The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice

Our plain-English summary of The therapeutic efficacy of S-1 against orthotopically implanted human pleural mesothelioma cells in severe combined immunodeficient mice, by T.T. Van, M. Hanibuchi, S. Kakiuchi, et al (Cancer Chemotherapy and Pharmacology, 2011).

The study

• Authors: T.T. Van, M. Hanibuchi, S. Kakiuchi, S. Sato, T. Kuramoto, H. Goto, A. Mitsuhashi, Y. Nishioka, S. Akiyama, S. Sone
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2011;68(2):497-504
• Cited by: 8 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Malignant pleural mesothelioma (MPM) is a highly lethal neoplasm. S-1 has been developed as a novel oral antineoplastic agent based on the modulation of 5-fluorouracil (5-FU) bioactivity. This study was conducted to investigate the preclinical therapeutic effect of S-1 on MPM.

Methods: We used three human MPM cell lines, Y-MESO-14, NCI-H290 and MSTO-211H. In vitro proliferation of human MPM cells was determined by MTT assay. Human MPM cells were orthotopically implanted into thoracic cavity of SCID mice. Tumor-bearing mice were treated with S-1 or vehicle.

Results: The combination of 5-FU and 5-chloro-2,4-dihydroxypyridine (CDHP) was more effective than 5-FU alone in inhibiting MPM cell proliferation in vitro. This combination was most effective in Y-MESO-14 cells, which co-expressed high protein level of dihydropyrimidine dehydrogenase (DPD) and thymidine phosphorylase (TP). In vivo data showed that treatment with S-1 significantly reduced thoracic tumors and pleural effusion produced by Y-MESO-14 cells. Moreover, treatment with S-1 prolonged the survival of Y-MESO-14 cell-bearing SCID mice.

Conclusions: We demonstrated that S-1 was effective for inhibiting the proliferation of MPM cells, particularly with both DPD and TP expressions, suggesting that S-1 might be therapeutically effective for control of MPM.

In plain English

This Japanese laboratory and animal study tested the oral anticancer drug S-1, based on 5-fluorouracil (5-FU), against malignant pleural mesothelioma. It did not study asbestos exposure or patients. The authors grew three human mesothelioma cell lines (Y-MESO-14, NCI-H290 and MSTO-211H) in dishes and implanted them into the chest cavity of male immune-deficient (SCID) mice. In dishes, adding CDHP, a component of S-1, to 5-FU significantly lowered the dose needed to halve cell growth in Y-MESO-14 and NCI-H290 cells, but not significantly in MSTO-211H. All three lines made the enzyme DPD. A second enzyme, TP, was detected in extracts of Y-MESO-14 cells only, and was clearly higher in Y-MESO-14 mouse tumors than in the others. S-1 given at 10 mg/kg daily significantly reduced chest tumors and pleural fluid from Y-MESO-14 cells in mice, but not significantly for the other two lines. Median survival with Y-MESO-14 tumors was 31 days on an inactive control and 42 days on either a 10-day or 14-day S-1 course. The authors concluded that S-1 may be a useful therapeutic agent for human pleural mesothelioma.

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: Preclinical laboratory study: experiments on cell lines in dishes and an animal experiment using an orthotopic (chest cavity) implantation model in mice. No human patients and no asbestos exposure were studied.
• Who was studied: Three human malignant pleural mesothelioma cell lines (Y-MESO-14, NCI-H290, MSTO-211H) and male SCID mice aged 6 to 7 weeks, kept under University of Tokushima animal care guidelines. The number of mice is not stated.
• Exposure: Treatment with the drug S-1 (tegafur plus the enzyme inhibitors CDHP and potassium oxonate), given orally at 5 or 10 mg/kg once daily to mice. In dishes, cells received 5-FU alone or 5-FU plus CDHP. Controls received vehicle (inactive solution). Asbestos exposure was not studied.
• Main results:
  • Y-MESO-14 cells in dishes: the dose of 5-FU needed to halve cell growth (IC50) was 0.22 with CDHP (95% CI 0.18 to 0.26) versus 0.92 with 5-FU alone (95% CI 0.75 to 1.1), P less than 0.0001.
  • NCI-H290 cells in dishes: IC50 was 0.41 with CDHP (95% CI 0.34 to 0.48) versus 0.59 with 5-FU alone (95% CI 0.50 to 0.70), P = 0.003.
  • MSTO-211H cells in dishes: IC50 was 0.57 with CDHP versus 0.77 with 5-FU alone, P = 0.20. The authors described this as the same tendency but not statistically significant.
  • In cell extracts, all three cell lines strongly expressed DPD protein. TP was expressed in Y-MESO-14 cells but was undetectable in the other two lines.
  • In chest tumors grown in mice, DPD levels were comparable among the three cell lines. TP was clearly higher in tumors from Y-MESO-14 cells than in tumors from NCI-H290 or MSTO-211H cells.
  • In mice, S-1 at 10 mg/kg daily from day 7 to day 20 significantly reduced thoracic tumors and pleural effusion from Y-MESO-14 cells compared with vehicle. For NCI-H290 cells there was a non-significant trend toward reduction. For MSTO-211H cells there was no obvious effect.
  • In Y-MESO-14 mice the effect was dose-dependent. The 10 mg/kg/day dose was significantly superior to 5 mg/kg/day in inhibiting tumor.
  • Shorter 10-day courses of S-1 (10 mg/kg/day, day 7 to 16 or day 11 to 20) both significantly reduced tumor weight and pleural effusion volume in Y-MESO-14 mice.
  • Median survival of Y-MESO-14 tumor-bearing mice was 31 days with vehicle, 42 days with 10-day S-1 and 42 days with 14-day S-1. Each S-1 group differed from vehicle with P = 0.02.
  • The authors reported that mice tolerated S-1 well, with no weight loss or other signs of toxicity, but the data were not shown.
• The authors' conclusion: The authors concluded that S-1 had promising antitumor effect on human mesothelioma cells that express both DPD and TP and prolonged survival of tumor-bearing mice. They suggested that S-1 may be a useful therapeutic agent for human malignant pleural mesothelioma.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm, Fluorouracil (5-FU), Pleural Effusion.

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