[in Japanese]

View full abstract

[in Japanese]

View full abstract

In this short review on hyperthermia, the role of vascular damage in hyperthermia and strategies for attacking tumor vasculature in hyperthermia were presented. Blood flow plays an important role in the tissue damage by hyperthermia. Tissue temperature is dependent on blood flow rate, and it also controls the intratumoral microenvironment, which affect the thermosensitivity of the tissue. In addition, hyperthermia itself selectively destroy the tumor vasculature at high heat dose. It is an interesting question whether vascular targeting by some vasoactive agents can enhance the effect of hyperthermia. Rationales of vascular targeting before hyperthermia are as follows. Selective destruction of tumor vasculature before heat treatment increases tumor temperatures because of decreased tumor blood flow, and changes the intratumoral environment more acidic and hypoxic. Both elevated tumor temperatures and acidic environment may enhance heat damage in vivo. It has been demonstrated that tumor necrosis factor (TNF), flavono acetic acid (FAA), and interleukin-1α (IL-1α) has sensitizing effects of hyperthermia by administrating before hyperthermia. In addition, we have shown IL-1α analogue, OCT-7000, has similar enhancing effects of hyperthermia. Another rationale is inhibition of angiogenesis following hyperthermia. We have demonstrated that a potent angiogensis inhibitor, TNP-470, substatially increased the response of murine SCC VII carcinoma to hyperthermia. Targeting tumor vasculature by several vasoactive compounds seems a promising strategy to enhance heat effects.

View full abstract

The cytotoxicity of some chemotherapeutic agents are enhanced at elevated temperatures in vitro and in vivo. It was reported misonidazole (MISO), a hypoxic cell radiosensitizer, can also act as a heatsensitizer and chemosensitizer. We investigated the multimodal effects of AK-2123, a 3-nitrotriazole derivative, using transplanted tumors in mice. Injections of AK-2123 (200mg/kg or 400mg/kg, i. p.) prior to X-irradiation or local hyperthermia enhanced the growth delay of tumor induced by X-irradiation with 15 Gy or hyperthermia (43°C, 30min.) alone. AK-2123 was also effective on thermo-chemotherapy with CDDP. Blood flow reduction was observed in tumors by AK-2123 administration. The relative concentration of CDDP in locally heated tumor was reduced to 25 % that of the controls when assessed 5 hours after hyperthermia by atomic absorption analysis, but it recovered to half the level of the nonheated controls by AK-2123 (400mg/kg) administration 30 minutes before hyperthermia. We also investigated the multimodality-treatments of a sequential use of a AK-2123 plus a bioreductive agent mitomycin C (MMC) and hydralazine (HDZ) as a vasodilative drug combined with radiothermotherapy on SCC VII tumors. The multimodality-treatment of (AK-2123-MMC) -10Gy/HDZ/HT induced the prolonged tumor doubling time which is as same as 50 Gy alone. Therefore, this multimodality-treatment induced the high dose modifying factor of 5.0. These results suggest that tumor vasculature is much more sensitive to AK-2123 than vasculature of normal tissues and that hyperthermia after AK-2123 administration can induce transient hypoxia and selective reduction of pH in tumor. Futhermore, these phenomena may cause to increase cell killing by bioreductive agent mitomycin C and hyperthermia.

View full abstract

It is said that the efficacy of hyperthermia for malignancies depend on various vasophsiological factors in the tumor, such as pH, blood flow and oxygen tension (p02). The present animal experiment was performed to ascertain how the effect of hyperthermia can be enhanced by administration of hydralazine (HYD), a vasodilator, wich is known to decrease the local blood flow selectively and accordingly, decelerate thermal diffusion in the tumor. HYD (2-5mg/kg) was injected intraperitoneally 20 min before hyperthermia, which was done for 20-30 min at 43°C by the use of a thermo-static water bath. The tumor quadrupling time was 4.5 days in the untreated FM3A group, 5.4 days in the HYD treated FM3A group, 8.5 days in the heat alon FM3A group and 11.2 days in the HYD plus heat treated FM3A group. Those in the respective SCC-VII group were 7.7 days, 9.0 days, 11.1 days and 14.0 days. The enhancement ratio was 2.48 in the treatment for FM3A tumor and 1.81 in the treatment for SCC-VII tumor. Thus, these results indicate that HYD can increase the therapeutic efficiency of local hyperthermia treatment by inducing the change of microenvironment i. e. low pH, tumor hypoxia, deficient nutrition secondary to blood flow diminution which increase the sensitivity of tumor to heat.

