed against P-glycoprotein message, and selected for high potency and efficacy in vitro will be tested in the animal tumor model for the ability to increase responsiveness to anti- cancer drugs.
