Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma.

Karatkevich, Darya; Deng, Haibin; Gao, Yanyun; Flint, Emilio; Peng, Ren-Wang; Schmid, Ralph Alexander; Dorn, Patrick; Marti, Thomas Michael (2022). Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma. International journal of molecular sciences, 23(19) MDPI 10.3390/ijms231911949

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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 γH2AX (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.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Karatkevich, Darya, Deng, Haibin, Gao, Yanyun, Peng, Ren-Wang, Schmid, Ralph, Dorn, Patrick, Marti, Thomas


600 Technology > 610 Medicine & health








Pubmed Import

Date Deposited:

17 Oct 2022 12:48

Last Modified:

05 Dec 2022 16:26

Publisher DOI:


PubMed ID:


Uncontrolled Keywords:

DNA damage chemotherapy cisplatin malignant pleural mesothelioma pemetrexed schedule-dependent treatment senescence




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