Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells

Our plain-English summary of Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells, by S. Maehara, J. Usuda, T. Ishizumi, et al (International Journal of Oncology, 2015).

The study

• Authors: S. Maehara, J. Usuda, T. Ishizumi, S. Ichinose, K. Ohtani, T. Inoue, K. Imai, H. Furumoto, Y. Kudo, N. Kajiwara, T. Ohira, N. Ikeda
• Journal: International Journal of Oncology
• Published: 2015;46(2):741-9
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

To identify a possible new treatment modality for malignant pleural mesothelioma (MPM), we examined whether combination treatment consisting of pemetrexed chemotherapy and photodynamic therapy (PDT) using the photosensitizer NPe6, enhanced the antitumor effect in both in vitro and in vivo models. We also investigated preclinical treatment schedules. Four human malignant mesothelioma cell lines (MSTO‑211H, H2052, H2452 and H28) were assayed using the WST assay after treatment with pemetrexed and NPe6‑PDT. The treatment schedule for the combination treatment was examined using nude mice. Pemetrexed pre‑treatment enhanced the lethal effect of NPe6‑PDT in the four malignant mesothelioma cell lines, but NPe6‑PDT followed by pemetrexed treatment did not enhance cell lethality in the in vitro assay. Pemetrexed pre‑treatment did not enhance the intracellular accumulation of NPe6, which is one of the determinants of the antitumor effect of PDT. In nude mice injected with MSTO‑211H cells and then treated using a combination of pemetrexed and NPe6‑PDT (10 mg/kg NPe6, 10 J/cm(2) laser irradiation), the tumor volume decreased by 50% but subsequently increased, reaching the pre‑treatment value after 14 days. Pemetrexed treatment followed by NPe6‑PDT resulted in an 80% reduction in the tumor size and inhibited re‑growth. NPe6‑PDT followed by pemetrexed treatment resulted in a 60% reduction in tumor size but did not inhibit re‑growth. NPe6‑PDT induced the expression of thymidylate synthase (TS), which confers resistance to pemetrexed, and NPe6‑PDT followed by pemetrexed treatment did not enhance the treatment outcome in vivo. In conclusion, combination treatment, consisting of pemetrexed followed by NPe6‑PDT, should be further investigated as a new treatment modality for MPM. In the future, this combination treatment may contribute to a reduction in local recurrence and a prolonged survival period in patients with MPM.

In plain English

This was a laboratory study of a possible treatment for malignant pleural mesothelioma, using human cancer cell lines and mice. It did not involve patients or examine asbestos exposure. The authors combined the chemotherapy drug pemetrexed with photodynamic therapy (PDT), in which a light-sensitive drug, NPe6, is activated by laser light. In four mesothelioma cell lines, giving pemetrexed before PDT increased cell killing. Giving PDT before pemetrexed showed no added effect. In MSTO-211H cells, pemetrexed pre-treatment made no significant difference to how much NPe6 the cells took up. In nude mice carrying MSTO-211H tumors, pemetrexed followed by PDT gave an 80% loss in tumor volume and inhibited regrowth. PDT alone cut tumor volume by 50%, but the tumors regrew. PDT followed by pemetrexed did not inhibit regrowth. PDT raised levels of thymidylate synthase, a protein linked to pemetrexed resistance, in the mouse tumors, and the authors suggested this may explain why that order failed. The authors concluded that pemetrexed followed by NPe6-PDT should be investigated further. The article reports some laser doses and timings inconsistently.

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 experiments: human mesothelioma cell lines in culture (in vitro) and tumors grown in nude mice (animal experiment)
• Who was studied: Four human mesothelioma cell lines (H28, H2452, MSTO-211H and H2052) bought from the American Type Culture Collection, plus a human breast cancer cell line (MCF-7c3). Also five-week-old BALB/c nude mice injected under the skin with MSTO-211H cells, with experiments done under Tokyo Medical University animal guidelines.
• Exposure: No asbestos exposure was studied. The treatments were the chemotherapy drug pemetrexed and photodynamic therapy using the photosensitizer NPe6 with 664 nm laser light, given in different orders. In mice, pemetrexed was given at 150 mg/kg daily for five days and NPe6 at 10 mg/kg.
• Main results:
  • Pemetrexed alone, in cell lines: the IC50 (the dose killing half the cells) was 1.2 µM for MSTO-211H, 0.1 µM for NCI-H2052, 10 µM for NCI-H2452 and 8.4 µM for NCI-H28.
  • NPe6-PDT alone, in cell lines: it reached an LD90 (90% cell kill) in all the cell lines.
  • Pemetrexed followed by NPe6-PDT, in cell lines: the IC50 values were 0.08 µM for MSTO-211H, 0.14 µM for H28, 0.23 µM for H2452 and 0.06 µM for H2052.
  • NPe6-PDT followed by pemetrexed, in cell lines: it did not reach an IC50 response except in H2052 cells, and no enhancement was observed.
  • In MSTO-211H cells only, pemetrexed pre-treatment produced no significant difference in how much NPe6 accumulated inside the cells.
  • In mice with MSTO-211H tumors, pemetrexed followed by NPe6-PDT gave an 80% loss in tumor volume and inhibited regrowth.
  • In mice, NPe6-PDT alone reduced tumor volume by 50%, but the tumors grew back to their pre-treatment size 10 days after PDT.
  • In mice, NPe6-PDT followed by pemetrexed did not inhibit tumor regrowth.
  • In mice, NPe6-PDT induced thymidylate synthase (TS) expression in MSTO-211H tumors 24 hours after laser irradiation.
  • The authors suggested that PDT followed by pemetrexed failed to enhance cell killing possibly because PDT induced TS expression.
• The authors' conclusion: The authors concluded that combination treatment with pemetrexed followed by NPe6-PDT should be further investigated as a new treatment for malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors stated that further study is needed to explain why giving pemetrexed before NPe6-PDT has an additive effect.

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: Pemetrexed (Alimta), Pleural Mesothelioma, Chemotherapy, Malignant Mesothelioma.

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