Evaluation of systemic external microwave hyperthermia for treatment of pleural metastasis in orthotopic lung cancer model.
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.
Motomura
Tadashi
T
Baylor College of Medicine, Michael E DeBakey Department of Surgery, Houston, TX 77030, USA. tmotomura@sbcglobal.net
Ueda
Kentaro
K
Ohtani
Shoichiro
S
Hansen
Erlend
E
Ji
Lin
L
Ito
Koichi
K
Saito
Kazuyuki
K
Sugita
Yoichi
Y
Nosé
Yukihiko
Y
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