Biomedical subjects
Publications and source records attributed to H Okada.
Various benzoylphenylurea derivatives were synthesized as candidate prodrugs and their antitumor activities were examined in vivo against P388 leukemia. All of the prodrugs were soluble in most organic solvents and showed good antitumor activities against P388 leukemia cells in mice when dosed intraperitoneally or orally.
As a step to breed a Saccharomyces cerevisiae strain able to produce ethanol directly from cellulose, we combined cDNA for Aspergillus aculeatus FI-CMCase (FI-carboxymethyl cellulase) with the GAP (glyceraldehyde-3-phosphate dehydrogenase) promoter of S. cerevisiae and used the resultant plasmid, pYEC91, to transform S. cerevisiae. The transformed cells produced active FI-CMCase within the cytoplasm. Western-blot analysis following SDS-polyacrylamide gel electrophoresis demonstrated that the cells contained a peptide having the same molecular mass and immunological identity as A. aculeatus FI-CMCase.
Norethindrone (NET; 17 alpha-ethynyl-19-nortestosterone), a progestogen component of the contraceptive pill, irreversibly inhibits aromatase activity in human placental microsomes. However, it is known also to be aromatized in vitro and in vivo to produce a biologically very active estrogen called ethynylestradiol (EE2). It is therefore inappropriate to administer a high dose of NET to estrogen-dependent cancer patients for a prolonged time period. In this study, we focused on 5 alpha-dihydronorethindrone (5 alpha-DHNET), a metabolite of NET that is not aromatizable, and the inhibitory effects of 5 alpha-DHNET on human placental and uterine leiomyoma microsomal aromatase and other steroid synthetases. 5 alpha-Dihydronorethindrone showed weak affinity for both estrogen and progestogen receptors. It inhibited significantly human placental aromatase activity in a dose-dependent manner (Ki = 9.0 mumol/l; Kinact = 0.024/min), as well as that of uterine leiomyoma, but did not influence cholesterol side-chain cleavage or 17 alpha-hydroxylase, 21-hydroxylase or 11 beta-hydroxylase activities. These results suggest that 5 alpha-DHNET may be useful as an aromatase inhibitor, whose use in large doses is expected to reduce the size of estrogen-dependent tumors.
To identify diffuse mucosal changes which may precede the development of colorectal cancer and a possible indicator for detecting high-risk populations, we immunohistochemically studied cell-cycle events in crypts of normal-appearing rectal mucosa of patients with colorectal adenoma and cancer using an in vitro labeling method with bromodeoxyuridine (BrdU). Biopsy specimens of endoscopically normal-appearing rectal mucosa were obtained during colonoscopy from 20 patients with colorectal adenocarcinoma, 20 with adenoma, and 15 without apparent colorectal diseases. The specimens were incubated with BrdU in vitro, and labeled S-phase cells were identified immunohistochemically using a monoclonal antibody to BrdU. Modification of the BrdU-labeling pattern in the normal appearing rectal mucosa, such as the presence of BrdU-labeled cells at the mucosal surface or in the upper one-fifth of the crypt column, was observed in 15 of the 20 patients with adenocarcinoma, 17 of the 20 patients with adenoma and 6 of the 15 controls. This upward shift in the frequency of proliferating cells in the crypt was significantly higher in the patients with colorectal adenoma and cancer than in the controls, and may be used to identify subjects at high risk for colorectal cancer.
A male patient suffered chronic renal failure due to lupus nephritis and was undergoing hemodialysis. Six years after beginning hemodialysis, anemia developed, which improved by erythropoietin. Unresponsiveness to erythropoietin gradually appeared, and with a suspicion of pure red cell aplasia, he was treated with a high-dose corticosteroid but the unresponsiveness did not improve. Neither his serum nor lymphocytes inhibited erythropoiesis of either normal bone marrow stem cells or his own in vitro. These observations suggest an impaired hematopoietic microenvironment in his bone marrow.
Although muscarinic receptor subtypes in the biliary system have been characterized, those in the vagal routes have not. This study was performed to characterize the muscarinic receptors in the vagal routes to the biliary system. The effects of four types of muscarinic antagonists, pirenzepine, AF-DX 116, p-F-HHSiD, and atropine, on excitatory responses in the gallbladder and sphincter of Oddi induced by electrical stimulation of the dorsal motor nucleus of the vagus (DMV) were studied in cervical cord-transected anesthetized dogs. Atropine 10 micrograms/kg and over and p-F-HHSiD 50 micrograms/kg and over significantly decreased the excitatory responses in both effectors, but it required a high dose of AF-DX 116 (1-2 mg/kg) to reduce those responses. Pirenzepine (50-300 micrograms/kg) significantly decreased the excitatory response in the gallbladder, but not that in the sphincter of Oddi. A high dose of atropine (0.5 mg/kg) abolished the gallbladder response, whereas a slight excitatory response remained in the sphincter. With the exception of pirenzepine, there was no significant difference in the effects of the three muscarinic blockers on the gallbladder response and sphincter response after reduction of the mean value of the atropine resistant responses from those of the sphincter responses after the muscarinic blockers. These results indicate that the excitatory vagal routes to the gallbladder include at least M1 receptors and those to the sphincter of Oddi may include M3 receptors.
A rare case of meningioma associated with intratumoral abscess formation occurred in a 64-year-old female presenting with septic meningitis and a right frontal mass lesion after a gynecological operation under spinal anesthesia. The mass lesion was totally removed and revealed as an incidental meningioma with an intratumoral abscess. Hematogenous infection of Bacteroides oralis was thought to be the cause of the intratumoral abscess formation.
Small cell carcinoma of the prostate is a rare disease, since only about 50 cases in the English literature and two cases in Japanese literature have been reported. Here we report a case that is the youngest ever described in the literature. A 24-year-old man was referred to our hospital with right dull lumbago and dysuria. He had the same symptom for one and half year before referral. IVP showed right non-visualizing kidney and left hydronephrosis. Form abdominal CT scans and cystoscopic findings a retrovesical tumor was highly suspicious. Transperineal needle biopsy specimens revealed an undifferentiated malignant tumor. His serum Neuron Specific Enolase (NSE) and LDH were remarkably high and whole body CT scan and upper GI tract examination demonstrated no lesion. He developed ileus and underwent exploratory laparotomy and colostomy was constructed. There was a large mass arising from the prostate which invaded into the peritoneal cavity, and multiple metastases were seen on the omentum and mesenteric lymph nodes. Specimens from the mass arising from the prostate and lymph nodes revealed small cell carcinoma pathologically. A panel of antibodies were used to seek potential tumor markers and to identify substances produced by the tumor cells including enzymes, cytoskeletal components and hormones. And stains were positive for the NSE and chronogranin. An intensive anti-cancer chemotherapy with VP-16 and CDDP was done with minor response (MR) and the serum tumor marker, LDH and NSE, decreased markedly. However, he had expired on the 58th hospital day.(ABSTRACT TRUNCATED AT 250 WORDS)
Granulocyte function of patients on anti-cancer chemotherapy was investigated. Five bladder cancer patients, who had undergone M-VAC neo-adjuvant, chemotherapy were select for this study. Their tumor stage was T3M0N0 and peripheral blood granulocyte and platelet counts were more than 1500/mm3 and 10 x 10(4)/mm3, respectively, before starting chemotherapy regardless of the course Flow-cytometric analyses were utilized to measure the function of phagocytosis and the ability to produce superoxide (bactericidal function) of granulocytes. During the course peripheral blood count, granulocyte function, urinalysis and blood chemistry were checked every other day and urine and blood culture were done once a week. Although the first course of M-VAC was completed without using rhG-CSF, the second course of M-VAC administration required rhG-CSF when the number of peripheral granulocytes was below 1000/mm3. The function of phagocytosis decreased from the onset of the first course of M-VAC until the nadir of granulocyte number, then recovered close the pre-chemotherapy level by the time when the chemotherapy was completed with the increase in the number of granulocyte but remained relatively low until starting the second course. The function deteriorated more rapidly with the second course than with the first course, but recovered rapidly after administration of rhG-CSF and was significantly higher when the nadir of granulocytes was noted with the first course of M-VAC than with the second course. As for the function of superoxide production, it decreased gradually until the nadir of granulocyte during the first course and then continued to recover toward starting the second course but failed to return to the pre-chemotherapy level.(ABSTRACT TRUNCATED AT 250 WORDS)
A new topoisomerase II inhibitor, designated BE-22179, was isolated from the culture broth of Streptomyces sp. A22179, which resembles "Streptomyces gangtokensis". The inhibitor was extracted from the mycelial cake of the culture broth with organic solvent and successively purified by silica gel chromatography. BE-22179 inhibited topoisomerase II strongly but not topoisomerase I and showed potent antitumor activity against various tumor cell lines both in vitro and in vivo.
