International Journal of Oncology 2014 November 10 [Epub ahead of print] [Link]
Maehara S, Usuda J, Ishizumi T, Ichinose S, Ohtani K, Inoue T, Imai K, Furumoto H, Kudo Y, Kajiwara N, Ohira T, Ikeda N.
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 (MSTOâ€‘211H, H2052, H2452 and H28) were assayed using the WST assay after treatment with pemetrexed and NPe6â€‘PDT. The treatment schedule for the combination treatment was examined using nude mice. Pemetrexed preâ€‘treatment enhanced the lethal effect of NPe6â€‘PDT in the four malignant mesothelioma cell lines, but NPe6â€‘PDT followed by pemetrexed treatment did not enhance cell lethality in the in vitro assay. Pemetrexed preâ€‘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 MSTOâ€‘211H cells and then treated using a combination of pemetrexed and NPe6â€‘PDT (10 mg/kg NPe6, 10 J/cm2 laser irradiation), the tumor volume decreased by 50% but subsequently increased, reaching the preâ€‘treatment value after 14 days. Pemetrexed treatment followed by NPe6â€‘PDT resulted in an 80% reduction in the tumor size and inhibited reâ€‘growth. NPe6â€‘PDT followed by pemetrexed treatment resulted in a 60% reduction in tumor size but did not inhibit reâ€‘growth. NPe6â€‘PDT induced the expression of thymidylate synthase (TS), which confers resistance to pemetrexed, and NPe6â€‘PDT followed by pemetrexed treatment did not enhance the treatment outcome in vivo. In conclusion, combination treatment, consisting of pemetrexed followed by NPe6â€‘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.