title: Evaluation of systemic external microwave hyperthermia for treatment of pleural metastasis in orthotopic lung cancer model.
abstract: External microwave (EMW) hyperthermia system (2.45 GHz wave frequency) was evaluated by in vitro studies and in vivo pleural metastasis animal model. Three different non-small-cell lung cancer cells and normal fibroblast cells (control) were treated once a day for 3 days with the prototype EMW system applying mild (39 degrees C), moderate (43 degrees C), and severe (47 degrees C) hyperthermia. On Day-4, tested cells were retrieved and examined by apoptosis assay kit and Western blot analysis. Cancer cells treated with moderate hyperthermia showed significant apoptosis; yet no major damage was observed to normal fibroblast cells. Western blot analysis indicated cleavage on caspase-3, -9 and PARP. Also in the cell cycle analysis, increase of sub G0-G1 population was identified. After optimization of the heating intensity for in vivo environment, we created pleural metastatic animal model in 24 immune deficiency mice (male nu/nu mice) to evaluate inhibitory effect of systemic EMW hyperthermia for disseminated tumor growth. Out of 24 mice, 8 received mild and 8 received moderate hyperthermia, and remaining 8 were the no treatment control. Whole chest area of the experimental animals was irradiated 3 times a week for 2 weeks (total of 6 time irradiations). No significant adverse event was observed including abnormal weight loss, skin burn, ulceration, and death. Metastasized tumors around the pleura and chest cavity were 75% reduced in size and weight compared to non-treated control group. Harvested tumors were stained and TUNEL assay demonstrated significant apoptosis in a moderate hyperthermia group. The EMW hyperthermia system may be possible alternative tool as a systemic hyperthermia therapy in severely advanced lung cancer patients. Further study is necessary to determine device safeness, efficacy, and synergistic effect to other possible combination therapies.
authors.affiliation: Baylor College of Medicine, Michael E DeBakey Department of Surgery, Houston, TX 77030, USA. tmotomura@sbcglobal.net
authors.forename: Tadashi
authors.initials: T
authors.lastname: Motomura
authors.forename: Kentaro
authors.initials: K
authors.lastname: Ueda
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohtani
authors.forename: Erlend
authors.initials: E
authors.lastname: Hansen
authors.forename: Lin
authors.initials: L
authors.lastname: Ji
authors.forename: Koichi
authors.initials: K
authors.lastname: Ito
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Saito
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Sugita
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Nosé
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000528:radiation effects; D004249:DNA Damage; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects / Q000379:methods*; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008872:Microwaves / Q000009:adverse effects / Q000627:therapeutic use*; D010997:Pleural Neoplasms / Q000378:metabolism / Q000556:secondary / Q000628:therapy*; D011829:Radiation Dosage; D015398:Signal Transduction / Q000528:radiation effects; D013997:Time Factors; D047368:Tumor Burden / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays