Inhibition of acyl-CoA: cholesterol acyltransferase by helminthosporol and its related compounds.
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Animals↗
Biomedical subjects
K Hasumi
Publications and source records attributed to K Hasumi.
Lateritin, a new inhibitor of acyl-CoA:cholesterol acyltransferase produced by Gibberella lateritium IFO 7188.
A new inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), designated lateritin, was isolated from the mycelial cake of Gibberella lateritium IFO 7188 by successive purification procedure of solvent extraction, silica gel column chromatography and reverse phase HPLC. Spectroscopic analyses of the compound yielded 4-methyl-6-(1-methylethyl)-3-phenylmethyl-1,4-perhydrooxazine-2,5- dione as the proposed structure. Lateritin inhibited rat liver ACAT activity by 50% at a concentration of 5.7 microM. This inhibition was time-dependent and irreversible.
Animals↗
Competitive inhibition of squalene synthetase by squalestatin 1.
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Binding, Competitive↗
[Point mutation of ras oncogene in endometrial carcinoma].
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Codon↗
[Treatment of advanced ovarian cancer--is residual tumor diameter less than 2cm optimal?].
The present study investigates whether residuum < 2cm is suitable for "optimal" by analyzing the impact of the size of the residuum on survival. Among 151 patients with stage III or IV ovarian cancer, 77 deemed "resectable" received debulking at initial laparotomy and received postoperative chemotherapy (PO group). The remaining 74 deemed "unresectable" had an exploratory laparotomy followed by neoadjuvant (NA) chemotherapy and subsequently received debulking (NA group). In the PO group, there was a significant difference in survival between patients with primary residuum < 2cm and > or = 2cm, and between < 0.5cm and > or = 0.5cm, respectively. Moreover, significant difference in survival was observed among each group with no residuum, macroscopic residuum but < 0.5cm, and 0.5cm < or = residuum < 2cm. The same trend was observed in the NA group. Altogether, a significant difference in survival was observed between patients with residuum < 0.5cm and those with 0.5cm < or = residuum < 2.0cm. In the PO interestingly, debulking the tumor to residuum < 2 cm did not influence the survival if postoperative chemotherapy was not effective. Thus, primary debulking of tumor to residuum < 2cm was significant when postoperative chemotherapy was effective. However, when we evaluated the residuum as an independent prognostic factor, residuum < 2 cm was insufficient but in view of the results of this study, < 0.5cm was judged to be suitable.
Adenocarcinoma, Clear Cell↗
[Studies on the point mutation of ras oncogene in ovarian tumor].
Thirty-five patients with ovarian tumors operated on between December, 1989 and June, 1991 were studied to detect K-ras codon 12 point mutation (PM). (1) Five of 35 ovarian tumors (14.3%) disclosed K-ras PM at codon 12 and all the PM cases were in transition from GGT to GAT. On the other hand only one case (5.3%) with K-ras oncogene amplification was found and no C-myc or erbB-2 amplification was detected. (2) The incidence of PM according to clinical stages was seen in 3 of 11 stage I cases (27.3%), in 1 of 3 stage II cases (33.3%), in 1 of 14 stage III cases (7.1%) and in neither of 2 stage IV cases. PM was therefore seen in relatively early stages. (3) The occurrence of PM according to the histologic type was found in 3 of 16 serous tumors (18.8%), in 2 of 5 mucinous tumors (40.0%) and in none of 7 clear cell carcinomas or 2 endometrioid carcinomas. (4) Concerning the relation of PM to the involvement of serosal surface of ovarian tumors and to the ascitic cytology, no particular correlation was observed in our study. (5) Regarding the cytologic findings in imprint smears of the tumors in reference to PM, such as nuclear size, shape, N/C ratio, chromatin pattern, nucleolar size and number, the cases with PM tended to have more multiple nucleoli than PM negative cases. No other findings seemed to indicate the clinical progress of cancer. In conclusion, our study indicated that PM in ovarian cancers was a relatively early event in carcinogenesis.
Adult↗
[Treatment of ovarian cancer at FIGO stage III and IV--prognostic factors for patients receiving neoadjuvant chemotherapy].
