1. Thermal Combination Therapy with HIFU
Ablation and Whole Body Hyperthermia
AKIRA TAKEUCHI1), HIDEKI GONDO1), JOTARO KOBAYASHI2), YUANTIAN XIA3), AKIRA ITABASHI3) and TAKASHI TAKEUCHI1)
A new high intensity focused ultrasound (HIFU) apparatus (Sonic CZ901 : Mianyang Sonic Electronic Ltd, China) was installed in our hospital last December. The device has been used 20 times in 12 advanced cancer patients, and some results concerning the use of HIFU ablation and Whole body hyperthermia (WBH) via far-infrared equipment (RHS 7500 : Enthermics Medical Systems, USA) can be reported. The first patient had pharyngeal cancer (20y.o, F) with lung and multiple liver metastases. The lung tumor shrank after WBH (weekly treatments, for a total of 4 treatments) and the liver tumor was clearly reduced by HIFU treatment. A second patient who received the combined treatment had a neck tumor with bone metastasis (65y.o, M). The patient received WBH after HIFU treatment for a 7th rib bone metastasis. After 10 days, the neck tumor developed internal necrosis, and ruptured. CT imaging showed necrotic changes focused in the neck tumor and also the rib bone metastasis.
These results may be a positive indication for HIFU treatment, but there are other positive indications for the primary organ tumour. This new thermal combination therapy appears to have great promise.
2. The effects inhibiting the proliferation of cancer cells by far-infrared radiation (FIR) are controlled by the basal expression level of heat shock protein (HSP) 70A.
Ishibashi J, Yamashita K, Ishikawa T, Hosokawa H, Sumida K, Nagayama M, Kitamura S.
Department of Oral and Maxillofacial Anatomy, Medical Science for Oral and Maxillofacial Regeneration, Graduate School of Health Biosciences, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8504, Japan.
We developed a tissue culture incubator that can continuously irradiate cells with far-infrared radiation (FIR) of wavelengths between 4 and 20 microm with a peak of 7-12 microm, and found that FIR caused different inhibiting effects to five human cancer cell lines, namely A431 (vulva), HSC3 (tongue), Sa3 (gingiva), A549 (lung), and MCF7 (breast). Then, in order to make clear the control system for the effect of FIR, the gene expression concerned to the inhibition effect by FIR were analyzed. In consequence, basal expression level of HSP70A mRNA was higher in A431 and MCF7 cells than in the FIR-sensitive HSC3, Sa3, and A549 cells. Also, the over expression of HSP70 inhibited FIR-induced growth arrest in HSC3 cells, and an HSP70 siRNA inhibited the proliferation of A431 cells by irradiation with FIR. These results indicate that the effect of a body temperature range of FIR suppressing the proliferation of some cancer cells is controlled by the basal expression level of heat shock protein (HSP) 70A.
This finding suggested that Far Infrared Rays (FIR) should be very effective medical treatment for some cancer cells which have a low level of HSP70. Still more, if the level of HSP70 in any cancer of a patient was measured, the effect of medical treatment by FIR can be foreseen for the cancer.
1. Evidence that irradiation of far-infrared rays inhibits mammary tumour growth in SHN mice.
Anticancer Res. 1999 May-Jun;19(3A):1797-800.
Nagasawa H, Udagawa Y, Kiyokawa S.Source
Source: Experimental Animal Research Laboratory, Meiji University, Kawasaki, Japan.
To evaluate the effect of irradiation of far infrared rays (FIR), the growth of spontaneous mammary tumours of SHN mice was compared among 3 groups: the control was kept until the end of experiment on the normal rack in the absence of FIR and Experimental group I was constantly exposed to FIR. Experimental group Il was raised as the control followed by movement to the FIR rack after mammary tumour appearance. While there was little difference between the control and Experimental group I in mammary tumour growth for 16 days, Experimental group II was significantly lower than the control in this parameter. Furthermore, the percentage of rapidly growing tumours showing greater than 200% of growth rate was apparently lower in Experimental group II. Associated with this, epidermal growth factor receptor expression in mammary tumours, anterior pituitary weight and serum leptin level were significantly decreased in Experimental group II.
The findings suggest that whole-body FIR irradiation at ambient temperature could be a possible way of a hyperthermic therapy for tumours.
2. Inhibition by whole-body hyperthermia with far-infrared rays of the growth of spontaneous mammary tumours in mice.
Anticancer Res. 1999 Sep-Oct;19(5B):4125-30.
Udagawa Y, Nagasawa H, Kiyokawa S.Source
Source:Experimental Animal Research Laboratory, Meiji University, Kawasaki, Japan.
