A new class of highly potent farnesyl diphosphate-competitive inhibitors of farnesyltransferase.
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3T3 Cells↗
Biomedical subjects
J Shibata
Publications and source records attributed to J Shibata.
A case of atypical aortic coarctation with refractory congestive heart failure--treatment with axillo-iliac artery bypass.
Coarctation of the aorta is rare. We present a case of atypical coarctation due to aortitis syndrome with congestive heart failure refractory to conventional medical treatment. Although indications for surgical treatment are not well established and, in general, treatment of choice is an aorto-aortic bypass, we selected axillo-iliac bypass with subcutaneous tunnel because of severe heart failure. Postoperatively, the pressure gradient disappeared and heart failure was improved.
Aged↗
TAC-101, a benzoic acid derivative, inhibits liver metastasis of human gastrointestinal cancer and prolongs the life-span.
We examined the anti-tumor effect of a novel benzoic acid derivative, TAC-101 (4-[3,5-bis(trimethylsilyl) benzamide] benzoic acid) on models with liver metastasis. Oral administration of TAC-101 significantly inhibited spontaneous liver metastasis of AZ-521 (human gastric cancer ) by orthotopic implantation to athymic nude mice. It also inhibited both the liver metastasis of AZ-521 induced by intrasplenic injection and the secondary lung metastasis from the liver. In addition, TAC-101 inhibited the proliferation of Co-3 (human colon adenocarcinoma) that formed a single nodule in the liver of athymic nude mice by intrahepatic implantation. The growth inhibitory effect of TAC-101 on AZ-521 experimental liver metastasis was observed when treatment was started on day 7, 14, or 21 which may correspond to the progressive stage of liver metastasis in clinical settings. Multiple administration of TAC-101 (8 mg/kg/day) significantly prolonged survival time of the animals with liver metastasis by intrasplenic injection of AZ-521 (T/C = 230%) and A549 (human lung adenocarcinoma; T/C = 186%). These effects of TAC-101 were stronger than those of 5-FU, CDDP or ATRA. Furthermore, TAC-101 inhibited the binding of AP-1 to DNA on electrophoretic mobility shift assay using nuclear extract of AZ-521 cells, although ATRA did not inhibit. These findings suggested that TAC-101 may be a candidate for a new class of anti-cancer agents for liver metastasis.
Adenocarcinoma↗
[Antitumor activity of miproxifene phosphate (TAT-59) against human mammary carcinoma].
DP-TAT-59, an active metabolite of miproxifene phosphate (TAT-59), showed a strong anti-proliferating activity against ER-positive human mammary carcinoma cell lines, MCF-7 and T-47D, in the presence of 1 nM of estradiol. The ED50 value of DP-TAT-59 for each cell line was 30-fold lower than that of tamoxifen. TAT-59 suppressed the growth of mammary carcinoma, MCF-7 and Br-10, xenografted into nude mouse at a dose of 5 mg/kg/day, which is equivalent to 20 mg/body of daily dose to the patients. TAT-59 inhibited the growth of tamoxifen-resistant breast cancer cell lines, R-27 and FST-1, but not tamoxifen, suggesting the possible efficacy of TAT-59 for tamoxifen-refractory patients. DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 detected in blood after oral administration in the patients, exhibited equal growth-inhibitory activity against human mammary tumor xenograft, meaning the antitumor activity of TAT-59 may equally depend on these two metabolites. In uterotrophic testing using both immature mice and ovariectomized rats, while the effective dose of TAT-59 was lower than that of tamoxifen, TAT-59 showed dose-dependent estrogenic activity against their uteri, similar to tamoxifen. These results suggested that TAT-59 had a stronger antagonistic activity against estrogen-dependent mammary tumor than tamoxifen. We expect that TAT-59 will become an effective therapeutic agent for patients with high estrogen levels in their blood, such as premenopausal women, and the patients with whom the tamoxifen modality failed.
Animals↗
Antiestrogenic activity of DP-TAT-59, an active metabolite of TAT-59 against human breast cancer.
