4T1マウス担癌モデルに対する局所高周波温熱療法の遠隔転移抑制効果
高周波温熱療法 (Radiofrequency hyperthermia, 以下RF) は悪性腫瘍の治療法として広く用いられ効果を上げている. 腫瘍の原発巣に対して温熱療法を行った症例の内, 転移巣の縮小を見る症例がある. 本研究ではマウスの担癌モデルを用いて, 局所温熱療法による原発巣および転移巣の抗腫瘍効果を検討したので報告する. 6週齢の雌BALB/cマウスの左下肢に4T1/lucマウス乳癌細胞を接種し, 8 MHzの高周波温熱治療器を用いて週2回, 3週間の温熱治療を行った. また別のモデルとして腫瘍細胞接種後7日目に腫瘍中心部にドキソルビシン (doxorubicin, 以下DXR)...
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| Published in | Thermal Medicine Vol. 26; no. 1; pp. 19 - 29 |
|---|---|
| Main Authors | , , , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本ハイパーサーミア学会
2010
|
| Online Access | Get full text |
| ISSN | 1882-2576 1882-3750 |
| DOI | 10.3191/thermalmed.26.19 |
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| Abstract | 高周波温熱療法 (Radiofrequency hyperthermia, 以下RF) は悪性腫瘍の治療法として広く用いられ効果を上げている. 腫瘍の原発巣に対して温熱療法を行った症例の内, 転移巣の縮小を見る症例がある. 本研究ではマウスの担癌モデルを用いて, 局所温熱療法による原発巣および転移巣の抗腫瘍効果を検討したので報告する. 6週齢の雌BALB/cマウスの左下肢に4T1/lucマウス乳癌細胞を接種し, 8 MHzの高周波温熱治療器を用いて週2回, 3週間の温熱治療を行った. また別のモデルとして腫瘍細胞接種後7日目に腫瘍中心部にドキソルビシン (doxorubicin, 以下DXR) を注入し増殖を抑制したモデルを作成した. 原発巣の腫瘍体積および重量の計測と転移巣の評価を組織学的に行う方法と, ルシフェラーゼによる蛍光活性を測定し評価した. 担癌マウスで脾臓の腫大を認めたため, 脾臓細胞内のリンパ球構成をフローサイトメトリーを用いて調べた. 原発巣の腫瘍体積および重量は, RFを行った群とDXRを腫瘍内注入した群で共に抑制されていたが, 肺転移は組織学的評価と蛍光活性を用いた評価とも, RFを行った群でのみ抑制されていた. 今回の実験では肝転移は認められなかった. さらにRFを行った群では生存期間の有意な延長を認めた. 脾臓細胞内のリンパ球構成では, RFを行った群でNK細胞数の有意な増加を認めた. 以上の結果から高周波温熱療法単独で, 腫瘍の縮小および肺転移の抑制効果が見られ, 生存期間も有意に延長を認めた. その機序については脾臓内リンパ球のフローサイトメトリーの結果からNK細胞の関与が最も考えられた. |
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| AbstractList | 高周波温熱療法 (Radiofrequency hyperthermia, 以下RF) は悪性腫瘍の治療法として広く用いられ効果を上げている. 腫瘍の原発巣に対して温熱療法を行った症例の内, 転移巣の縮小を見る症例がある. 本研究ではマウスの担癌モデルを用いて, 局所温熱療法による原発巣および転移巣の抗腫瘍効果を検討したので報告する. 6週齢の雌BALB/cマウスの左下肢に4T1/lucマウス乳癌細胞を接種し, 8 MHzの高周波温熱治療器を用いて週2回, 3週間の温熱治療を行った. また別のモデルとして腫瘍細胞接種後7日目に腫瘍中心部にドキソルビシン (doxorubicin, 以下DXR) を注入し増殖を抑制したモデルを作成した. 原発巣の腫瘍体積および重量の計測と転移巣の評価を組織学的に行う方法と, ルシフェラーゼによる蛍光活性を測定し評価した. 担癌マウスで脾臓の腫大を認めたため, 脾臓細胞内のリンパ球構成をフローサイトメトリーを用いて調べた. 原発巣の腫瘍体積および重量は, RFを行った群とDXRを腫瘍内注入した群で共に抑制されていたが, 肺転移は組織学的評価と蛍光活性を用いた評価とも, RFを行った群でのみ抑制されていた. 今回の実験では肝転移は認められなかった. さらにRFを行った群では生存期間の有意な延長を認めた. 脾臓細胞内のリンパ球構成では, RFを行った群でNK細胞数の有意な増加を認めた. 以上の結果から高周波温熱療法単独で, 腫瘍の縮小および肺転移の抑制効果が見られ, 生存期間も有意に延長を認めた. その機序については脾臓内リンパ球のフローサイトメトリーの結果からNK細胞の関与が最も考えられた. |
| Author | 永谷, 祐子 岡田, 秀親 小島, 清秀 水谷, 潤 大塚, 隆信 古谷, 愛晴 石黒, 雅江 |
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| References | 24) Pross H.F., Lotzová E. : Role of natural killer cells in cancer. Nat Immun, 12 : 279-292, 1993. 7) Wendtner C.M., Abdel-Rahman S., Krych M., Baumert J., Lindner L.H., Baur A., Hiddemann W., Issels R.D. : Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts long-term survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas. J Clin Oncol, 20 : 3156-3164, 2002. 17) Zhang H.G., Mehta K., Cohen P., Guha C. : Hyperthermia on immune regulation : a temperature's story. Cancer Lett, 271 : 191-204, 2008. 21) DuPré S.A., Hunter K.W. Jr. : Murine mammary carcinoma 4T1 induce a leukemoid reaction with splenomegaly : association with tumor-delivered growth factors. Exp Mol Pathol, 82 : 12-24, 2007. 22) Ostapenko V.V., Tanaka H., Miyano M., Nishide T., Ueda H., Nishide I., Tanaka Y., Mune M., Yukawa S. : Immune-related effects of local hyperthermia in patients with primary liver cancer. Hepatogastroenterology, 52 : 1502-1506, 2005. 3) Kim J.H., Hahn E.W., Antich P.P. : Radiofrequency hyperthermia for clinical cancer therapy. Natl Cancer Inst Monogr, 61 : 339-342, 1982. 4) Marmor J.B., Kozak D., Hahn G.M. : Effects of systemically administered bleomycin or adriamycin with local hyperthermia on primary tumor and lung metastases. Cancer Treat Rep, 63 : 1279-1290, 1979. 9) Yonezawa M., Otsuka T., Matsui N., Tsuji H., Kato K.H., Moriyama A., Kato T. : Hyperthermia induces apoptosis in malignant fibrous histiocytoma cells in vitro. Int J Cancer, 66 : 347-351, 1996. 12) Heppner G.H., Dexter D.L., DeNucci T., Miller F.R., Calabresi P. : Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Cancer Res, 38 : 3758-3763, 1978. 2) Marmor J.B., Hahn N., Hahn G.M. : Tumor cure and cell survival after localized radiofrequency heating. Cancer Res, 37 : 879-883, 1977. 1) Woodhall B., Pickrell K.L., Georgiade N.G., Mahaley M.S., Dukes H.T. : Effect of hyperthermia upon cancer chemotherapy ; application to external cancers of head and face structures. Ann Surg, 151 : 750-759, 1960. 23) Kim S., Iizzuka K., Weissman I.L., Yokoyama W.M. : In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA, 97 : 2731-2736, 2000. 8) Otsuka T., Yonezawa M., Kamiyama F., Matsushita Y., Matsui N. : Results of surgery and radio-hyperthermo-chemotherapy for patients with soft-tissue sarcoma. Int J Clin Oncol, 6 : 253-258, 2001. 6) Anscher M.S., Samulski T.V., Dodge R., Prosnitz L.R., Dewhirst M.W. : Combined external beam irradiation and external regional hyperthermia for locally advanced adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys, 37 : 1059-1065, 1997. 10) Yonezawa M., Otsuka T., Kato T., Moriyama A., Kato K.H., Asai K., Matsui N. : Hyperthermic induction of apoptosis in malignant fibrous histiocytoma cells : possible involvement of a p53-independent pathway in the induction of bax gene. J Orthop Sci, 7 : 117-122, 2002. 25) Terunuma H., Wada A., Deng X., Yasuma Y., Onishi T., Toki A., Abe H. : Mild hyperthermia modulates the relative frequency of lymphocyte cell subpopulations : an increase in a cytolytic NK cell subset and a decrease in a regulatory T cell subset. Thermal Med, 23 : 41-47, 2007. 20) Laginha K.M., Verwoert S., Charrois G.J., Allen T.M. : Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer model. Clin Cancer Res, 11 : 6944-6949, 2005. 19) Injac R., Strukeli B. : Recent advances in protection against doxorubicin-induced toxicity. Technol Cancer Res Treat, 7 : 498-516, 2008. 16) Hiraga T., Williams P.J., Ueda A., Tamura D., Yoneda T. : Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res, 10 : 4559-4567, 2004. 15) Hiraga T., Ueda A., Tamura D., Hata K., Ikeda F., Williams P.J., Yoneda T. : Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer. Int J Cancer, 106 : 973-979, 2003. 5) Masunaga S., Hiraoka M., Takahashi M., Jo S., Akuta K., Nishimura Y., Nagata Y., Abe M. : Clinical results of thermoradiotherapy for locally advanced and/or recurrent breast cancer-comparison of results with radiotherapy alone. Int J Hyperthermia, 6 : 487-497, 1990. 11) Yanase M., Shinkai M., Honda H., Wakabayashi T., Yoshida J., Kobayashi T. : Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes. Jpn J Cancer Res, 89 : 775-782, 1998. 