Biomedical subjects
Publications and source records attributed to K Akagi.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Histogenesis and mechanisms of catechol-induced rat glandular stomach carcinogenesis were investigated in male F344 rats. Groups of 5 or 6 rats were treated with dietary catechol at doses of 1, 0.5, 0.1, and 0.01% for 12 hr or for 1, 2, 3, or 7 days or at a dose of 0.8% for 1, 2, 4, 12, and 24 wk; rats were then euthanatized. The initial morphological changes were edema of the gastric wall, inflammatory-cell infiltration, erosion in the pyloric region close to the duodenum, and considerable increase in apoptosis at 12 hr; later, changes included augmented DNA synthesis and cell proliferation, as evaluated by bromodeoxyuridine labeling index and thickness of mucosa, respectively, on day 1. Downward hyperplasia due to excess regeneration appeared at edges of ulceration at week 2. This lesion disappeared, and then submucosal hyperplasia appeared in the course of adenoma development. Only slight expression of c-myc or c-fos was apparent after 30-min oral administration or 1-, 3-, and 6-hr oral administration of catechol. No increase in lipid peroxide levels was evident in gastric epithelium fed catechol for 1 wk. The amount of catechol distributed in the glandular stomach and forestomach epithelium, which is not a target for carcinogenesis, did not differ 1, 3, 6, and 24 hr after a single intragastric dose of 75 mg/kg body weight. Amounts of catechol bound to tissue protein were also not specifically high in the glandular stomach. These results indicate that regenerative cell proliferation due to toxicity plays an important role in catechol-induced glandular stomach carcinogenesis. Protein binding and free radicals may not be largely responsible for the toxicity.
The temperature in the mediastinum during hyperthermia is difficult to determine accurately. We measured the temperature in the azygos vein, using a new technique, and compared the measurements with temperatures in the oesophagus. Eight patients with mediastinal tumours resulting from lung cancer or oesophageal cancer were given hyperthermo-radiotherapy. The temperatures in the azygos vein and in the oesophagus were measured before and during blockage of the blood flow of the azygos vein using an angiographic balloon catheter. None of the patients had complications as a result of these procedures, and hyperthermia by capacitative heating was safely performed. The temperature in the azygos vein increased by a mean of 1.7 degrees C (0.2-2.8 degrees C) after blockage of the blood flow. The temperature in the oesophagus was 0.83 +/- 1.09 degrees C (mean +/- SD) higher than that in the azygos vein. Measurement of the temperature in the azygos vein gives a more accurate estimate of mediastinal temperature than does oesophageal temperature but it is an invasive procedure.
An electron-affinic compound, AK-2123, and the anti-hypertensive agent, hydralazine, were combined with radiation and hyperthermia for treatment of murine SCC-VII tumours. Hydralazine markedly decreased tumour perfusion while AK-2123 had no influence on it. Hydralazine enhanced the tumouricidal effects of hyperthermia alone and in combination with radiation. AK-2123 provided a radiosensitization which was significant only in tumours irradiated without supplementary hyperthermia. The greatest tumour response was achieved when thermoradiotherapy was combined with hydralazine alone; the additional use of AK-2123 with this treatment combination did not further increase the effect. It is concluded that hydralazine plus heat virtually eliminated a hypoxia-related radioresistance in tumours, thus removing the requirement for AK-2123 administration.
Exposure of mammalian cells to a temperature between 42 and 44 degrees C produces multiple effects on cellular metabolism. However, none of these effects have been demonstrated to be casually related to cell death. The plasma membrane has also been suggested to be one of the targets for hyperthermia. Hyperthermia influences the membrane fluidity and membrane fluidity affects both passive diffusion and active transport process. Here, we examined the effect of hyperthermia on the transmembrane potential V-79 cells using a lopophilic probe and flow cytometry. The underlying principle on which this method is based is that a freely diffusible cation distributes itself across the membrane according with the transmembrane potential and with the concentration gradient. By these methods, we tried to find the relation between the change of surviving fraction and membrane potential. We revealed that the membrane potential becomes to be depolarized by heat treatment between 41 and 44 degrees C immediately after heat treatment. In the relationship between the change in membrane potential and cell surviving fraction, the difference between 43 and 44 degrees C was not statistically significant but between 42 and 43 degrees C was statistically significant. These results imply that the cell membrane (potassium ion channel) is one of the targets of heat treatment and that duration of depolarized condition leads to cell death.
Irradiation, dose-dependently, increases the percentage of cells in the G2 + M phase and the duration of cell cycle arrest, reflected by changes in cell kinetics in the first 48 h. Cells in the G2 + M phase are considered radiosensitive but little is known about their proliferative ability. We studied proliferative ability of irradiated G2 phase-arrested cells following flow cytometric cell sorting using fluorescent Hoechst 33342 staining. Although proliferative ability of non-irradiated cells was not different between G1 and G2 + M phases, cells arrested in G2 + M after irradiation, especially at higher doses, showed less ability than cells in G1. Proliferative ability also correlated well with of G2 block duration.