To evaluate possible therapeutic benefits of irradiation with far-infrared rays (FIR) on breast cancer, we examined combined effects of the chronic exposure to FIR at ambient temperature (26.5-27.5 degrees C) and the whole-body hyperthermia induced by FIR (WBH) (35-41 degrees C) on the growth of spontaneous mammary tumours of mice. A high mammary tumour strain of SHN virgin mice born on the normal rack or FIR rack were maintained on the respective racks until mammary tumour appearance. When the mammary tumour size reached approximately 7 mm, some mice in each group received no further treatment (Control and FIR groups, respectively) and the remaining mice received 3 hours of WBH each of 5 consecutive days (C + WBH and FIR + WBH groups, respectively). There was little difference between the control and FIR groups in the tumour growth over 10 days of examination. On the other hand, the tumour growth was inhibited significantly in both C + WBH and FIR + WBH groups and the degree of inhibition was similar. The data confirmed that the chronic exposure to FIR at ambient temperature has little effect on the growth of spontaneous mammary tumours in mice.
Whole-Body Hyperthermiawith FIR, however, strongly inhibited the tumour growth without deleterious side-effects, while chronic FIR irradiation itself again had little effect in this process.
This Whole-Body Hyperthermiaregimen may serve as a useful animal model for long-term studies of a noninvasive treatment of breast cancer.
3. Effects of combined treatment with coffee cherry and whole-body hyperthermia on the growth of spontaneous mammary tumours in SHN mice.
In Vivo. 2000 May-Jun;14(3):431-5.Links
Udagawa Y, Nagasawa H.
Source:Experimental Animal Research Laboratory, Meiji University, Kawasaki, Japan.
Based on findings that free access in drinking water of the extract of coffee cherry (CC), the residue left after the removal of coffee beans, and whole-body hyperthermia (WBH) induced by far-infrared ray (FIR) can markedly inhibit the growth of spontaneous mammary tumours of SHN mice, the effects of the combined treatment with these agents were examined in this study.
The significant inhibition of tumour growth by single treatment with either CC or WBH was not enhanced by their combination.
Meanwhile, the body weight loss during WBH was significantly decreased by CC. Normal and preneoplastic growth of mammary glands and plasma component levels were affected little by either treatment.
The findings confirmed the "normalization effects" of CC usually obtained with natural products and stress the need for prudence in the choice of any agent, natural or synthetic, to be applied simultaneously to increase the efficacy of WBH.
4. Effects of hydroxyapatite in combination with far-infrared rays on spontaneous mammary tumorigenesis in SHN mice.
Am J Chin Med. 2002;30(4):495-505.
Udagawa Y1, Ishigame H, Nagasawa H
We have found that the administration of a diet containing 5% hydroxyapatite (HAP) derived from pig and cattle bones, and exposure to far-infrared rays (FIR) markedly inhibited spontaneous mammary tumorigenesis in SHN mice.
Thus, the effect of combined treatment with HAP and FIR on mammary tumorigenesis was examined. The significant inhibition of tumor development by individual treatment with HAP or FIR was not enhanced by combined treatment; instead, the decrease in the inhibitory effect of HAP with age was ameliorated. Associated with this, life span was elongated and a decline in ovarian function was prevented by HAP plus FIR. Normal and preneoplastic growth of mammary glands and plasma component levels were not significantly affected by any treatment.
The findings indicate that hydroxyapatite and far-infrared rays have characteristics common to most natural products; in combination with other agents, they have little additive effect, when each is highly active.
5. Far Infrared Ray Irradiation Induces Intracellular Generation of Nitric Oxide in Breast Cancer Cells
Ting-Kai Leung, Chi-Ming Lee, Ming-Yu Lin, Yuan-Soon Ho, Ching-Shyang Chen, Chih-Hsiung Wu, Yung-Sheng Lin
Far infrared radiation has been used in many health-promoting applications, but the cellular mechanisms have not been elucidated. We investigated the influence of non-thermal-enhanced Far infrared radiation for generating nitric oxide (NO) in breast cancer cells. We used MCF-7 breast cancer cells treated with FIR irradiation or left untreated, and measured the inducible NO concentrations using the DAF-FM diacetate (4-amino-5-methylamino-2’,7’-difluorofluorescein) technique. Mean fluorescence intensities of DAF-FM assays from different breast cancer cells showed progressive and cumulative increases in NO with Far infrared irradiation. Significant inductions of NO synthesis in breast cancer cells were observed both during and after Far infrared irradiation. Including data from a literature review, we discuss possible therapeutic roles of Far infrared radiation for breast cancers through the induction of NO generation.
‘‘Nitric Oxide seems to act in vitro as an inhibitory factor of carcinogenesis in Human breast Cancer cells.’’- Reveneau et al 1999.
6. A novel thermal treatment modality for controlling breast tumor growth and progression.
Conf Proc IEEE Eng Med Biol Soc. 2012; 2012:5703-6. doi: 10.1109/EMBC.2012.6347290.
