Journal of Okayama Medical Association
Published by Okayama Medical Association

Full-text articles are available 3 years after publication.

Differential Hypothermiaのハムスター移植腫瘍におよぼす影響について I) Shallow Differential Hypothermiaと抗癌剤併用の効果について

Ohashi, Takeo
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How to treat the malignant brain tumors has been one of the biggest problems in neurosurgery. It has been in the past, and it is still now. In addition to surgical removal of tumors, various non-surgical method have been tried for the treatment of malignant gliomas. The use of heating or of cooling are some of these methods. They have been tried for a long time. Already in 1866 Busch,W. observed disappearance of sarcoma in patients suffering from erysipelas. Westermark,N. in 1927 observed that rat transplanted tumors were caused to disappear by exposing to heating, while the adjacent normal tissues were not damaged under conditions lethal to the tumors. In 1960 Woodhall,B. heated tumors locally that were perfused with chemotherapy. Shingleton,W.W., in 1962, heated localized tumor tissue on the patients with cancer, combined with regional chemotherapy under generalized hypothermia. According to Popovic,V.P. et'al. in 1965, they were first to report that differential hypothermia, keeping tumors normothermic under total body hypothermia at a temperature of 4℃ during a period of 10 hours in experimental animals, induced disappearance of tumor without resuming their growth afterward. Popovic,V.P., et al. in 1966 carried out further experiments and observed that tumors of the animals disappeared also subsequent to cooling whole body to 4℃ for 1 hours with anti-tumor agent, as well as to cooling whole body to 30℃ for 24 hours without chemotherapy while the tumor kept at 37℃. However, in order to induce tumor disappearance the differential hypothermia has to last at least 4℃ for 1-10 hours, or 30℃ for 24 hours. Since deep hypothermia lasting several hours or shallow hypothermia for long time is not well tolerated in non-hibernators, namely human beings, present experiment has been performed in an attempt to simulate the conditions of clinical work as close as possible. For this purpose the bodies of 22 hamsters were mildly cooled to a temperature of 30℃, while cheek pouch transplanted tumors induced originally by adenovirus type 12 remained uncooled at 37℃ for 10 hours (Fig. 1, 2). The dose of 50mg/kg of 5-fluorouracil (5-FU) was administered intraperitoneally in single injection at the beginning of treatment of shallow differential hypothermia (Table 1, Fig. 2). This resulted in that within 7 days later 4 out of 22 tumors (20 % ) disappeared completely without resuming their growth afterward, and 12 out of 22 tumors (55 % ) regressed temporarily for a period of 10 days after treatment (Table 2, 3, Fig. 6-b, 8). When the same amount of 5-FU was administered into normothermic tumor-bearing animals or into hypothermic animals with hypothermic tumors, tumor size of the animals was not affected (Table 1, Fig. 5-a, 6-a). When shallow differential hypothermia was treated without any anti-tumor agent, neither normothermic tumor size nor hypothermic one of the animals was also affected (Table 1, Fig. 7-a). Histological findings were degeneration of tumor cells. Stainability of nucleolar RNA and nuclear DNA by means of methyl green-pyronine and Feulgen's methods was decreased already immediately after the shallow differential hypothermia treatment for 10 hours with 5-FU administration (Fig. 10-a). This was followed by, at 24 hours after the treatment, marked decreasing and loss of the stainability of nucleolar RNA and nuclear DNA as well as dismixture of chromatin and karyolysis of nuclei (Fig. 11-a, b). Scattered necrotic foci in the tumor tissue were obviously revealed 48 hours after the treatment. Tumor cells showed selectively these degenerative finding after treatment, while adjacent mucosal tissue of cheek pouch preserved their normal appearance almost wholly even 12 hours after the treatment (Fig. 10-c). Although inflammatory cell infiltration was observed 48 hours after the treatment, and followed by fibrocytic fibrosis in the submucosa thereafter, degenerative and necrotic change was never showed (Fig. 11-c, 12-a, b). The author discussed that 1) combination with differential hypothermia and anti-tumor agent was effective for experimental tumor, 2) selective destroying and normothermic state of the treatment should be useful for non-surgical therapy of malignant brain tumor, as well as 3) cellular sensitive function of differential hypothermia might be exsisted in nucleolus or nucleus of tumor cell.