View full abstract

To improve local hyperthermic effects, local injection of epinephrine and chemotherapeutic agents combined with hyperthermia (LIECH therapy) was studied in an in vivo experimental system. The local injection of anticancer drugs, BLM or Cis-platinum, was supposed to act on tumor cells directly, and also enhance hyperthermic effects. In addition, the local injection of epinephrine sensitized not only the hyperthermic effect, but also the chemotherapeutic effect, due to vasoconstriction by epinephrine and subsequently induced the changes in the environment around the tumor. By the combination of these three modalities, strong effects were obtained even at mild hyperthermia. The biological background and clinical experience for LIECH therapy were described.

View full abstract

[in Japanese]

View full abstract

A Pase I / II clinical trial has been initiated to determined the feasibility of an interstitial hyperthermia using 13.56 MHz radiofrequency (RF) antennas in the treatment of malignant brain tumors. The needle type applicator (RF antennas) with diameter of 1.0 mm was used. A single or multiple (24) antennas were inserted into the brain tumor using a CT-guided stereotactic apparatus. The temperature of the brain and the tumor were monitored by the copper-constantan thermocouple sensors. The RF interstitial hyperthermia was performed on 30 patients with malignant brain tumors, 22 malignant gliomas (10 primary and 12 recurrent), 7 metastatic tumor and 1 malignant lymphoma. The rin of the tumors which were defined by contrast enhanced CT was heated at 43.0°C for 60 minutes. The heating was repeated 39 (mean 5) times, once or twice a week, combined with conventional radiation or chemotherapy. The recurrent gliomas were treated with heat alone. The patients complained no local pain or heat sensation and well tolerated the repeated heating. No major complication occurred except liquorrhea in 2 cases, subcutaneous infection in one case intratumoral hemorrhage in one case and trasient neurological symptoms in 2 cases. The antitumor effects were evaluated by CT and the treated tumors showd CR in 8 PR in 10, ST in 9 and PD in 3 cases, respectivery. In most of CR cases, the perifocal low density lesion also disappeared. These preliminary results indicated that the RF intersitial hyperthermia seemed to be effective in treatment of malignant brain tumors, this technique is less invasive and the tumors in aged or poor risk patients as well as deep-seated tumors can be good candidates for the application.

View full abstract

Interstitial hyperthermia of brain tumors has been developed and made by an implant heating system (IHS) using ferromagnetic implant (Fe-Pt alloy) with low Curie temperature. Induction heating of the implants which are stereotactically placed in a tumor is obtained by eddy current under high frequency (240 kHz) magnetic field. The whole tumor is heated by heat conduction from the implant.
Safe, repeated and longterm treatments of 35 cases of malignant brain tumor have been made using IHS. The effectiveness of combined treatment with interstitial hyperthermia and external irradiation was confirmed by repeated CT and pathological examination. Over all response rate was 31.4%, while those of metastatic tumor and deep-seated, malignant glioma were 50% and 36.4% respectively. The characteristic and common pathological finding of treated tumor was circumscribed, ellipoid shape of coagulation necrosis around the implant. Regarding the future prospects of IHS, following projects have been on going. A large induction coil (φ 60 cm) has been developed and been used for the malignancies of other systemic organs. Three dimentional arrangement of implants in a tumor to cover whole tumor properly and effectively will be made by computer simulation. The combination treatment of interstitial hyperthermia by IHS and brachytherapy with isotope seeds using common after loading catheter will be promissing. The developement of new implant which is not influenced by the direction of magnetic field and also of ultra-small grain (powder) implant for the intracellular hyperthermia are possible.