PURPOSE: The purpose of this study was to clarify the mechanism(s) of antiestrogenic action of DP-TAT-59 ((Z)-2-(4-(1-(4-hydroxyphenyl)-2-(4-isopropyl-phenyl)- 1-butenyl)phenoxy)-N,N-dimethylethylamine), the main active metabolite of TAT-59. METHODS: Using 4-OH-tamoxifen (a hydroxylated metabolite of tamoxifen) as a reference compound, we examined the relationship between hormone-dependent tumor cells and DP-TAT-59 and characterized estrogen receptor (ER) complexes with DP-TAT-59 using ion-exchange chromatography. RESULTS: DP-TAT-59 inhibited the in vitro proliferation of MCF-7 cells under serum-free conditions at a lower concentration than did 4-OH-tamoxifen. The conditioned medium (CM) obtained from the culture supernatant of MCF-7 cells in the presence of these antiestrogens suppressed the growth of ER-negative cell lines, but that from ER-negative human mammary carcinoma MX-1 cells did not. The CM from DP-TAT-59-treated cells showed a higher growth-inhibitory potency against human mammary carcinoma ZR-75-1 cells than did that from 4-OH-tamoxifen-treated cells. The growth-inhibitory potency of the CM was neutralized by the addition of the anti-TGF-beta antibody. The CM obtained from cells treated with DP-TAT-59 contained more TGF-beta and less TGF-alpha than that treated with 4-OH-tamoxifen. As the antiestrogenic activity of TAT-59 might be mediated through ER, the interaction of these antiestrogens with a cytoplasmic receptor of MCF-7 cells was examined. While the competitive binding of [3H]-estradiol with these antiestrogens to ER was similar, ER complexes with DP-TAT-59 showed a different elution profile by ion-exchange chromatography, indicating that DP-TAT-59 formed a different complex with ER from either 4-OH-tamoxifen or estradiol. CONCLUSION: These findings suggest that at least a part of the growth suppressive ability of DP-TAT-59 against human mammary carcinoma might depend on the production of growth inhibitory factors and/or the suppression of production of growth factors from ER-positive cells, and that the production of growth inhibitory factors might be stimulated by ER complexes with antiestrogens rather than with estrogen.
Binding, Competitive↗
Three-dimensional helical computed tomography with intravenous cholangiography for sclerosing cholangitis manifested as postcholecystectomy symptom.
A 46-year-old woman who had upper abdominal pain 10 years after cholecystectomy, and who had incidental sclerosing cholangitis (SC), was investigated by three-dimensional helical computed tomographic (3-DHCT) cholangiography with contrast medium, because endoscopic retrograde cholangiography (ERC) was unsuccessful and a second ERC was not permitted by the patient. The cholangiogram demonstrated annular strictures of the bilateral hepatic duct at the confluence of the common hepatic duct, and dilatation of the left intrahepatic biliary duct. Although we could not clarify the cause of the biliary tract deformity at the time of the 3-DHCT, the tentative diagnosis of postcholecystectomy deformity of the biliary tree led to successful treatment by right liver lobectomy and hepaticojejunostomy. Histologic findings were compatible with SC. From this experience and the literature, we suggest that 3-DHCT cholangiography with contrast medium can contribute to the preoperative diagnosis of morphological changes in the biliary tree in patients with postcholecystectomy symptoms.
Cholangiography↗
[Evaluation of ileocolon interposition after total gastrectomy].
The most serious complaints after total gastrectomy are alkaline esophagitis and postalimentary syndrome. We have performed ileocolon interposition as a gastric substitution which uses the ileocecal valve to prevent bile reflux. The ileocolon segment consists of 7 cm of terminal ileum and 10 cm of coecum and ascending colon on a vascular pedicle. This isolated segment is rotated upwards between the esophagus and the duodenum. To evaluate the function of the ileocolon as a gastric substitute, Barium X rays, O-GTT and gastric emptying time (99Tc EDTA) were examined. Barium X-rays showed that the air at the coecal portion looks like a gastric fornix and there is no barium reflux into the esophagus even in the supine position. Likewise, there were no complaints from patients of symptoms of reflux esophagitis. In case of Rouxen-Y reconstructions, blood sugar level after O-GTT show oxyhyperglycemia. Those in ileocolon interposition rose rapidly, but almost to the same degree as in normal subjects. The appearance of the gastric emptying curve using Tc-DTPA in case of ileocolon interposition shows that there is good reservoir function.
Colon↗
[Continuous arterial infusion of low-dose cisplatin, 5-fluorouracil as adjuvant therapy in cytoreductive surgery for advanced hepatocellular carcinoma].