14) Michigami T., Hiraga T., Williams P.J., Niewolna M., Nishimura R., Mundy G.R., Yoneda T. : The effect of the bisphosphonate ibandronate on breast cancer metastasis to visceral organs. Breast Cancer Res Treat, 75 : 249-258, 2002. 26) Multhoff G. : Activation of natural killer cells by heat shock protein 70. Int J Hyperthermia, 18 : 576-585, 2002. 13) Heppner G.H., Miller F.R., Shekhar P.M. : Nontransgenic models of breast cancer. Breast Cancer Res, 2 : 331-334, 2002. 18) Wust P., Hildebrandt B., Sreenivasa G., Rau B., Gellermann J., Riess H., Felix R., Schlag P.M. : Hyperthermia in combined treatment of cancer. Lancet Oncol, 3 : 487-497, 2002. |
| References_xml | – reference: 8) Otsuka T., Yonezawa M., Kamiyama F., Matsushita Y., Matsui N. : Results of surgery and radio-hyperthermo-chemotherapy for patients with soft-tissue sarcoma. Int J Clin Oncol, 6 : 253-258, 2001. – reference: 7) Wendtner C.M., Abdel-Rahman S., Krych M., Baumert J., Lindner L.H., Baur A., Hiddemann W., Issels R.D. : Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts long-term survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas. J Clin Oncol, 20 : 3156-3164, 2002. – reference: 25) Terunuma H., Wada A., Deng X., Yasuma Y., Onishi T., Toki A., Abe H. : Mild hyperthermia modulates the relative frequency of lymphocyte cell subpopulations : an increase in a cytolytic NK cell subset and a decrease in a regulatory T cell subset. Thermal Med, 23 : 41-47, 2007. – reference: 9) Yonezawa M., Otsuka T., Matsui N., Tsuji H., Kato K.H., Moriyama A., Kato T. : Hyperthermia induces apoptosis in malignant fibrous histiocytoma cells in vitro. Int J Cancer, 66 : 347-351, 1996. – reference: 4) Marmor J.B., Kozak D., Hahn G.M. : Effects of systemically administered bleomycin or adriamycin with local hyperthermia on primary tumor and lung metastases. Cancer Treat Rep, 63 : 1279-1290, 1979. – reference: 15) Hiraga T., Ueda A., Tamura D., Hata K., Ikeda F., Williams P.J., Yoneda T. : Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer. Int J Cancer, 106 : 973-979, 2003. – reference: 23) Kim S., Iizzuka K., Weissman I.L., Yokoyama W.M. : In vivo natural killer cell activities revealed by natural killer cell-deficient mice. Proc Natl Acad Sci USA, 97 : 2731-2736, 2000. – reference: 5) Masunaga S., Hiraoka M., Takahashi M., Jo S., Akuta K., Nishimura Y., Nagata Y., Abe M. : Clinical results of thermoradiotherapy for locally advanced and/or recurrent breast cancer-comparison of results with radiotherapy alone. Int J Hyperthermia, 6 : 487-497, 1990. – reference: 6) Anscher M.S., Samulski T.V., Dodge R., Prosnitz L.R., Dewhirst M.W. : Combined external beam irradiation and external regional hyperthermia for locally advanced adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys, 37 : 1059-1065, 1997. – reference: 3) Kim J.H., Hahn E.W., Antich P.P. : Radiofrequency hyperthermia for clinical cancer therapy. Natl Cancer Inst Monogr, 61 : 339-342, 1982. – reference: 13) Heppner G.H., Miller F.R., Shekhar P.M. : Nontransgenic models of breast cancer. Breast Cancer Res, 2 : 331-334, 2002. – reference: 17) Zhang H.G., Mehta K., Cohen P., Guha C. : Hyperthermia on