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K-Ras-independent effects of the farnesyl transferase inhibitor L-744,832 on cyclin B1/Cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells

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dc.contributor.author송시영-
dc.date.accessioned2019-11-11T05:21:52Z-
dc.date.available2019-11-11T05:21:52Z-
dc.date.issued2000-
dc.identifier.issn1522-8002-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/171811-
dc.description.abstractPancreatic ductal adenocarcinoma is a highly lethal malignancy that is resistant to traditional cytotoxic therapy. High rates of activating codon 12 K-Ras mutations in this disease have generated considerable interest in the therapeutic application of novel farnesyl transferase inhibitors (FTIs). However, a comprehensive analysis of the effects of FTI treatment on pancreatic cancer cells has not been performed. Treatment of five different human pancreatic cancer cell lines with FTI L-744,832 resulted in inhibition of anchorage-dependent growth, with wide variation in sensitivity among different lines. Effective growth inhibition by L-744,832 correlated with accumulation of cells with a tetraploid (4N) DNA content and high levels of cyclin B1/cdc2 kinase activity, implying cell cycle arrest downstream from the DNA damage-inducible G2/M cell cycle checkpoint. In addition, sensitive cell lines underwent apoptosis as evidenced by changes in nuclear morphology and internucleosomal DNA fragmentation. L-744,832 at a concentration of 1 microM additively enhanced the cytotoxic effect of ionizing radiation, apparently by overriding G2/M checkpoint activation. The effects of FTI treatment on cell growth and cell cycle regulation were associated with changes in posttranslational processing of H-Ras and N-Ras, but not K-Ras. The results confirm the potential therapeutic efficacy of FTI treatment in pancreatic cancer, and suggest that farnesylated proteins other than K-Ras may act as important regulators of G2/M cell cycle kinetics.-
dc.description.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherNeoplasia Press-
dc.relation.isPartOfNeoplasia-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHAntineoplastic Agents/pharmacology*-
dc.subject.MESHApoptosis/drug effects*-
dc.subject.MESHCarcinoma, Ductal, Breast/pathology*-
dc.subject.MESHCyclin B/metabolism*-
dc.subject.MESHCyclin B1-
dc.subject.MESHEnzyme Inhibitors/pharmacology*-
dc.subject.MESHG2 Phase/drug effects-
dc.subject.MESHGenes, ras/physiology*-
dc.subject.MESHHumans-
dc.subject.MESHMethionine/analogs & derivatives*-
dc.subject.MESHMethionine/pharmacology-
dc.subject.MESHMitosis/drug effects-
dc.subject.MESHPancreatic Neoplasms/pathology*-
dc.titleK-Ras-independent effects of the farnesyl transferase inhibitor L-744,832 on cyclin B1/Cdc2 kinase activity, G2/M cell cycle progression and apoptosis in human pancreatic ductal adenocarcinoma cells-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학교실)-
dc.contributor.googleauthorSi-Young Song-
dc.contributor.googleauthorIngrid M. Meszoely-
dc.contributor.googleauthorRobert J. Coffey-
dc.contributor.googleauthorJennifer A. Pietenpol-
dc.contributor.googleauthorSteven D. Leach-
dc.identifier.doi10.1038/sj.neo.7900088-
dc.contributor.localIdA02035-
dc.relation.journalcodeJ02312-
dc.identifier.eissn1476-5586-
dc.identifier.pmid10935512-
dc.subject.keywordfarnesylation-
dc.subject.keywordcyclin B/cdc2-
dc.subject.keywordmitosis-
dc.subject.keywordpancreas-
dc.subject.keywordcancer-
dc.contributor.alternativeNameSong, Si Young-
dc.contributor.affiliatedAuthor송시영-
dc.citation.volume2-
dc.citation.number3-
dc.citation.startPage261-
dc.citation.endPage272-
dc.identifier.bibliographicCitationNeoplasia, Vol.2(3) : 261-272, 2000-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers

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