Xie Y1, Liu P, Xu LX.
The new concept of keeping primary tumour under control in situ to suppress distant foci sheds light on the novel treatment of metastatic tumour. Hyperthermia is considered as one of the means for controlling tumour growth. In this study, a novel thermal modality was built to introduce hyperthermia effect on tumour to suppress its growth and progression using 4T1 murine mammary carcinoma, a common animal model of metastatic breast cancer.
A mildly raised temperature (i.e.39°C) was imposed on the skin surface of the implanted tumor using a thermal heating pad. Periodic heating (12 hours per day) was carried out for 3 days, 7 days, 14 days, and 21 days, respectively.
The tumour growth rate was found significantly decreased in comparison to the control without hyperthermia. Biological evidences associated with tumour angiogenesis and metastasis were examined using histological analyses.
Accordingly, the effect of mild hyperthermia on immune cell infiltration into tumours was also investigated. It was demonstrated that a delayed tumour growth and malignancy progression was achieved by mediating tumour cell apoptosis, vascular injury, degrading metastasis potential and as well as inhibiting the immunosuppressive cell myeloid derived suppressor cells (MDSCs) recruitment. Further mechanistic studies will be performed to explore the quantitative relationship between tumour progression and thermal dose in the near future.
1. Antitumor effect of whole body (Far Infrared) hyperthermia with alpha-galactosylceramide in a subcutaneous tumor model of colon cancer.
Int J Hyperthermia. 2007 Nov;23(7):591-
Hattori T, Kokura S, Okuda T, Okayama T, Takagi T, Handa O, Naito Y, Yoshida N, Yoshikawa T.
Source: Inflammation and Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Whole body hyperthermia (WBH) has been used clinically as an adjunct to radio- and chemotherapy in patients with various cancers. Recently, it has been reported that an activation of the immune system has recently been reported as a possible contributor to the therapeutic effects of WBH. Conversely, the glycolipid alpha-galactosylceramide (alpha-GalCer) is recognized by natural killer (NK) T cells together with the monomorphic MHC-like antigen, CD1d, in mice and humans. This study investigated the antitumor effects of WBH combined with alpha-GalCer in a mouse subcutaneous tumor model of colon cancer.
Colon26 cells were inoculated subcutaneously into male BALB/c mice to establish subcutaneous tumor. Colon26-bearing mice were treated with Whole body hyperthermia using far infrared rays three times/week. Rectal temperature was maintained for 60 min at 41 degrees C. In some experimental groups, alpha-GalCer was intraperitoneally injected before WBH. We investigated the therapeutic effects of WBH, alpha-GalCer and combined therapy.
(1) Compared with controls, Whole Body Hyperthermia alone resulted in significant inhibition of tumor growth. (2) No inhibitory effect on tumor growth was seen with alpha-GalCer. (3) The combination of WBH and alpha-GalCer showed significant inhibition of tumor growth and prolongation of survival. (4) Serum IFN-gamma increased after 3 h and returned to basal levels by 24 h after alpha-GalCer administration. (5) CTL activity was enhanced following combination therapy with WBH and alpha-GalCer.
Whole Body Hyperthermia showed antitumor effects in a mouse subcutaneous tumor model of colon cancer. Addition of alpha-GalCer increased the efficacy of Whole Body Hyperthermia, probably via enhancement of immune response.
1. Non-Thermal Effects of Far-Infrared Ray (FIR) on Human Hepatocellular Carcinoma Cells HepG2 and their Tumours
J Cancer Sci Ther 2009 1: 078-082. doi:10.4172/1948-5956.1000012
Tatsuo Ishikawa, Jun Ishibashi, Kikuji Yamashita, Shine-Od Dalkhsuren, Kaori Sumida, Takahumi Masui and Seiichiro Kitamura
Source: Department of Oral and Maxillofacial Anatomy, Medical Science for Oral and Maxillofacial Regeneration, Graduate School of Health Biosciences, University of Tokushima, 3-18-15 Kuramoto, Tokushima, 770-8504 Japan
Background:We developed a cell culture CO2 incubator and a mice rack that can continuously irradiate cells or murine with Far Infrared Ray. Our goal is to make clear the non-thermal effect of FIR on HepG2 with these instruments morphologically.
Methods: By using them, in vitro , we examined the proliferation of cultured HepG2 cells with hematocytometer, BrdU assay, WST-1 assay, HE staining, Toluidine blue staining and microarray studies. And in vivo, we measured the tumors, observed the sections by IHC, DAPI staining with light microscopes and performed microarray studies.