To evaluate changes in the spontaneous baroreflex sensitivity for heart rate and for muscle sympathetic nerve activity (MSNA) during sleep, we simultaneously recorded MSNA from the tibial nerve and monitored ECG, EEG, EOG, EMG and blood pressure during the resting awake stage and sleep. Blood pressure, ECG and MSNA waves were changed to equidistant time series data of each second by cubic spline interpolation. Cross correlations between the MSNA and diastolic blood pressure and between the instantaneous heart rate and systolic blood pressure were analyzed. Spontaneous baroreflex sensitivities for MSNA and for heart rate were assessed from the slope of the regression lines for each. During sleep, the spontaneous baroreflex sensitivity for MSNA gradually decreased as the non-REM sleep stages advanced. Spontaneous baroreflex sensitivity for heart rate did not show any apparent changes. These results suggest that baroreflex modulations for heart rate and for MSNA differ during sleep.
Complement regulatory membrane proteins act either on C3/C5 convertase enzymes of the classical and alternative pathways or prevent the formation of membrane attack complexes (MAC). 5I2 is a monoclonal antibody (mAb) directed against a rat erythrocyte membrane inhibitor of the C3 convertase step which seems to be the rat counterpart of mouse Crry/p65. 6D1 is a mAb against rat CD59 which inhibits formation of MAC. Tissue distribution of these membrane inhibitors was visualized by immunohistochemical staining with the appropriate mAb. Rat CD59 (6D1 antigen) and 5I2 antigen were both widely distributed, being predominantly expressed on endothelial cells of the arteries, veins and capillaries as well as on all circulating cells. 6D1 antigen and 5I2 antigen were also detected on immature hepatocytes, systemic endothelial cells, skin fibroblasts, bronchial epithelial cells and bile canaliculi. Both were also expressed in the Schwann sheath of peripheral nerve fibres and ependymal cells. However, glial cells and myelin sheath in the central nervous system were not stained. Anti-CD59 (6D1) staining of epithelial and endothelial cells was observed in the cornea, while 5I2 stained only the epithelial cell layer.
We examined the effects of a calcium-channel blocker amlodipine on progression of renal failure in 5 of 6 nephrectomized spontaneously hypertensive rats (SHR) fed a high-salt diet. Twelve SHR, 5 of 6 with nephrectomy and salt-loading, were divided into two group: group 1 as control (n = 6) and group 2 treated with 2 mg/kg/day amlodipine (n = 6). During the 10 study weeks, body weight, systolic blood pressure (SBP), and daily urinary protein excretion were measured every 2 weeks. At the end of the study, serum creatinine, urea nitrogen, and total protein and albumin were determined. Renal tissues were obtained for light microscopic examination. The increase in SBP after 10 study weeks was significantly less in the treated group than in the control group (control 287 +/- 5 mm Hg; amlodipine 237 +/- 23 mm Hg (p < 0.01)). Urinary protein excretion was also suppressed in the amlodipine-treated group (p < 0.01). Although in the control group glomerular sclerosis and hyalinosis were marked, they were significantly less in the amlodipine-treated group. These results illustrate that amlodipine can attenuate BP increase and inhibit progression of hypertensive renal injury in this rat model.