View full abstract

We reported the responses and the indications of thermochemotherapy using magnetic induction hyperthermia (Implant Heating System : IHS) for oral cancer. An IHS consists of three parts; ferromagnetic implant with low Curie temperature, induction coil and generator. The generator has 2.5 kw of maximum power. Ferromagnetic implant is composed of Fe-Pt alloy with Curie temperature of 68°C.
Fifteen patients with primary cancer of the oral cavity were treated by thermochemotherapy. They received two courses of chemotherapy, which included intra-arterial infusion of 100mg of cisplatin and 25mg of peplomycin in principle. Nine cases were preoperative treated. As a result, clinical complete response was observed in 8 cases and partial response in 1, and postoperative pathological examination showed no residual tumor cells in specimen of 8 patients. Six cases were treated thermochemotherapy only. As a result, clinical complete response was observed in 6 cases, however, the recurrence was observed in one case (hard palate cancer) at 3 months after treatment.
Cancers of the tongue and floor of mouth as T1, T2 were good indication of thermochemotherapy using IHS, however, cancers of hard palate and gingiva were not indications because of the bone adjoining.

View full abstract

A capactive heating has been mainly performed as a radio-frequency hyperthermia. The acquired area by heating is large and nonselective. A seleotive heating of cancer cells is difficult by a capacitive heating. On the other, it is possible to create a selective heating area by an inductive heating using magnetic particles. In this study, we have investigated the properties of an new heating material and the therapeutical methods of tumor cells of experimental animals. DEXTRAN MAGNETITE (DM, 3-15 nm in diameter and 3/gFe in susceptibility) particle was used as the nanometer particle. DM is not simple mixture of dextran and ferrate but nanometer complex. Chained dextran surrounds core of ultra fine magnetite. DM particles have a very high inductive heating efficiency, excellent colloidal stability in vivo, low toxicity and good metabolizability in vivo. The temperature rise of DM particles is higher than the other particles at a inductive field of the frequency of 500 KHz. The relation of the physical and chemical properties of DM particles to the temperature rise by an induction heating is positive in concentration, susceptibility of DM aqueous zol and diameter of the iron oxide portion, and negative in molecular weight of dextran. When the distribution of DM particles were examined histologically, they were taken intracellularly in cancer cells by phagocytosis at 24 hours after administration. In previous study, we have investigated hyperthermic treatments for various tumor models, and obtained the good results of treatments. In the experimental treatments, we have designed various heating methods. The designed methods are classified as follows. 1) intracellular hyperthermia, 2) interstitial hyperthermia with tubular implants filled with DM aqueous zol, 3) intraluminal hyperthermia with a balloon and DM aqueous zol. Since the DM aqueous zol configuration can be readily changed, treatment of various cancer is possible. The DM particles were very promising in the treatment of cancer by inductive heating of 500 KHz.