We investigated the effectiveness of continuous arterial infusion of low-dose CDDP, 5-FU for residual cancer after cytoreductive surgery for advanced hepatocellular carcinoma. Thirty-one patients with unresectable advanced hepatocellular carcinoma were classified into two groups by adjuvant therapy after reduction surgery: 1) Low-dose FP Group: 17 patients; continuous arterial infusion of low-dose CDDP, 5-FU via implanted port system; 2) Conventional group: 8 patients; Lipiodolization (6 cases) and transcatheter arterial embolization (2 cases). The five-year survival rate in the low-dose FP group was 34.8%, the efficacy was 64.7%, CR: 6 (35.3%); PR: 5; NC: 4; PD: 2. Thus, continuous arterial infusion of low-dose CDDP, 5-FU was effective as adjuvant therapy in cytoreductive surgery for advanced hepatocellular carcinoma.
Antineoplastic Combined Chemotherapy Protocols↗
Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer.
We synthesized a potent new antitumor podophyllotoxin derivative (4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin; TOP-53) in our search for a drug that has strong activity against lung cancer and lung metastatic cancer. TOP-53 exhibited twice the inhibitory activity of etoposide (VP-16) against topoisomerase II and induced DNA strand breaks but showed no inhibitory activity against tubulin polymerization. The in vitro cytotoxic activity of TOP-53 assessed as IC50 was 0.016-0.37 microg/ml and 0.26-8.9 microg/ml against marine tumor and human non-small cell lung cancer (NSCLC) cell lines, respectively. TOP-53 exerted significant efficacy equivalent to that of VP-16 on s.c.-implanted murine solid tumors (Colon 26, B16-BL6, and Lewis lung carcinoma) at doses 3-5 times lower than that of VP-16. In human tumor xenografts using NSCLC, TOP-53 was active for four of five tumors, whereas VP-16 was active for two of five tumors. Potent inhibitory activity of TOP-53 was also found against a lung tumor (Lewis lung carcinoma) and four lung metastatic tumors (NL-22 and NL-17 colon cancer, UV2237M fibrosarcoma, and K1735M2 melanoma). TOP-53 appeared to be more active against four of them than VP-16. Thus, TOP-53 is not only active against s.c.-implanted lung cancers but also strongly active against lung localized tumor and metastatic tumors in the lungs. The high selectivity of TOP-53 was attributed to its high distribution into the lung and its persistence. TOP-53 is expected to be highly effective against lung cancer including NSCLC and various lung metastatic tumors in the clinical field.
Animals↗
A case of obstructive icterus caused by incarceration of a pancreatic stone in the common channel of the pancreatobiliary ducts.
A 51-year-old man had repeated admissions and discharges from the hospital for alcohol dependence and alcoholic hepatitis. Thereafter, with a diagnosis of chronic pancreatitis, he was examined on an outpatient basis. He presented with right hypochondriac pain as the chief complaint, and was admitted to the hospital because of a suspected acute exacerbation of chronic pancreatitis. Pyrexia and jaundice were present from about the 5th hospital day, and he was admitted to Kurume University Hospital with a diagnosis of obstructive icterus. Percutaneous transhepatic biliary tract drainage (PTBD) was immediately performed. A roentgenogram revealed moderate dilatation of the extrahepatic bile ducts and stricture of the intrapancreatic common bile duct. No calculi were observed in the gallbladder or bile ducts by ultrasonography of the abdominal region. The main pancreatic duct was dilated to 10 mm, and a strong echo, probably a calculus, was observed in the main pancreatic duct. Pancreatoduodenectomy was performed with a diagnosis of stricture of the common bile duct due to chronic pancreatitis with a pancreatic stone. Examination of the excised specimens revealed a rigid pancreatic head; and when the common bile duct was incised, no stricture was observed. A milk-white calculus about 10 mm in diameter was observed in the common channel of the lower portion of the common bile duct. The orifice of the pancreatic duct was also observed at the same site. The common channel was about 20 mm long, and malfusion of the pancreatobiliary ducts was observed. The obstructive icterus was due to an impaction of the pancreatic stone at the confluence of the pancreatobiliary ducts. The calculus was composed of calcium carbonate, and the histopathological findings in the pancreas showed chronic pancreatitis.
Gallstones↗
[Usefulness of continuous arterial infusion chemotherapy for post operative multiple recurrence and residual hepatocellular carcinoma].
Twenty five patients with postoperative multiple recurrence and residual hepatocellular carcinoma received continuous arterial infusion of CDDP and 5-FU via implanted reservoir. For the next five days, 10 mg/body of CDDP and 250 mg/body of 5-FU using arterial infusion were administered. It was discontinued for two days as one course, and 4 courses were basally administered. The efficacy rate was 60%, and there were 7 (28%) CR (complete response) cases. The survival rate was 76.0% for 1 year and 36.5% for 3 years, which is a favorable result considering their advanced stage. Thus, this treatment seemed to be effective for multiple hepatocellular carcinoma.