The antitumor effect of an angiogenesis inhibitor, TNP-470 (AGM-1470, 6-0-(N-chloroacetylcarbamoyl)-fumagillol), administered via the hepatic artery in a medium-chain triglyceride (MCT) solution, in which TNP-470 is very stable, was examined in rats bearing Walker 256 carcinosarcoma in the liver. The MCT solution containing 0.1 mg of TNP-470 completely suppressed tumor growth after a single arterial injection, and the solutions containing 0.5 approximately 5 mg of TNP-470 caused tumor regression function. These antitumor effects lasted for at least 2 weeks. Moreover, the administration of the MCT solution containing 5 mg of TNP-470 also caused remarkable regression of well-developed enlarged tumors 2 weeks after inoculation, indicating potential in the treatment of unresectable hepatic cancer. When the MCT solution containing radiolabeled TNP-470 was injected via the hepatic artery, the initial radioactivity in the tumor was 22 times that in the normal part of the liver and 5.7 times that in the tumor when an aqueous solution of radiolabeled TNP-470 was injected. Also, in the case of the MCT solution, the radioactivity in the tumor was maintained at a relatively high level for over 2 weeks after injection. These results indicate that the remarkable antitumor effect resulted from the selective delivery and prolonged retention of TNP-470 at the tumor site.
We report a case of a müllerian duct cyst associated with a 46, XYq- chromosome anomaly. Müllerian duct cyst is a consequence of the abnormal regression of paramesonephric derivative. In the past many different manifestations have been associated with the 46, XYq-, anomaly. We discuss the possibility that a müllerian duct cyst may be one clinical manifestation of 46, XYq-.
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AKBR is a metabolic indicator related to NAD-linked dehydrogenase system, according to the REDOX theory. In order to estimate whether AKBR is a sensitive indicator of liver injury or not, we measured AKBR before and immediately after cardiopulmonary bypass (CPB) in 20 patients undergoing cardiac surgery and thoracic aortic aneurysmectomy. Twenty patients were divided into two groups: one with AKBR more than 0.7 (normal group) and the other with AKBR less than 0.7 (abnormal group). The AKBR in the abnormal group was significantly decreased after CPB (p < 0.05), though the AKBR in the normal group was unchanged. In addition, the normal group significantly showed high AKBR compared to the abnormal group after CPB (p < 0.01). Among 5 patients with GPT more than 50 IU/l, the number of patients with AKBR more than 0.7 was zero and with AKBR less than 0.7 was 5 patients. The normal group has a lower risk of liver injury than the abnormal group. The normal group had a higher hepatic perfusion pressure compared with abnormal group. However, there were not significant differences in the cardiac functions (cardiac output, LVSWI and RVSWI) after the CPB between two group, whereas the CPB time and the aortic clamping time in the abnormal groups were longer than those in the normal group. We concluded that the AKBR is a sensitive indicator of liver function after the CPB.
The monoclonal antibody 5I2 recognizes and functionally inhibits a Crry-like complement regulator molecule on rat cells (corresponding to human decay accelerating factor and membrane cofactor protein activity). The inhibition of complement regulatory activity by 5I2 antibody results in complement deposition on rat cell membranes exposed to homologous complement. Two subclones of KDH-8 rat hepatoma were selected for the experiments; one expressing high (CrryH) and the second low (CrryL) amounts of Crry-like antigen. Both sublines grow in vivo in syngeneic rats, but at lower cell doses (< 10(5) cells/rat) the survival time of rats injected with CrryL cells is prolonged. Injection of tumour-bearing rats with 5I2 monoclonal antibody intraperitoneally did not influence the tumour growth. However, it resulted in 50% mortality within a few hours, accompanied by severe haemorrhage in the peritoneal cavity. Pretreatment of the tumour cells with 5I2 monoclonal antibody or its F(ab')2 fragment substantially increased the survival time of recipient rats. Even permanent survivors were found, indicating that cell membrane-associated complement regulatory activity, which provides protection against attack of homologous complement, is necessary for in vivo tumour growth.