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• W86363574 abstract "There have been many reports linking the overexpression of the lung resistance-related protein (LRP) with cross-resistance to chemotherapeutic drugs. However, no conclusive evidence existed to link LRP with a direct role in multidrug resistance (LRP). The OAW42SR is a cell line derived from a serous adenocarcinoma of the ovaries, and displays an increase in resistance to cytotoxic drugs concomitant with a moderate increase in LRP expression. Anti- LRP ribozyme and antisense expression plasmids were employed in this study in order to inhibit LRP expression in the OAW42SR cell line and examine any resulting effect on the drug resistance of the cells. Antisense oligonucleotides were also used to decrease LRP expression in the OAW42SR cell line in order to provide a clearer picture of whether LRP is involved in MDR.A large number of clones were isolated after transfection of the OAW42SR cell line with anti- LRP ribozyme and antisense expression plasmids. These clones displayed varying levels of LRP at both the mRNA and protein level. Cells transfected with only a control vector also displayed decreases in LRP expression, highlighting the extent of clonal variation within the OAW42SR population. The anti-LRP ribozyme construct appeared to significantly reduce LRP expression at both the mRNA and protein level. The anti-LRP antisense RNA construct failed to reduce LRP mRNA expression levels, but dramatically reduced LRP at the protein level. This demonstrated that antisense RNA acts mainly through steric inhibition of mRNA processing rather than cleavage of the target RNA, as with ribozymes. Resistance to anthracyclines and Vinca alkaloids was reduced in many of the clones. However, the levels of LRP expression could not be correlated with the reduction in resistance to the tested drugs. The levels of expression of the MDR facilitators, multidrug resistance gene 1 (mdr-1) and multidrug resistance-associated protein (MRP), within the clones was largely invariant, and could not be directly correlated with the observed reductions in drug resistance. The drug resistance profiles of the OAW42SR clones were, however, strikingly similar to that of typical mdr-1 overexpressing cell lines. It cannot be ruled out, therefore, that variation in Pglycoprotein activity, due to post-translational modifications, may be the sole mechanism of drug resistance in these clones. Antisense oligonucleotides targeted to LRP, reduced expression at both the mRNA and protein level in the OAW42SR cells, but failed to induce a reduction in resistance to adriamycin. This thesis provides the first direct evidence that LRP is not involved in multidrug resistance, at last within the OAW42SR cell line." @default.
• W86363574 created "2016-06-24" @default.
• W86363574 creator A5024954618 @default.
• W86363574 date "1998-01-01" @default.
• W86363574 modified "2023-09-24" @default.
• W86363574 title "Investigation of the role of LRP in multidrug resistance" @default.
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