Antineoplastic Combined Chemotherapy Protocols↗
Comparative pharmacodynamic analysis of TAT-59 and tamoxifen in rats bearing DMBA-induced mammary carcinoma.
TAT-59 suppressed the growth of DMBA-induced mammary tumors in rats earlier and more strongly than tamoxifen (TAM). After oral administration of the drugs, DP-TAT-59, one of the main metabolites of TAT-59, was found in 10- to 15-fold higher concentrations in both the tumor and blood compared to 4-OH-TAM, an active metabolite of TAM. In a 3-day antiuterotrophic test, every detected metabolite of TAT-59 showed stronger antiestrogenic activity than did TAM. In a competition assay, the affinity of the metabolites for estrogen receptors ranged from that of estradiol to that of TAM. These results suggest that the superior antiestrogenic activity of TAT-59 compared to TAM was either due to its higher penetration into tumor tissue or to the stronger antiestrogenic activity of its metabolites.
9,10-Dimethyl-1,2-benzanthracene↗
Clinical study of IgA antibody against hepatitis C virus core antigen in patients with type C chronic liver disease.
Immunoglobulin A class antibody to hepatitis C virus core antigen (IgA anti-HCc) was measured in the serum of 128 patients with type C chronic liver disease. Fifty-eight patients (45.3%) were seropositive. IgA anti-HCc was detected in only one of 20 patients with chronic persistent hepatitis; however, 52.3% (46/88) of patients with chronic active hepatitis and 55% (11/20) of patients with liver cirrhosis were seropositive. Histological examination revealed that 22 (71.0%) of 31 patients with severe disease activity were seropositive compared to 35 (44.9%) of 78 patients with moderate (P < 0.05) and one (5.3%) of 19 patients with mild (P < 0.01) histological changes. IgA anti-HCc was measured sequentially in 65 patients who underwent interferon therapy. There was a significant difference between responders and other patients in the mean ratio of IgA anti-HCc titers one month after therapy. Three months after therapy, IgA anti-HCc was detectable in only two of 15 responders who were IgA anti-HCc seropositive at the start of therapy. In contrast, IgA anti-HCc reappeared three months after therapy despite a temporary decrease to undetectable levels in all nonresponders. We conclude that IgA anti-HCc is a useful marker to identify the presence of active type C liver disease and that the disappearance of IgA anti-HCc three months after interferon therapy predicts a good response in treated patients.
Adolescent↗
Follow-up of 2,733 Japanese patients with myocardial infarction.
Two thousand, seven hundred and thirty-three patients with acute myocardial infarction (AMI) who were admitted to our 11 institutions between 1983 and 1988, examined by coronary arteriography and discharged alive, were followed for an average of 2.9 years. During the follow-up period, 212 patients (7.6%) died. The factors that governed the prognosis of myocardial infarction after discharge were advanced age, female gender, obesity, previous infarction, angina pectoris more than 1 month before the onset of AMI, post-infarction angina, multiple-vessel diseases, advanced stage by Killip's and/or Forrester's classification on admission, elevated pulmonary capillary arterial pressure, decreased cardiac index, decreased left ventricular ejection fraction, increased left ventricular end-diastolic volume and left ventricular aneurysm before hospital discharge. Patients with ventricular tachycardia or ventricular fibrillation during hospitalization showed a poor prognosis. In contrast, patients who received intracoronary thrombolysis, or emergent and/or elective percutaneous transluminal coronary angioplasty showed a favorable prognosis.
Adult↗
Factors governing re-infarction in patients with myocardial infarction in Japan.
The subjects consisted of 2,733 patients with acute myocardial infarction (AMI) who were admitted to our 11 institutions between 1983 and 1988, examined by coronary arteriography, and discharged alive. The patients were followed for an average of 2.9 years after discharge. During the follow-up period, re-infarction occurred in 172 patients (6.3%). The factors associated with re-infarction were total cholesterol of more than 250 mg/dl, HDL-cholesterol of less than 35 mg/dl and diabetes mellitus. The rate of re-infarction was also high in patients who had had a previous infarction before admission, angina pectoris before or after the onset of AMI or multiple-vessel disease. In contrast, intracoronary thrombolysis reduced the rate of re-infarction.
Angina Pectoris↗
Pancreatojejunal sutural insufficiency occurring after pancreatoduodenectomy and countermeasures.
