{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T18:05:45Z","timestamp":1781201145775,"version":"3.54.1"},"reference-count":50,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,1,22]],"date-time":"2019-01-22T00:00:00Z","timestamp":1548115200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res & Perspec"],"published-print":{"date-parts":[[2019,2]]},"abstract":"Abstract<\/jats:title>Pretubulysin (PT<\/jats:styled-content>), a potent tubulin\u2010binding antitumoral drug, and the well\u2010established antimetabolite methotrexate (MTX<\/jats:styled-content>) were tested separately or in combination (PT<\/jats:styled-content>+MTX<\/jats:styled-content>) for antitumoral activity in L1210 leukemia cells or KB<\/jats:styled-content> cervix carcinoma cells in\u00a0vitro and in\u00a0vivo in NMRI<\/jats:styled-content>\u2010nu\/nu tumor mouse models. In cultured L1210 cells, treatment with PT<\/jats:styled-content> or MTX<\/jats:styled-content> displays strong antitumoral effects in\u00a0vitro,<\/jats:italic> and the combination PT<\/jats:styled-content>+MTX<\/jats:styled-content> exceeds the effect of single drugs. PT<\/jats:styled-content> also potently kills the MTX<\/jats:styled-content> resistant KB<\/jats:styled-content> cell line, without significant MTX<\/jats:styled-content> combination effect. Cell cycle analysis reveals the expected arrest in G1\/S by MTX<\/jats:styled-content> and in G2\/M by PT<\/jats:styled-content>. In both cell lines, the PT<\/jats:styled-content>+MTX<\/jats:styled-content> combination induces a G2\/M arrest which is stronger than the PT<\/jats:styled-content>\u2010triggered G2\/M arrest. PT<\/jats:styled-content>+MTX<\/jats:styled-content> does not change rates of apoptotic L1210 or KB<\/jats:styled-content> cells as compared to single drug applications. Confocal laser scanning microscopy images show the microtubule disruption and nuclear fragmentation induced by PT<\/jats:styled-content> treatment of L1210 and KB<\/jats:styled-content> cells. MTX<\/jats:styled-content> changes the architecture of the F\u2010actin skeleton. PT<\/jats:styled-content>+MTX<\/jats:styled-content> combines the toxic effects of both drugs. In the in\u00a0vivo setting, the antitumoral activity of drugs differs from their in\u00a0vitro cytotoxicity, but their combination effects are more pronounced. MTX<\/jats:styled-content> on its own does not display significant antitumoral activity, whereas PT<\/jats:styled-content> reduces tumor growth in both L1210 and KB<\/jats:styled-content> in\u00a0vivo models. Consistent with the cell cycle effects, MTX<\/jats:styled-content> combined at moderate dose boosts the antitumoral effect of PT<\/jats:styled-content> in both in\u00a0vivo tumor models. Therefore, the PT<\/jats:styled-content>+MTX<\/jats:styled-content> combination may present a promising therapeutic approach for different types of cancer.<\/jats:p>","DOI":"10.1002\/prp2.460","type":"journal-article","created":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T08:17:30Z","timestamp":1548317850000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Combined antitumoral effects of pretubulysin and methotrexate"],"prefix":"10.1002","volume":"7","author":[{"given":"Sarah","family":"Kern","sequence":"first","affiliation":[{"name":"Pharmaceutical Biotechnology Center for System\u2010Based Drug Research, and Center for Nanoscience (CeNS) Ludwig\u2010Maximilians\u2010Universit\u00e4t Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines","family":"Truebenbach","sequence":"additional","affiliation":[{"name":"Pharmaceutical Biotechnology Center for System\u2010Based Drug 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