Among 165 patients with stage III and IV ovarian cancer, 74 received neoadjuvant (NA) chemotherapy. The response to NA chemotherapy was 85% (17/20) for CP, 79% (26/33) for CAP, and 33% (7/21) for FAMT. Following NA chemotherapy, 43 patients received debulking surgery, of whom 34 received optimal debulking (OD: residuum < 2cm). The remaining 31 patients did not receive debulking, of whom 18 responded to NA chemotherapy. The rate of OD was significantly higher in patients with CAP/CP than in those with FAMT. There was a tendency for the OD rate to be higher in patients with the serous or endometrioid type than in those with the clear cell or mucinous type. The procedures employed in 34 patients receiving OD following NA chemotherapy included basic surgery for 24 patients and more extensive surgery for 10 patients. Significant prognostic factors for patients receiving NA chemotherapy were, 1) response to NA chemotherapy, 2) radicality of debulking following NA chemotherapy, 3) regimen of NA chemotherapy (CAP/CP), and 4) histologic type (serous, endometrioid).
Chemotherapy, Adjuvant↗
[Treatment of stage III and IV ovarian cancer--is neoadjuvant chemotherapy effective?].
One hundred and thirty-eight patients with stage III and 27 with stage IV ovarian malignant tumors were registered during 1969-1991. Seventy-seven patients deemed resectable received primary debulking followed by postoperative (PO) chemotherapy. Eighty-two patients considered to be unsuitable for curative surgery underwent an exploratory laparotomy, of whom 74 received neoadjuvant (NA) chemotherapy and the remaining 8 did not receive planned NA chemotherapy because of their poor performance status (PS). Therefore, the patients in the NA group had a more aggressive disease and had a poorer PS than those in the PO group. Thirty-five patients in the PO group received optimal debulking (OD: residuum < 2cm) at initial laparotomy, indicating that the OD rate for the initial surgical attempt for stage III and IV disease is 21% (35/165). The response to chemotherapy by the PO and NA groups was 42% and 68%, respectively. Among 74 patients receiving NA chemotherapy, 34(46%) had OD. Survival (5 year, median) for each subgroup was 42%, 38 mo for OD-->PO (35 cases), 6%, 18 mo for subOD-->PO (42 cases), 66%, 82 mo for NA-->OD (34 cases), and 7%, 18 mo for NA-->subOD (40 cases). In all, 19% 21 mo for the PO group and 34%, 31 mo for the NA group. Survival for NA-->OD was significantly higher than that for OD-->PO and almost equal to that for stage II (54%, 72 mo). The present study with a selection bias set at the initial laparotomy clearly indicates that NA chemotherapy followed by OD is a recommendable treatment for improving the prognosis of advanced ovarian cancer.
Antineoplastic Combined Chemotherapy Protocols↗
[Increase in CDDP therapeutic index by lower concentration and longer infusion time--home chemotherapy for ovarian cancer].
Twenty-two patients with ovarian cancer stage III and IV received combination chemotherapy with CDDP, adriamycin (ADM) and cyclophosphamide (CPM), and were studied for response and side-effects. Patients were divided into two groups according to the following CDDP infusion schedules. (CAP 1) CDDP 7mg/sqm/8 hrs/saline 500 ml/d1-d10, ADM 35 mg/sqm/d1, CPM 350 mg/sqm/d1: 8 cases; (CAP 2) CDDP 70 mg/sqm/2 hrs/d1, ADM 35 mg/sqm/d1, CPM 350 mg/sqm/d1: 14 cases. The overall response rate (CR + PR) was 62.5% in CAP 1, and 50% in CAP 2 (on statistical difference: NS). The 3-year survival rate was 54.7% in CAP 1 and 38.5% in CAP 2 (NS). Side effects of nausea, vomiting and nephrotoxicities were remarkably reduced in CAP 1. These data suggest that lower concentration and longer infusion time of CDDP administration increases the therapeutic index. This infusion schedule is suitable for chemotherapy at home or on an outpatient clinic basis, especially in patients with ovarian cancer.
