Biomedical subjects
Publications and source records attributed to H Mogami.
Chemotherapy of malignant glioma has been discussed in relation to recent attempts to enhance the effect, such as multi-drug combination, local administration and high dose with rescue. Recent studies on drug resistance and attempts to overcome the resistance were also reviewed.
Explore the source record for details and available documents.
Werner's syndrome is rare and autosomal recessive condition with multiple progeroid features. There is an increased incidence of neoplasm such as meningioma or sarcoma in association with this syndrome. However, the pathogenesis of this subject is still controversial. To date, only two cases have been reported, dealing with surgical operation. Our present case of a 39-year-old woman who had a meningioma associated with Werner's syndrome is the third of such cases. In this rare case we did histopathological examinations including electron microscopic and immunohistochemical studies, which showed intense proliferation of the connective tissue in the tumor tissue. The present morphological study may imply a close relationship between proliferation of collagen fibers in the meningioma and the aberration of connective tissue metabolism in context of theory of the pathogenesis of Werner's syndrome.
Today, many gynecologists consider that the first choice of the treatment of prolactinomas is bromocriptine therapy. Because bromocriptine not only decreases the levels of serum prolactin but also reduces the tumor size. On the other hand, the patients with non-functioning adenoma sometimes show hyperprolactinemia, probably because PIF (prolactin inhibiting factor) cannot reach the normal prolactin-producing cells of the adenohypophysis. Therefore non-functioning adenoma with elevated serum prolactin levels should be distinguished from prolactinoma. Eighty five patients with non-functioning adenoma were treated with transsphenoidal operation at Hiroshima University Hospital, and Kansai Rosai Hospital from May, 1978 to March, 1981 and at Osaka University Hospital, The Center for Adult Diseases, and Kansai Rosai Hospital from April, 1981 to May, 1986. Non-functioning adenomas were diagnosed by clinical feature, endocrinologic examination, and immunohistochemical study. There were 42 male and 43 female patients, whose age ranged from 17 to 76 years (mean: 49). The most frequent chief complaint was visual disturbance (86%). Amenorrhea-galactorrhea was complained by 9 female patients. However, 7 of them had visual disturbance at the same time. Hyperprolactinemia was seen in 21 patients (30%). The highest serum level of prolactin was 163.2 ng/ml. All of the patients had macroadenomas. There were 2 invasive adenomas and 83 expensive adenomas in them. After operation, cure or improvement of the visual disturbance was noted in almost all the patients. The serum levels of prolactin were normalized in 16 of 17 hyperprolactinemic patients. In conclusion, transsphenoidal operation is the best treatment of non-functioning adenomas. However, it is difficult to decide before operation whether the macroadenoma with serum prolactin level between 100 and 200 ng/ml is non-functioning adenoma or prolactinoma.(ABSTRACT TRUNCATED AT 250 WORDS)
A nitrosourea derivative, ACNU (nimustine hydrochloride), is often used in the chemotherapy of brain tumors and shows considerable efficacy, since it crosses the blood-brain barrier (B.B.B.). This drug is also considered to be useful for intrathecal treatment of meningeal gliomatosis (MG) because of its short half-life in the blood or cerebrospinal fluid (CSF) and its strong cytotoxicity for glioma cells. In order to evaluate the efficacy of intrathecal therapy of MG with ACNU, MG models, which were produced by intracisternal inoculation of rat C6 glioma, were treated with intrathecal or intravenous administration of ACNU. When intrathecally administered 1 day or 3 days after tumor inoculation, ACNU (1 mg/kg) significantly prolonged the survival time of MG rats, where ILS was 35.7 to 42.9% and 24.1 to 25.0%, respectively. In MG rats which were treated intrathecally with ACNU (1 mg/kg) 5 days after tumor inoculation or intravenously with ACNU (15 mg/kg), ACNU failed to prolong survival time compared with the controls. It might therefore be suggested that intrathecal chemotherapy with a low dose of ACNU is effective in the early stages of MG, in which intravenous treatment with a high dose of ACNU is ineffective.
