Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment

Our plain-English summary of Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment, by D. Karatkevich, T. Losmanova, P. Zens, et al (Scientific Reports, 2024).

The study

• Authors: D. Karatkevich, T. Losmanova, P. Zens, H. Deng, C. Dubey, T. Zhang, C. Casty, Y. Gao, C. Neppl, S. Berezowska, W. Wang, R.W. Peng, R.A. Schmid, P. Dorn, T.M. Marti
• Journal: Scientific Reports
• Published: 2024;14(1):18206
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism. This study investigated a schedule-dependent treatment strategy, proposing that initial chemotherapy induces CDA expression, sensitizing cells to subsequent capecitabine treatment. Basal CDA protein expression was low in different mesothelioma cell lines but increased in the corresponding xenografts. Standard chemotherapy increased CDA protein levels in MPM cells in vitro and in vivo in a schedule-dependent manner. This was associated with epithelial-to-mesenchymal transition and with HIF-1alpha expression at the transcriptional level. In addition, pretreatment with cisplatin and pemetrexed in combination sensitized MPM xenografts to capecitabine. Analysis of a tissue microarray (TMA) consisting of samples from 98 human MPM patients revealed that most human MPM samples had negative CDA expression. While survival curves based on CDA expression in matched samples clearly separated, significance was not reached due to the limited sample size. In non-matched samples, CDA expression before but not after neoadjuvant therapy was significantly associated with worse overall survival. In conclusion, chemotherapy increases CDA expression in xenografts, which is consistent with our in vitro results in MPM and lung cancer. A subset of matched patient samples showed increased CDA expression after therapy, suggesting that a schedule-dependent treatment strategy based on chemotherapy and capecitabine may benefit a selected MPM patient population.

© 2024. The Author(s).

In plain English

This laboratory study from Bern, Switzerland, tested whether standard chemotherapy for malignant pleural mesothelioma (cisplatin plus pemetrexed) raises levels of cytidine deaminase (CDA), an enzyme that helps convert the drug capecitabine into its active form. The study did not examine asbestos exposure. CDA was generally low in mesothelioma cell lines but rose after 24 hours of chemotherapy in MESO-1 cells, peaking on day 6. In mice carrying MESO-1 tumors, the authors gave chemotherapy first and capecitabine one week later. With this schedule, the accelerated tumor regrowth seen with other regimens did not occur before the experiment ended on day 100. This schedule also gave the lowest tumor weights; no regimen significantly affected body weight. In tumor samples from 98 patients, only 14.4% of samples stained positive for CDA. In non-matched samples, CDA before neoadjuvant therapy was significantly associated with worse overall survival (p = 0.029, n = 57); CDA after therapy was not significantly associated (p = 0.71, n = 69). The authors concluded this sequenced approach may be a promising and affordable option. They noted that the mice were not followed beyond 100 days.

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 study combining cell-line experiments, a mouse xenograft treatment experiment, analysis of public gene-expression databases, and a tissue microarray analysis of patient tumor samples
• Who was studied: Seven malignant pleural mesothelioma (MPM) cell lines and one non-small cell lung cancer cell line (H358). RAG mice of mixed sex, aged 6 to 8 weeks, with MESO-1 tumors implanted under the skin (n = 4 or 5 per group). Tumor samples from 98 patients with consecutively resected MPM at Bern University Hospital, Switzerland (867 tissue cores: 327 before and 540 after neoadjuvant therapy). Public gene-expression data, including 82 MPM tumors from TCGA. Study dates not given.
• Exposure: No asbestos or fiber exposure was studied. The exposures were cancer drugs. In mice: cisplatin (4 mg/kg) plus pemetrexed (300 mg/kg); capecitabine (360 mg/kg by mouth for 5 days every second week); or the triple combination, with capecitabine given 1 week after chemotherapy, over 3 two-week cycles. In cells: 10 μM cisplatin and 5 μM pemetrexed for 24 h, the capecitabine metabolite 5’-DFCR, and low oxygen (hypoxia).
• Main results:
  • The MPM cell lines MESO-1 and JL-1 were relatively insensitive to 5’-DFCR on its own; the concentrations needed to halve cell viability (IC50) were 3.3 mM and 5.0 mM, respectively.
  • In MESO-1 cells, CDA rose over time after 24 h of cisplatin plus pemetrexed, peaking on day 6 after treatment.
  • In MESO-1 tumors in mice, chemotherapy increased CDA compared with untreated tumors. The increase was seen at 24 h, continued up to day 13, and persisted.
  • In mice, the schedule with chemotherapy on day 1 and capecitabine on days 8 to 12 did not reach the accelerated tumor growth phase before the experiment ended on day 100.
  • On day 100, tumor weight in mice was lower after concurrent triple therapy than after chemotherapy or capecitabine alone, and lower still after the schedule-dependent triple therapy.
  • Mouse body weight was not significantly affected by any of the treatment regimens.
  • In the patient tissue microarray, only 14.4% of samples stained positive for CDA. Before neoadjuvant therapy, 11 of 57 patient samples expressed CDA.
  • In 28 patients with samples from both before and after neoadjuvant therapy, CDA scores did not differ significantly overall (p = 0.185). Considering only tumor centers, CDA was significantly higher after therapy (p = 0.035, n = 26).
  • In non-matched patient samples, CDA before neoadjuvant therapy was significantly associated with worse overall survival (p = 0.029, n = 57).
  • In non-matched patient samples, CDA after neoadjuvant therapy was not significantly associated with overall survival (p = 0.71, n = 69).
  • In the 28 paired patient samples, an increase in CDA was not significantly associated with worse survival (p = 0.18), although the survival curves separated.
  • In 82 MPM tumors from the TCGA database, high CDA expression significantly correlated with a higher epithelial-to-mesenchymal transition (EMT) score.
• The authors' conclusion: The authors concluded that a schedule-dependent, capecitabine-based therapy (standard chemotherapy first, capecitabine later) may be a promising and affordable option for lung cancer, MPM and other rare cancers. They also suggested it may benefit a selected MPM patient population.
• Limitations the authors state:
  • Tumor growth in the mice given the schedule-dependent triple regimen was not followed beyond 100 days, the point when control tumors reached maximum tolerable size.
  • An immune-competent animal model with tumors grown in the pleura (orthotopic) would better evaluate the combination therapy and its possible interaction with immunotherapy.
  • The paired patient survival analysis was limited by sample size.
  • Hypoxia was tested only at 1% oxygen, while actual tumor oxygen levels are likely lower.
  • Only two sarcomatoid tumors were available in the public dataset used to compare CDA across tumor types.

Topics

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

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, Capecitabine, Cisplatin, Pemetrexed (Alimta), Fluorouracil (5-FU), Mesothelioma, Neoadjuvant Therapy.

Related studies

• Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma — D. Karatkevich, H. Deng, et al. (2022)
• Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts — P.M. Tedeschi, Y.K. Kathari, et al. (2014)
• Starvation-induced activation of ATM/Chk2/p53 signaling sensitizes cancer cells to cisplatin — Y. Shi, E. Felley-Bosco, et al. (2012)
• The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma — N. Erčulj, V. Kovač, et al. (2012)
• Agonist activation of estrogen receptor beta (ERβ) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity — G. Pinton, A.G. Manente, et al. (2014)
• Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth — R.G. van der Most, A.J. Currie, et al. (2009)

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