Arterial ligation was combined with hyperthermia in rabbits with VX2 tumors implanted in the leg. For seven days after arterial ligation, blood flow was decreased and the pH was low in both normal muscle and tumor tissue. The temperature of normal muscle and tumor tissue increased faster and reached a higher level on heating immediately after ligation than without ligation. The antitumor effect of hyperthermia was stronger immediately after ligation than two or seven days afterwards. However, damage to normal muscle was severe with this combination therapy, so a better method of therapeutic arterial blockade is needed.
The efficacy of temporary arterial embolization using degradable starch microspheres combined with hyperthermia was investigated in rabbits bearing VX2 tumors. Microsphere injection caused a marked decrease of tumor blood flow and pH. During heating, there was a marked increase of the maximum temperature in tumor tissue compared with normal muscle. Tumor growth was suppressed 330% times at 3 weeks after hyperthermia alone and 270% times following combined treatment with microspheres and hyperthermia. Damage to normal muscle tissue was mild. In conclusion, this combination therapy may be useful for causing selective tumor damage and reducing the effect on normal tissues.
Arterial chemoembolization using degradable starch microspheres and adriamycin was combined with hyperthermia to treat advanced liver cancer. The prolonged peak adriamycin level in hepatic venous blood suggested that the drug persisted for longer in the liver after injection containing microspheres. Heating efficiency was increased more in tumor tissue than in normal liver tissue after embolization. This combined therapy was performed in eight patients with advanced liver cancer and was effective in three (complete or partial remission). The mean survival time was 25 weeks and there were no severe side effects. This combined therapy may be useful for liver cancer.
Antitumor effects of hyperthermia are enhanced by lowering the pH in the tumor tissue with administration of glucose. This decreased pH in the tumor tissue with glucose administration was determined using mouse experimental tumors. 31P-MRS microelectrodes were used for the measurement of pH. By using these two measurement methods, time course change in the tumor tissue was determined in the controls and the groups treated with 6 g/kg of intraperitoneal glucose. The determination of pH with 31P-MRS was calculated from the chemical shift of the peak of creatine phosphate (Pcr) and that of inorganic phosphate (Pi). Following glucose administration, the tumor tissue showed a decrease of 0.3 pH units with the microelectrode method, but did not show any significant decrease in pH with the MRS determination. This finding suggested that 31P-MRS showed intracellular pH (pHi) due to the localization of Pi and that the microelectrode indicated interstitial or extracellular pH (pHe). The ATP/Pi ratio obtained in tumor tissue 24 h after heat treatment (with, without glucose) was correlated with tumor inhibition.
Indomethacin (Ind), an inhibitor of prostaglandin synthesis, was previously shown to increase the thermosensitivity of murine tumors. The potency of drug to modify the thermal response of murine skin has been evaluated in mice heated in water bath at 44 degrees C for 30, 60 and 90 min. Ind was administered subcutaneously (s.c.) at dose of 5 mg/kg body weight (b.w.) 1.5 h before heating. The mouse foot skin reactions (FSR) were assessed using the scoring system of Urano et al (1979). The severity of skin thermal damage was decreased markedly by Ind. At the time when heating of the control group at 44 degrees C for 60 min resulted in the irreversible FSR in some mice, pretreatment with Ind before heating lead to the complete recovery from the heat damage in all mice. Similarly, after heating at 44 degrees C for 90 min, the degree of FSR was diminished by Ind from score 4.5 to score 2. It is concluded that Ind selectively protected normal skin during the hyperthermic treatment. Further clinical study is warranted.
The intracellular calcium ion concentration of SCK cells was measured after the cells were heated to determine the relationship between thermotolerance and intracellular calcium concentration. SCK cells, which are breast cancer cells that spontaneously arise in A/J mice, were used. Exponentially growing cells were trypsinized and incubated for 60 min with fura-2/AM at a concentration of 10 M. The incubation was carried out at a density of 1x106 cells/ml in serum-free RPMI medium. Thermotolerance was induced by incubating cells for 5 h at 37yC after heating them at 43yC for 30 min. When heated at 44yC in a calcium containing buffer, the intracellular calcium concentration of non-thermotolerant and thermotolerant cells increased continuously as the cells were heated for longer periods of time. The same increase in intracellular calcium concentration was seen in these two cell lines when heated at 43yC in a calcium-free buffer. Thus, our data indicated that intracellular calcium ion increased during heating due to an influx into the cytoplasm from both internal stores and the extracellular medium.
We investigated the effect of angiogenesis inhibitors (FR118487 and TNP-470) on two murine tumors (FM3A and SCC-VII) with and without hyperthermia. When angiogenesis inhibitors were administered immediately after tumor implantations there was no tumor growth. As the tumor diameter increased, the antitumor effect of the inhibitors decreased. When FR118487 was combined with hyperthermia, the antitumor effect was potentiated. This study suggested that angiogenesis inhibitors show their maximal effect against small tumors and have increased activity when combined with hyperthermia.