A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxicity of ACNU in vitro in rat C6 glioma, 9L gliosarcoma and their ACNU-resistant sublines (C6/ACNU and 9L/ACNU). Uptake and retention of ACNU in these cells were studied with [14C]ACNU in the absence or presence of trifluoperazine. The results indicated that intracellular uptake and retention of ACNU in C6 and 9L cells were larger than those in C6/ACNU and 9L/ACNU cells, and that trifluoperazine increased the cellular uptake and retention of ACNU in C6 and 9L, especially in C6/ACNU and 9L/ACNU cells. The amounts of ACNU in C6/ACNU and 9L/ACNU cells reached almost the same level as those detected in C6 and 9L cells. When trifluoperazine were added along with ACNU to the culture in vitro at a concentration of 10 and 20 microM, ACNU resistance was completely overcome. Furthermore, treatment of C6 and C6/ACNU cells with 20 microM trifluoperazine did not change the cellular uptake rate of [14C]AIB (alpha-aminoisobutyric acid), which might indicate that the membrane permeability of the cells was kept intact during the drug treatment. The same phenomenon was observed in 9L and 9L/ACNU cells. It might be concluded that the enhanced effect of cytotoxicity of ACNU in ACNU-resistant rat brain tumor cells presented in this study is presumably due to the increase of intracellular concentration of ACNU resulting from the inhibition of the efflux of ACNU by trifluoperazine from the resistant cells. It was also suggested that ACNU resistance in malignant brain tumors could be overcome by combination chemotherapy with ACNU and calmodulin inhibitors.
In the previous reports, we demonstrated that intracisternal ACNU is effective in prolonging the survival time of rats with meningeal carcinomatosis induced by intracisternal inoculation of Walker 256 carcinosarcoma cells, and systemic and local toxicity can be avoided by adjusting the drug dose. In this experiment, we studied distribution of 14C-ACNU in the rat brain after intracisternal administration using a macroscopical autoradiographic method. One muCi of ethylene-14C-ACNU was percutaneously injected into the cisterna magna of normal female Wistar rats weighing approximately 150 g. The animals were sacrificed 5 and 30 minutes, and 3 hours after injection (3 animals in each group). The brain was quickly removed and frozen in Freon. 14C-ACNU autoradiograms were made in coronal sections of the brain, which were cut in 20 mu thick and exposed to the film for 7 days. In 5 minutes after administration, high radioactivity was distributed in the subarachnoid space of the basal and ambient cisterns and hypocampal fissures, and subpial brain tissue up to 1 or 2 mm in depth. High radioactivity was also present in the ventricles and subependymal layer. In 30 minutes after administration, total radioactivity has already reduced in amount, however, local distribution has not changed so much as compared to that of 5 minutes after injection. No radioactivity was observed in the deeper part of the brain. In 3 hours after administration, only a small amount of radioactivity remained in the subarachnoid space and subpial region.(ABSTRACT TRUNCATED AT 250 WORDS)
A calmodulin inhibitor, trifluoperazine, was found to enhance the cytotoxic action of ACNU in C6, especially in ACNU-resistant (C6/ACNU) glioma cells in vitro. In order to clarify the efficacy of trifluoperazine in vivo, 1 X 10(7) C6 or C6/ACNU cells were percutaneously implanted into the cisterna magna of Wistar rats to produce meningeal gliomatosis (MG) models as a chemosensitivity assay system. MG rats were treated with ACNU and trifluoperazine according to a variety of schedules. Trifluoperazine in doses of 250 to 500 micrograms/kg intrathecally (it) administered with 1 mg/kg ACNU 1 day after the tumor inoculation significantly increased the life span of the C6/ACNU bearing (C6/ACNU MG) rats. At doses of 250 and 500 micrograms/kg of trifluoperazine in the C6/ACNU MG rats, values of increased life span of 22 and 30% were obtained with a 1 mg/kg dose of ACNU, respectively. These values were statistically significant compared with that obtained in the C6/ACNU MG rats treated with ACNU alone at 1 mg/kg. It might be concluded that the combination chemotherapy with ACNU and such a calmodulin inhibitor as trifluoperazine could overcome ACNU resistance in malignant brain tumors.
For the purpose to study reasonable treatment for recurrent gliomas, in vitro immunochemosensitivity tests were performed by using human malignant glioma cell line (ONS-12) and its ACNU-resistant cell line (ONS-12/ACNU), which were established in our laboratory. ONS-12/ACNU cells showed a cross-resistance to Ara-C, but not for cisplatin and methotrexate. The lymphokine-activated killer (LAK) cells induced in vitro from the peripheral blood lymphocytes (PBL) of healthy subjects, showed stronger cytotoxicity to ONS-12/ACNU than ONS-12 cells. From these data, selection of appropriate anti-tumor agents on the in vitro sensitivity tests was a most useful method for the treatment of recurrent gliomas, and the adoptive immunotherapy with LAK cells may be useful for ACNU-resistant gliomas.
