Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma

Our plain-English summary of Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma, by D. Karatkevich, H. Deng, Y. Gao, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: D. Karatkevich, H. Deng, Y. Gao, E. Flint, R.W. Peng, R.A. Schmid, P. Dorn, T.M. Marti
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(19)
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

In this laboratory study, the authors tested whether the timing of two standard chemotherapy drugs for malignant pleural mesothelioma, pemetrexed and cisplatin, changes how well they work. They used two mesothelioma cell lines grown in dishes, ACC-MESO-1 and NCI-H28. No patients or animals were studied, and asbestos exposure was not examined. Cells received pemetrexed for 72 hours plus 24 hours of cisplatin, started either at the same time as pemetrexed, after 24 hours of it, or after 48 hours of it. At day 10, giving both drugs together showed the greatest growth inhibition in both cell lines. Over the longer term, however, 48 hours of pemetrexed pretreatment significantly reduced the cells' ability to regrow compared with the other two schedules. In MESO-1 cells, about 30%, 40% and 70% of cells showed a marker of senescence (a lasting growth arrest) after the same-time, 24-hour and 48-hour schedules, respectively. A DNA damage signal (H2AX phosphorylation) was still higher on days 20 and 24 after the 48-hour pretreatment than after the other schedules. The authors concluded that adjusting the schedule can increase the combination's effectiveness in vitro, and that studies in living organisms are warranted.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study comparing three drug-timing schedules in mesothelioma cell lines
• Who was studied: Two malignant pleural mesothelioma cell lines, ACC-MESO-1 (MESO-1) and NCI-H28 (H28), purchased from the American Type Culture Collection; no human or animal subjects
• Exposure: Chemotherapy drugs, not asbestos: pemetrexed (MTA) at 1 µM for 72 hours, combined with cisplatin at 5 µM for 24 hours, started at 0 hours (concomitant), 24 hours, or 48 hours after pemetrexed began
• Main results:
  • At the end of the short-term assay (day 10), concurrent treatment showed the highest growth inhibitory effect in both cell lines
  • Compared with the other two schedules, 48 hours of pemetrexed pretreatment significantly reduced the long-term growth capacity of the mesothelioma cells
  • In MESO-1 cells, about 30% showed a senescent phenotype (by beta-galactosidase staining) after concomitant treatment, compared with 40% after 24-hour and 70% after 48-hour pemetrexed pretreatment
  • On day 17 of recovery, the share of enlarged, granular (F/S-high) cells was 26.4% after concomitant treatment, 33.9% after 24-hour pretreatment and 45.6% after 48-hour pretreatment
  • A marker of the DNA damage response (H2AX phosphorylation) was still increased on days 20 and 24 after 48-hour pemetrexed pretreatment, compared with the other two schedules
• The authors' conclusion: The authors concluded that the efficacy of pemetrexed-cisplatin combination therapy can be increased in vitro by adjusting the treatment schedule. They attributed the higher efficacy of prolonged pemetrexed pretreatment to persistent DNA damage leading to senescence.
• Limitations the authors state:
  • The authors stated that further experiments are needed on how folate supplementation might affect this strategy in an immunocompetent tumor model before clinical use
  • The authors stated that the findings need further investigation in vivo (in living organisms)
  • The authors stated that additional studies are needed on how tumor stage and tumor-specific DNA repair changes affect the efficacy and safety of these strategies

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Pemetrexed (Alimta), Cisplatin.

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• Efficacy of second-line treatment and prognostic factors in patients with advanced malignant peritoneal mesothelioma: a retrospective study — R. Kitadai, T. Shimoi, et al. (2021)
• Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients — C.J. Jennings, B. Murer, et al. (2015)

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