View full abstract

Eighteen patients with invasive bladder carcinomas were treated with local hyperthermia by using the Thermotron RF-8 combined with radiation, chemotherapy and immunotherapy during the 6 years from 1987 to 1993 at Nagoya City University Hospital. Preliminary staging revealed 7 cases of T2, 2 cases of T3, 5 cases of T4 and 4 cases of recurrence in pelvic cavity after total cystectomy. The histopathological diagnoses were 9 cases of transitional cell carcinoma (TCC) grade 2 ; 7 cases of TCC grade 3 ; 1 case of TCC grade 3 + squamous cell carcinoma (SCC) and 1 case of SCC.
Hyperthermia was applied using a Thermotron RF-8 (Yamamoto Vinitor Co. Osaka, Japan) by radiofrequency (RF) with a pair of 30 cm diameter electrodes coupled to the pelvis for heating the bladder. Hyperthermia was carried out from 2 to 11 sessions for each case, about once every week or every two weeks.
As treatments combined with hyperthermia, hydroxypropylcellulose-adriamycin (HPC-ADM) was instilled in the bladder in 7 cases ; radiation was performed in 6 cases and other chemotherapies and immunotherapies were applied for 5 cases.
The clinical results with local hyperthermia demonstrated 5 cases of complete response (27.8%), 7 cases of partial response (38.9%), 5 cases of no change (27.8%) and 1 case of progressive disease (5.5%). No severe adverse effects on systemic conditions were observed accompanying the hyperthermia.
Comparison of survival rates with histopathological maligancy based upon the Kaplan-Meier method revealed a significantly better survival ratio for the TCC grade 2 group than for the TCC grade 3 + SCC group. There was a difference in survival ratios between T2 and T3 + T4 +recurrence after total cystectomy.
These results indicate that local hyperthermia is useful for T2 stage invasive bladder carcinomas and suggest that investigation of its appplicaiton with other intensive care therapies should be considered for stage T3-T4 tumors.

View full abstract

An experimental study was conducted to investigate effect of hyperthermia to the liver in rabbits. The whole liver was heated at 43°C for 30 min by a RF capacitive heating device, and subsequent changes were observed by scintigraphy using ^99mTc-EHIDA and ^99mTc-Sn-colloid. The excretory ratio (Ke value) of ^99mTc-EHIDA and the uptake ratio (K value) of ^99mTc-Sn-colloid were measuared to estimate hyperthermia induced hepatic injury for a month. Blood chemistory analysis was also conducted during this period. Also, the uptake of ³H-methyl-thymidine into the DNA of hypatocytes was asseyed 2 and 5 days after heating. Concurrently, histopathological changes were observed.
The Ke value showed a transient increase and returned to the level prior to heating after approximataly one week. A distinct increase in GPT was observed. The uptake of ³H-methyl-thymidine showed a marked rise 2 days after hyperthermia, which demonstrated regeneration of the previously damaged hepatocytes. Pathologically, overall liver congestion and hepatocytes necrosis were noted. Also, both enlargement of the nuclei and binuclear hepatocytes were present, pathologically proving hepatocytes regeneration. The K value showed a transient decrease, showing that he reticuloendothelial function and blood flow of the liver were temporarily reduced.
These results indicate the whole liver function damaged by hyperthermia is reversible.

View full abstract

As it is suggested that the effect of anticancer drugs can be affected by the activation of oncogenes in cells, we have studied the effects of adriamycin (ADR) on the susceptibility and effect of hyperthermia of several oncogene-transfected NIH3T3 cell lines to this drug. In the present work, the results showed that an ADR-resistance-effect appeared in cell lines transfected with following oncogenes : high resistance in c-Ki-ras, c-Ki-ras (Val-12), v-abl and v-src; a slight resistance in v-Ha-ras; however an ADR-sensitive-effect appeared in N-ras, v-sis and v-myc when they were compared with a pSV2neo-transfected cell line as a control. The results suggested that the susceptibility of the call lines to ADR which were observed from the survival of cells was dependent upon the dose of ADR uptake by cells. The amount of ADR uptake by cells increased by a factor of 1.14-1.29 after adding CEP, a p-glycoprotein inhibitor. There was no change in the capacity of ras family-transfected cell lines to excrete ADR compared with the control cell lines. In addition, free intracelluar calcium was found to relate to the amount of ADR uptake by cells. Differences in the extent of ADR uptake among cell lines was attenuated after treatment by heating at 42°C. These data suggest that it is the penetration of the cell membrane by ADR that may be responsible for the different cell line capacities for ADR uptake and not changes in excretion of ADR by cells as the factor that determines the different susceptibilities of oncogene-transfected cell lines to ADR treatment.

View full abstract