Phenytoin is a highly effective anticonvulsant agent that is widely administrated to prevent some kinds of patients with brain tumor. But it has been said that phenytoin may have some immunosuppresive potential for hosts. In this study, we evaluated the effects of phenytoin upon cellular immunity such as NK, CTL and LAK activity in murine models. Fresh splenocytes were taken out from mice (CBA/J, C 3 H/HeN, C 57 BL/6) into which phenytoin had been injected intraperitoneally at a daily dose of 1,000 micrograms for 28 days. The serum concentration of phenytoin in the experimental models was 10-20 micrograms/ml. The cytotoxic activities were estimated by a 4-hr 51Cr release assay. The mitogen-stimulated lymphocyte function was evaluated by 3H-thymidine incorporation into DNA. The NK activity was estimated by cytotoxicity of splenocytes of CBA/J mice against NK-sensitive YAC-1 cells. The cytotoxic T-lymphocyte (CTL) activity was estimated by cytotoxicity of splenocytes of C 57 BL/6 mice which were stimulated in vitro for 5 days by splenocytes of C 3H/HeN treated with mitomycin C, against RSV-M glioma cells. Lymphokine-activated killer (LAK) activity was estimated by cytotoxicity of LAK cells, which were induced from splenocytes of C 3 H/HeN mice by human recombinant interleukin-2 (rIL-2), against syngeneic RSV glioma and allogeneic 203 glioma cells. 3H-thymidine incorporation of splenocytes of C 57 BL/6 mice was reduced significantly (p less than 0.01) in phenytoin-treated mice. The cytotoxicity of splenocytes of non-treated CBA/J mice against YAC-1 cells was 75%, but that of phenytoin-treated CBL/J mice was a few %.(ABSTRACT TRUNCATED AT 250 WORDS)
Bromocriptine (CB) not only lowers serum prolactin (PRL) levels but also reduces tumor size of human prolactinomas. Gen et al and we have suggested that the size reduction of human prolactinomas by bromocriptine treatment results from the reduction in size of individual tumor cell as well as the reduction in number of tumor cells secondary to cell necrosis. This implies that bromocriptine has a cytosuppressive action and possibly a cytocidal action on human prolactinomas which causes reduction in cell size and cell necrosis, respectively. The mechanism of cytosuppressive action of CB has been investigated by using mostly non-neoplastic pituitary tissues of experimental animals. A decrease in exocytosis of secretory granules and a subsequent accumulation of granules within the cells are suggested to cause the reduction in serum levels of PRL in early stage of CB treatment. However we have reported that in spite of a pronounced reduction of serum PRL levels, the number of exocytosis of the granules in human prolactinomas treated with CB for 2 weeks increased to more than 4 times much as that in the untreated prolactinomas. This is a phenomenon which contradictory to the current hypothesis. The present study is intended to clarify whether the phenomenon we observed is specific for human prolactinomas or common also to the prolactinomas in experimental animals. Seventeen female SD rats were used. They were implanted subcutaneously with a pellet of 20 mg of 17 estradiol-benzoate (20% in cholesterol), and left to grow a pituitary tumor for 10 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)
The antitumor efficacy of recombinant interferon-beta (rIFN-beta) on human glioblastomas was investigated in vitro and in meningeal gliomatosis(MG) models. A total of 1.5 X 10(5) human glioma (ONS-12 and ONS-20) cells were suspended in 2 ml of RPMI-1640 with 10% fetal calf serum and placed in plastic dishes (Falcon #3001). rIFN-beta 10(2)-10(5) units were then added to each culture dish on days 3, 5 and 7. Both ONS-12 and ONS-20 human glioma cells were suppressed with a low dose of rIFN-beta. As MG models, 5 X 10(7) ONS-12 glioma cells were suspended in saline and transcutaneously inoculated into the cisterna magna of BALB/c nu/nu mice using a 27-gauge needle. The median survival times (MST) of MG models which were treated by intrathecal administration of 10(3) U of rIFN-beta and intraperitoneal injection of 10(4) U of rIFN-beta were 11.0 and 8.0 days, compared with an MST of 7 days for control mice. The rIFN-beta was not effective by intraperitoneal administration but was effective by intrathecal administration in the MG models. The MSTs of MG models which were treated by administration of 10(5) U, 10(3) U of rIFN-beta and 0.1 ml saline were 15.0, 19.0 and 9.0 days, respectively. The therapeutic efficacy in MG models depended on the administration route of rIFN-beta, and as far as could be determined from the MG models, high-dose administration of rIFN-beta was not always useful.
