{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:00:39Z","timestamp":1761058839885},"reference-count":38,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2008,6,19]],"date-time":"2008-06-19T00:00:00Z","timestamp":1213833600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2008,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Development of medical therapies for high\u2010grade cervical intraepithelial neoplasia (CIN II\/III) is hampered by the lack of CIN II\/III cell lines. Tumor necrosis factor\u2010related apoptosis\u2010inducing ligand (TRAIL) induces apoptosis upon binding to its receptors DR4 or DR5. Proteasome inhibition by MG132 sensitized cervical cancer cell lines to recombinant human (rh)TRAIL. In our study, we aimed to develop an <jats:italic>ex vivo<\/jats:italic> model for CIN II\/III and to investigate the apoptosis\u2010inducing effect of rhTRAIL and\/or MG132 in cervical explants from CIN II\/III patients. A short\u2010term <jats:italic>ex vivo<\/jats:italic> culture system was optimized for cervical biopsies, in which explants from normal cervix and CIN II\/III lesions were exposed to either rhTRAIL (1 \u03bcg\/ml), MG132 (5 \u03bcM) or the combination and compared to untreated explants for apoptosis induction. Normal cervix (<jats:italic>n<\/jats:italic> = 90) and CIN II\/III (<jats:italic>n<\/jats:italic> = 24) explants could be reproducibly put in culture and kept viable for up to 7 days using a transwell membrane system. CIN II\/III explants (<jats:italic>n<\/jats:italic> = 5) were highly sensitive to rhTRAIL plus MG132 (mean % apoptosis: 91 \u00b1 5) compared to normal cervix (<jats:italic>n<\/jats:italic> = 10) treated with rhTRAIL plus MG132 (mean % apoptosis: 24 \u00b1 10, <jats:italic>p<\/jats:italic> &lt; 0.0001), while monotherapy with either rhTRAIL, MG132 or medium resulted in a mean % apoptosis &lt;10 in both CIN II\/III and normal cervix. Our <jats:italic>ex vivo<\/jats:italic> model system allows preclinical evaluation of (topical) medical therapies for CIN II\/III. A strong synergistic apoptosis\u2010inducing effect of the combination of rhTRAIL and MG132, especially in CIN II\/III lesions indicates that rhTRAIL combined with proteasome inhibitors deserves exploration as medical treatment for CIN II\/III. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.23684","type":"journal-article","created":{"date-parts":[[2008,6,19]],"date-time":"2008-06-19T18:39:10Z","timestamp":1213900750000},"page":"1457-1465","source":"Crossref","is-referenced-by-count":13,"title":["A robust <i>ex vivo<\/i> model for evaluation of induction of apoptosis by rhTRAIL in combination with proteasome inhibitor MG132 in human premalignant cervical explants"],"prefix":"10.1002","volume":"123","author":[{"given":"Brigitte M.T.","family":"Hougardy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Reesink\u2010Peters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona A.J.","family":"van den Heuvel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaske A.","family":"ten Hoor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harry","family":"Hollema","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth G.E.","family":"de Vries","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"de Jong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ate G.J.","family":"van der 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