Results:Proliferation of HepG2 cells were suppressed (e.g., cell count declined by 34% after 10 days of Far Infrared Ray irradiation), tumor volumes reduced by 86% after 30 days of Far Infrared Ray irradiation, mRNA of Vascular Endothelial Growth Factor (VEGF) decreased by 48%, vascular area in cross sections from the tumors decreased 60% compared with the control. More frequent properties in apoptosis were observed by TUNEL and DAPI staining in FIR-treated groups. Body weight of mice increased compared with the control. Oxydation and Reduction (Redox) reactions by H+ (proton and electron)/O2- (a kind of Reactive Oxygen Species (ROS)) were induced by FIR.
Conclusions:These results clarified that Far Infrared Rays inhibited the proliferation of HepG2 at non-thermal circumstances (at 25±0.5, 37±0.5°C). Far Infrared Rays will serve as a tool against diseases induced by HepG2.
1. Middle Infrared Radiation Induces G2/M Cell Cycle Arrest in A549 Lung Cancer Cells
PLoS ONE 8(1): e54117. doi:10.1371/journal.pone.0054117
Hsin-Yi Chang, Meng-Her Shih, Hsuan-Cheng Huang,Shang-Ru Tsai,3 Hsueh-Fen Juan, and
There were studies investigating the effects of broadband infrared radiation (IR) on cancer cell, while the influences of middle-infrared radiation (MIR) are still unknown. In this study, a MIR emitter with emission wavelength band in the 3–5 µm region was developed to irradiate A549 lung adenocarcinoma cells. It was found that MIR exposure inhibited cell proliferation and induced morphological changes by altering the cellular distribution of cytoskeletal components. Using quantitative PCR, we found that MIR promoted the expression levels of ATM (ataxia telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related and Rad3-related), TP53 (tumor protein p53), p21 (CDKN1A, cyclin-dependent kinase inhibitor 1A) and GADD45 (growth arrest and DNA-damage inducible), but decreased the expression levels of cyclin B coding genes, CCNB1 and CCNB2, as well as CDK1 (Cyclin-dependent kinase 1). The reduction of protein expression levels of CDC25C, cyclin B1 and the phosphorylation of CDK1 at Thr-161 altogether suggest G2/M arrest occurred in A549 cells by MIR. DNA repair foci formation of DNA double-strand breaks (DSB) marker γ-H2AX and sensor 53BP1 was induced by MIR treatment, it implies the middle-infrared radiation induced G2/M cell cycle arrest resulted from DSB.
This study illustrates a potential role for the use of middle-infrared radiation in lung cancer therapy by initiating double-strand breaks (DSB) and blocking cell cycle progression.
1. Far-infrared rays control prostate cancer cells in vitro and in vivo
Hiroki Shima, Shingo Yamamoto, Jun Qiu, Mayumi Shincho, Seiichi Hirota, Yoshie Yoshikawa, Reigetsu Yoshikawa & Tomoko Hashimoto-Tamaoki
We introduce a new effective method to control hormone refractory prostate cancer cells by using an activated rubber/resin form (RB), far-infrared ray emitter, with or without sodium butyrate (SB). The growth of three human prostate cancer cell lines (Du145, PC-3 and LNCaP) was suppressed in vitro and in vivo by using RB, and the cells were eradicated with RB + 3 mM SB. G1 arrest and apoptotic pathway proteins were induced by RB with intensified expressions of apoptosis – related mRNA on cDNA microarray.
RB radiates the infra-red rays of the 4 to 25 μm wavelengths to an object which exert a favourable influence on a cancer control.
These results may render us a new therapeutic modality in hormone refractory prostate cancer.
1. Inhibitory Effects of Far-Infrared Irradiation Generated by Ceramic Material on Murine Melanoma Cell Growth
Ting-Kai Leung, Chin-Feng Chan, Ping-Shan Lai,3 Chih-Hui Yang, Chia-Yen Hsu, and Yung-Sheng Lin
The biological effects of specific wavelengths, so-called “far-infrared radiation” produced from ceramic material (cFIR), on whole organisms are not yet well understood. In this study, we investigated the biological effects of cFIR on murine melanoma cells (B16-F10) at body temperature. cFIR irradiation treatment for 48 h resulted in an 11.8% decrease in the proliferation of melanoma cells relative to the control. Meanwhile, incubation of cells with cFIR for 48 h significantly resulted in 56.9% and 15.7% decreases in the intracellular heat shock protein (HSP)70 and intracellular nitric oxide (iNO) contents, respectively. Furthermore, cFIR treatment induced 6.4% and 12.3% increases in intracellular reactive oxygen species stained by 5-(and 6)-carboxyl--dichlorodihydrofluorescein diacetate and dihydrorhodamine 123, respectively. Since malignant melanomas are known to have high HSP70 expression and iNO activity, the suppressive effects of cFIR on HSP70 and NO may warrant future interest in antitumor applications.