Combination effect of photodynamic therapy using NPe6 with pemetrexed for human malignant pleural mesothelioma cells.
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.
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Sachio
S
Maehara
Department of Thoracic Surgery, Nippon Medical School, Tokyo 113‑8603, Japan.
Jitsuo
J
Usuda
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Taichiro
T
Ishizumi
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Shuji
S
Ichinose
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Keishi
K
Ohtani
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Tatsuya
T
Inoue
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Kentaro
K
Imai
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Hideyuki
H
Furumoto
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Yujin
Y
Kudo
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Naohiro
N
Kajiwara
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Tatsuya
T
Ohira
Department of Surgery, Tokyo Medical University, Tokyo 160‑0023, Japan.
Norihiko
N
Ikeda
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D005971:Glutamates / Q000008:administration & dosage*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D000068437:Pemetrexed; D010778:Photochemotherapy; D010997:Pleural Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011166:Porphyrins / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
D005971:Glutamates; D011166:Porphyrins; D000068437:Pemetrexed; D006147:Guanine; C053434:Talaporfin; D002945:Cisplatin