Pancreatojejunal sutural insufficiency occurring after pancreatoduodenectomy and countermeasures are discussed. In the Department of Surgery at Kurume University School of Medicine, 318 patients underwent pancreatoduodenectomies. The present study includes 15 of these patients, all of whom had pancreatojejunal sutural insufficiency. The frequency of sutural insufficiency was 4.7%. Five patients had bile duct cancer, 5 had cancer of the papilla of Vater, 2 had a carcinoma of the pancreatic head, 1 each had gallbladder cancer, chronic pancreatitis, and papillitis. Six (40%) of the 15 patients died during hospitalization. The presence or absence of sutural insufficiency was confirmed mainly by radiography and determining the properties and amylase levels of the drainage fluid. There was no significant difference due to the method of anastomosis. End-to-side anastomosis had a rate of 5 (5.9%) of 85 patients, while end-to-end had 10 (4.3%) of 233 patients. The sutural insufficiency was manifested as a major leakage in 6 patients and a minor leakage in 9. The degree of lymph node dissection was D0 in 6.1%, D1 in 1.4%, D2 in 4.8% and D3 in 10.8%, with a high incidence of sutural insufficiency in D3 patients. The pancreatic duct diameter was smaller than 4 mm in 10, 5-7 mm in 4 and over 8 mm in 1 patient. The intraoperative pancreatic findings were a soft pancreas in 8, slightly hard in 3, and hard in 4 patients. Fibrosis of the pancreas was normal to slight in 11 and moderate in 4 patients. Drainage by relaparotomy was performed in 4 of the 6 patients with major leakages to control sutural insufficiency, and the other 2 underwent continuous aspiration with an intraperitoneal drain inserted during the operation. The 9 patients with minor leakage underwent conservative treatment including continuous aspiration via an intraperitoneal drain inserted during surgery, fasting, intravenous hyperalimentation, and antibiotic administration. All of the patients with major leakage died from an associated occurrence of hepatic insufficiency, renal insufficiency, intraperitoneal hemorrhage or diffuse peritonitis during hospitalization. However, 8 of the 9 patients with minor leakage had some healing, and the 1 remaining patient developed a pancreatic fistula. The frequency of pancreatojejunal sutural insufficiency was high in patients with minimal pancreatic fibrosis, with soft pancreatic tissue without dilatation of the pancreatic duct, and with relatively good pancreatic function.
Anastomosis, Surgical↗
[The study of continuous arterial infusion chemotherapy with CDDP and 5-FU in patients with hepatocellular carcinoma].
Between Feb. 1992 and April in 1995, 22 patients with hepatocellular carcinoma (10, recurrence; 12, unresectable) received continuous arterial infusion of CDDP and 5-FU via implanted reservoir. For the next five days, 10 mg/body of CDDP and 250 mg/body of 5-FU using arterial infusion were administered. It was discontinued for two days as one course, and 4 courses were basally administered. Patients were divided into 2 groups (6 hours group and 24 hours group) according to the duration of the administration of 5-FU. There were no differences in efficacy rate between the 2 groups (6 hours group, 64%; 24 hours group, 62.5%), but CR (complete response) cases appeared in only the 6 hours group. There were no severe side effects in the 2 groups, but systemic side effects appeared in 6 hours group more often than in 24 hours group. Only in the 24 hours group, 2 patients had the narrowing and obstruction of hepatic artery which was suggested to be caused by intimal injury due to continuous administration of 5-FU. Continuous arterial infusion chemotherapy with CDDP and 5-FU seemed to be effective. Further study on adequate time and volume of administration including pharmacokinetics is needed to enhance the clinical effectiveness of continuous arterial infusion of CDDP and 5-FU.
Aged↗
[Analysis of p53 expression and DNA ploidy pattern in esophageal cancer].
DNA ploidy pattern analyzed by cytofluorometry and p53 protein expression using immunohistochemical method were studied in 35 cases of esophageal cancer. p53 protein were positive in 19 cases (54%), and DNA aneuploidy pattern were detected in 26 cases (74%). There was no relationship between DNA ploidy pattern or p53 expression and clinico-pathological factors. DNA aneuploidy or p53 positive cases were significantly poor prognoses in five-year survival rate. DNA aneuploidy and p53 positive cases were worst in four groups. It is effective for evaluation of biological malignancy and detection of post operative schedules to study not only clinico-pathological factors but also DNA ploidy pattern and p53 expression in esophageal cancer.
DNA, Neoplasm↗