{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T11:36:55Z","timestamp":1770291415282,"version":"3.49.0"},"reference-count":29,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T00:00:00Z","timestamp":1665187200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004361","name":"the Swiss Cancer Research to TMM","doi-asserted-by":"publisher","award":["KFS-5405-08-2021-R"],"award-info":[{"award-number":["KFS-5405-08-2021-R"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004361","name":"the Swiss Cancer Research to TMM","doi-asserted-by":"publisher","award":["2020.0046"],"award-info":[{"award-number":["2020.0046"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004361","name":"the Swiss Cancer Research to TMM","doi-asserted-by":"publisher","award":["KFS-4851-08-2019"],"award-info":[{"award-number":["KFS-4851-08-2019"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004361","name":"the Swiss Cancer Research to TMM","doi-asserted-by":"publisher","award":["310030_192648"],"award-info":[{"award-number":["310030_192648"]}],"id":[{"id":"10.13039\/501100004361","id-type":"DOI","asserted-by":"publisher"}]},{"name":"a Swiss Government Excellence Scholarship","award":["KFS-5405-08-2021-R"],"award-info":[{"award-number":["KFS-5405-08-2021-R"]}]},{"name":"a Swiss Government Excellence Scholarship","award":["2020.0046"],"award-info":[{"award-number":["2020.0046"]}]},{"name":"a Swiss Government Excellence Scholarship","award":["KFS-4851-08-2019"],"award-info":[{"award-number":["KFS-4851-08-2019"]}]},{"name":"a Swiss Government Excellence Scholarship","award":["310030_192648"],"award-info":[{"award-number":["310030_192648"]}]},{"name":"the Swiss Cancer Research Foundation","award":["KFS-5405-08-2021-R"],"award-info":[{"award-number":["KFS-5405-08-2021-R"]}]},{"name":"the Swiss Cancer Research Foundation","award":["2020.0046"],"award-info":[{"award-number":["2020.0046"]}]},{"name":"the Swiss Cancer Research Foundation","award":["KFS-4851-08-2019"],"award-info":[{"award-number":["KFS-4851-08-2019"]}]},{"name":"the Swiss Cancer Research Foundation","award":["310030_192648"],"award-info":[{"award-number":["310030_192648"]}]},{"name":"the Swiss National Science Foundation","award":["KFS-5405-08-2021-R"],"award-info":[{"award-number":["KFS-5405-08-2021-R"]}]},{"name":"the Swiss National Science Foundation","award":["2020.0046"],"award-info":[{"award-number":["2020.0046"]}]},{"name":"the Swiss National Science Foundation","award":["KFS-4851-08-2019"],"award-info":[{"award-number":["KFS-4851-08-2019"]}]},{"name":"the Swiss National Science Foundation","award":["310030_192648"],"award-info":[{"award-number":["310030_192648"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis. Cisplatin causes direct DNA damage, such as intra-strand and inter-strand cross-links, which are repaired by the nucleotide excision repair pathway, which depends on relatively high nucleotide levels. We hypothesized that prolonged pretreatment with pemetrexed might deplete nucleotide pools, thereby sensitizing cancer cells to subsequent cisplatin treatment. The MPM cell lines ACC-MESO-1 and NCI-H28 were treated for 72 h with pemetrexed. Three treatment schedules were evaluated by initiating 24 h of cisplatin treatment at 0 h (concomitant), 24 h, and 48 h relative to pemetrexed treatment, resulting in either concomitant administration or pemetrexed pretreatment for 24 h or 48 h, respectively. Multicolor flow cytometry was performed to detect \u03b3H2AX (phosphorylation of histone H2AX), a surrogate marker for the activation of the DNA damage response pathway. DAPI staining of DNA was used to analyze cell cycle distribution. Forward and side scatter intensity was used to distinguish subpopulations based on cellular size and granularity, respectively. Our study revealed that prolonged pemetrexed pretreatment for 48 h prior to cisplatin significantly reduced long-term cell growth. Specifically, pretreatment for 48 h with pemetrexed induced a cell cycle arrest, mainly in the G2\/M phase, accumulation of persistent DNA damage, and induction of a senescence phenotype. The present study demonstrates that optimizing the treatment schedule by pretreatment with pemetrexed increases the efficacy of the pemetrexed-cisplatin combination therapy in MPM. We show that the observed benefits are associated with the persistence of treatment-induced DNA damage. Our study suggests that an adjustment of the treatment schedule could improve the efficacy of the standard chemotherapy regimen for MPM and might improve patient outcomes.<\/jats:p>","DOI":"10.3390\/ijms231911949","type":"journal-article","created":{"date-parts":[[2022,10,8]],"date-time":"2022-10-08T23:39:31Z","timestamp":1665272371000},"page":"11949","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma"],"prefix":"10.3390","volume":"23","author":[{"given":"Darya","family":"Karatkevich","sequence":"first","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"},{"name":"Graduate School of Cellular and Biomedical Sciences, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6823-313X","authenticated-orcid":false,"given":"Haibin","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanyun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9125-6559","authenticated-orcid":false,"given":"Emilio","family":"Flint","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1199-6520","authenticated-orcid":false,"given":"Ren-Wang","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ralph Alexander","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7203-3122","authenticated-orcid":false,"given":"Patrick","family":"Dorn","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3005-220X","authenticated-orcid":false,"given":"Thomas Michael","family":"Marti","sequence":"additional","affiliation":[{"name":"Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Murtenstrasse 28, 3008 Bern, Switzerland"},{"name":"Oncology-Thoracic Malignancies, Department of BioMedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6881","DOI":"10.1200\/JCO.20005.14.589","article-title":"Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: An intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada","volume":"23","author":"Gaafar","year":"2005","journal-title":"J. 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