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dc.contributor.authorJason, Tracey L. H.
dc.contributor.authorBerg, Randal W.
dc.contributor.authorVincent, Mark D.
dc.contributor.authorKoropatnick, James
dc.date.accessioned2018-10-31T06:23:41Z
dc.date.available2018-10-31T06:23:41Z
dc.date.issued2007
dc.date.modified2009-12-11T06:44:52Z
dc.identifier.issn15553884
dc.identifier.urihttp://hdl.handle.net/10072/27359
dc.description.abstractThymidylate synthase (TS) catalyses the only de novo pathway to produce thymidylate for DNA replication and repair and is an important target for cancer chemotherapy. Preexisting or acquired drug resistance in tumor cells limits clinical efficacy of TS-targeting drugs. Cells selected for higher TS protein activity have decreased sensitivity to TS-targeting chemotherapeutic agents (5-FUdR and raltitrexed). New therapeutic strategies are required to overcome treatment resistance. Among these, upregulation of drug resistance mediators in normal, nontarget cells and/or antisense wnregulation of those mediators (alone or in combination with protein-targeting drugs) are candidate strategies. We have targeted human TS mRNA with antisense oligodeoxynucleotides (AS ODNs), complementary to the translation start site (TSS), the coding region, and the 3' untranslated region. We report here that, in response to treatment with a novel TSS-targeting AS ODN 791, TS gene transcription in a human cervical carcinoma cell line (HeLa) was unexpectedly increased by 70%. Interestingly, the increased TS gene transcription and nuclear TS RNA did not elevate levels of total cellular TS mRNA, but did increase TS protein activity by 35% and TS protein level by 150%. Increased TS protein activity and level did not alter proliferation rate or sensitivity to TS-targeting drugs (5-FUdR or raltitrexed). To assess concentration-dependent effects of TS on sensitivity to TS-targeting drugs, incremental increases of TS protein levels were generated by transfection of a mammalian TS expression vector. Increases in TS protein of less than approximately 400% did not significantly affect sensitivity to TS-targeting drugs, while greater TS protein levels did. These data indicate that AS ODNs targeting TS mRNA can upregulate TS expression and activity in a manner dependent on the sequence being targeted, and that there exists a threshold increase (greater than approximately 400-700% in HeLa cells), required to initiate resistance to TS-targeting drugs.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherCognizant Communication Corporation
dc.publisher.placeUSA
dc.publisher.urihttp://www.ingentaconnect.com
dc.relation.ispartofstudentpublicationY
dc.relation.ispartofpagefrom227
dc.relation.ispartofpageto239
dc.relation.ispartofissue4-5
dc.relation.ispartofjournalGene Expression
dc.relation.ispartofvolume13
dc.rights.retentionY
dc.subject.fieldofresearchGenetics
dc.subject.fieldofresearchcode0604
dc.titleAntisense targeting of thymidylate synthase (TS) mRNA increases TS gene transcription and TS protein: effects on human tumor cell sensitivity to TS enzyme-inhibiting drugs
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionVersion of Record (VoR)
gro.rights.copyright© 2006 Cognizant Communication Corporation. The attached file is reproduced here in accordance with the copyright policy of the publisher. Please refer to the journal's website for access to the definitive, published version.
gro.date.issued2007
gro.hasfulltextFull Text
gro.griffith.authorJason, Tracey


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