immune regulation : a temperature's story. Cancer Lett, 271 : 191-204, 2008. – reference: 19) Injac R., Strukeli B. : Recent advances in protection against doxorubicin-induced toxicity. Technol Cancer Res Treat, 7 : 498-516, 2008. – reference: 20) Laginha K.M., Verwoert S., Charrois G.J., Allen T.M. : Determination of doxorubicin levels in whole tumor and tumor nuclei in murine breast cancer model. Clin Cancer Res, 11 : 6944-6949, 2005. – reference: 11) Yanase M., Shinkai M., Honda H., Wakabayashi T., Yoshida J., Kobayashi T. : Antitumor immunity induction by intracellular hyperthermia using magnetite cationic liposomes. Jpn J Cancer Res, 89 : 775-782, 1998. – reference: 18) Wust P., Hildebrandt B., Sreenivasa G., Rau B., Gellermann J., Riess H., Felix R., Schlag P.M. : Hyperthermia in combined treatment of cancer. Lancet Oncol, 3 : 487-497, 2002. – reference: 26) Multhoff G. : Activation of natural killer cells by heat shock protein 70. Int J Hyperthermia, 18 : 576-585, 2002. – reference: 10) Yonezawa M., Otsuka T., Kato T., Moriyama A., Kato K.H., Asai K., Matsui N. : Hyperthermic induction of apoptosis in malignant fibrous histiocytoma cells : possible involvement of a p53-independent pathway in the induction of bax gene. J Orthop Sci, 7 : 117-122, 2002. – reference: 24) Pross H.F., Lotzová E. : Role of natural killer cells in cancer. Nat Immun, 12 : 279-292, 1993. – reference: 12) Heppner G.H., Dexter D.L., DeNucci T., Miller F.R., Calabresi P. : Heterogeneity in drug sensitivity among tumor cell subpopulations of a single mammary tumor. Cancer Res, 38 : 3758-3763, 1978. – reference: 16) Hiraga T., Williams P.J., Ueda A., Tamura D., Yoneda T. : Zoledronic acid inhibits visceral metastases in the 4T1/luc mouse breast cancer model. Clin Cancer Res, 10 : 4559-4567, 2004. – reference: 21) DuPré S.A., Hunter K.W. Jr. : Murine mammary carcinoma 4T1 induce a leukemoid reaction with splenomegaly : association with tumor-delivered growth factors. Exp Mol Pathol, 82 : 12-24, 2007. – reference: 22) Ostapenko V.V., Tanaka H., Miyano M., Nishide T., Ueda H., Nishide I., Tanaka Y., Mune M., Yukawa S. : Immune-related effects of local hyperthermia in patients with primary liver cancer. Hepatogastroenterology, 52 : 1502-1506, 2005. – reference: 1) Woodhall B., Pickrell K.L., Georgiade N.G., Mahaley M.S., Dukes H.T. : Effect of hyperthermia upon cancer chemotherapy ; application to external cancers of head and face structures. Ann Surg, 151 : 750-759, 1960. – reference: 14) Michigami T., Hiraga T., Williams P.J., Niewolna M., Nishimura R., Mundy G.R., Yoneda T. : The effect of the bisphosphonate ibandronate on breast cancer metastasis to visceral organs. Breast Cancer Res Treat, 75 : 249-258, 2002. – reference: 2) Marmor J.B., Hahn N., Hahn G.M. : Tumor cure and cell survival after localized radiofrequency heating. Cancer Res, 37 : 879-883, 1977. |
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| Snippet | 高周波温熱療法 (Radiofrequency hyperthermia, 以下RF) は悪性腫瘍の治療法として広く用いられ効果を上げている. 腫瘍の原発巣に対して温熱療法を行った症例の内, 転移巣の縮小を見る症例がある. 本研究ではマウスの担癌モデルを用いて,... |
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| Title | 4T1マウス担癌モデルに対する局所高周波温熱療法の遠隔転移抑制効果 |
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