A prospective high performance liquid chromatography (HPLC) study was performed in eighteen patients with head injury and stroke and four control volunteers to evaluate creatinine and purine metabolites concentration (adenosine, inosine, hypoxanthine, uric acid) in cerebrospinal fluid (CSF). The present HPLC method is rapid, accurate and sensitive in the same isocratic run and no specimen pretreatment of 0.02 ml CSF is necessary. The creatinine level in CSF was increased from 122 to 169 mumol/l in some patients, and was found unrelated to that of serum. The uric acid levels varied between 5.8 and 121 mumol/l and were associated with decrease in Glasgow Coma Scale score and had a critical point of 30 mumol/l. We present initial results in application of HPLC method to measure the creatinine and purine metabolites in CSF. This preliminary report presents that these high levels in CSF of head injury and stroke patients probably reflect tissue damage and an increased tissue catabolism.
Explore the source record for details and available documents.
To elucidate the environmental influence on the growth of a tumor, bromodeoxyuridine (BrdU) uptake in multiple tumor foci within the intracranial cavity was studied immunohistochemically with a monoclonal antibody. Walker 256 tumor implanted intracerebrally produced multifocal tumors presented as intraparenchymal solid tumor, tumor in the choroid plexus, and leptomeningeal dissemination. The BrdU-labeling indices, or the S-phase fractions (% of nuclei labeled by BrdU divided by the number of tumor cell nuclei scored; LI), of those tumors were 48.4 +/- 1.1, 59.1 +/- 1.3, and 27.9 +/- 5.9, respectively (mean +/- SEM). These differences in LI, or the tumor growth activity, are discussed in relation to the different environmental conditions in different host structures. These host structure-related modification of tumor growth would be important in evaluating the proliferative activity of tumors growing at various intracranial structures.
Ninety-eight patients (16 male, 82 female) with prolactinomas were treated by transsphenoidal operation. The postoperative course was closely related to the tumor size and the preoperative levels of serum prolactin. In 37 (74%) of 50 patients with microadenomas, the levels of serum prolactin returned to normal postoperatively. There were 48 patients with macroadenomas; 27 of these were expansive and 21 were invasive. In 9 (33%) of the 27 patients with expansive macroadenomas, the postoperative levels of prolactin returned to normal; this was not the case in any of the 21 patients with invasive macroadenomas. Of 81 premenopausal women, 35 (43%) resumed normal menstruation postoperatively. All patients with preoperative deficits in the visual field experienced postoperative improvement. There were no postoperative deaths or serious complications in this series. Our data indicate that microprolactinomas are highly curable by transsphenoidal operation alone. In women who plan to have children, prolactinomas should be removed immediately. On the other hand, in patients with macroprolactinomas who manifest high levels of serum prolactin, initial treatment with bromocriptine should be considered because there is little hope for surgical cure and postoperative bromocriptine treatment might be necessary.
Reserpine was found to enhance the cytotoxicity of ACNU on ACNU-resistant C6 glioma (C6/ACNU) cells in vitro. When reserpine was added along with ACNU to the C6/ACNU cells in vitro. When reserpine was added along with ACNU to the C6/ACNU culture in vitro at a concentration of 10 microM, the IC50 of ACNU for C6/ACNU cells decreased to the level of that for C6 cells and ACNU resistance was completely overcome in vitro. Furthermore, intracellular uptake of ACNU increased in both sensitive (C6) and resistant (C6/ACNU) glioma cells when 20 microM reserpine was added to the culture medium. Reserpine (20 microM) enhanced the cellular level of ACNU in C6 cells 1.5-fold and enhanced the level of ACNU in C6/ACNU cells 4-fold. The amount of ACNU incorporated into C6/ACNU cells reached the same level as that incorporated into C6 cells. The enhanced cytotoxicity of ACNU in vitro could be explained by the effective intracellular accumulation of ACNU resulting from the increase of intracellular uptake of ACNU in C6/ACNU cells by reserpine.
Alterations in the regional CBF after occlusion of the posterior communicating, middle cerebral, or common carotid artery were investigated in the gerbil with a quantitative autoradiographic technique using [14C]iodoantipyrine. Occlusion of the posterior communicating artery produced severe ischemia in the ipsilateral hippocampus, thalamus, and dorsal mesencephalon. Occlusion of the middle cerebral artery produced severe ischemia in the ipsilateral rostral and central cerebral cortex and lateral caudate-putamen. Occlusion of the common carotid artery produced ipsilateral hemispheric ischemia of variable degrees. The distribution and degree of cerebral ischemia produced by occlusion of one of these arteries correlated closely to the arterial territory and the extent of collateral blood supply. Since the areas affected after occlusion of the posterior communicating or middle cerebral artery differ, those models will be useful for the comparative investigation of the ischemia-related cerebral pathophysiology associated with different sites of primary lesion.