Adult↗
[Chemotherapy of ovarian cancer with a combination of low-dose consecutive CDDP and cyclophosphamide].
Sixty-six patients with ovarian cancer were treated with low-dose consecutive CP (LDC-CP) consisting of cyclophosphamide (CPM: 500 mg/m2, day 1) and CDDP (10 mg/m2, days 1-7). Two-9 (median: 4) courses of LDC-CP were given following reduction surgery (42 cases) or preceding primary debulking (24 cases). Among 66 cases, 12 with stage Ic were not evaluable (NE). The response rate (CR + PR/evaluable) for stages II-IV was 57.4% (12 + 19/54). Histologically, serous and endometrioid type showed a significantly (p < 0.001) higher response rate (77.5% among 40 evaluable) compared to the other histologic type (0% among 14). Toxicities including nausea/vomiting and renal impairment were markedly mild or almost absent despite the lack of any particular care. Grade 3 leucopenia and thrombocytopenia were observed only in 4.2%, and 2.5% of total 284 courses, respectively. Mean survival time by stage was 1,309 days for stage I, 809 days for stage II, 1,180 days for stage III, and 691 days for stage IV, with a significant difference among stages (p = 0.0452). In stages III and IV disease, significant prognostic factors included 1) response to chemotherapy, 2) no. of LDC-CP courses, 3) histologic subtype, 4) performance status, and 5) tumor size. Thus, LDC-CP is considered to be a useful chemotherapeutic regimen for serous and endometrioid type ovarian cancer.
Adult↗
Inhibition of the acidification of endosomes and lysosomes by the antibiotic concanamycin B in macrophage J774.
The antibiotic concanamycin B was found to inhibit oxidized-low-density-lipoprotein(LDL)-induced accumulation of lipid droplets in the macrophage J774 at a concentration of 5-10 nM. Concanamycin B inhibited cholesteryl-ester synthesis from [14C]oleate by 50% at 14 nM without affecting the synthesis of triacylglycerol and polar lipids. Degradation of internalized oxidized 125I-LDL was inhibited by about 80% in cells treated with 25 nM concanamycin B, while cell-surface binding of oxidized 125I-LDL at 4 degrees C, uptake of surface-bound oxidized 125I-LDL and microsomal acyl-CoA:cholesterol acyltransferase activity were not significantly affected by the antibiotic at 25 nM. When J774 cells were treated with 25 nM concanamycin B at 37 degrees C for 60 min, there was a reduction of about 50% in the activity of cell-surface receptors. This reduction appeared to be due to partial trapping of the receptors within the cells. Concanamycin B significantly inhibited ATP-dependent acidification of endosomes and lysosomes of the J774 cells at a concentration of 4 nM. Since acidic condition of these organelles is required for receptor recycling and hydrolysis of lipoproteins, the results demonstrate that concanamycin-B inhibition of oxidized-LDL-induced accumulation of lipid droplets and cholesteryl esters in macrophages J774 is associated with reduced ATP-dependent acidification of these organelles.
Adenosine Triphosphate↗
Inhibition of the accumulation of lipid droplets in macrophage J774 by bafilomycin B1 and destruxin E.
Two microbial metabolites, bafilomycin B1 and destruxin E, have been found to inhibit significantly the oxidized low density lipoprotein (LDL)-induced accumulation of lipid droplets at 3 nM and 0.5 microM, respectively, in macrophage J774. The incorporation of [14C]oleate into cholesteryl esters in the cells incubated with oxidized LDL was inhibited to the same extent by the two compounds. Both compounds had no effect on the cell surface binding at 4 degrees C and the internalization of oxidized 125I-LDL as well as on the activity of acyl-CoA:cholesterol acyltransferase. However, when incubated with these compounds at 37 degrees C, receptors for oxidized LDL were partially trapped within the cell. In accordance with receptor accumulation, ATP-dependent acidification of endosomes and lysosomes was significantly inhibited by 50 nM bafilomycin B1 and 1 microM destruxin E, respectively. From these results it was concluded that the inhibition of ATP-dependent acidification of endosomes and lysosomes by bafilomycin B1 and destruxin E resulted in the reduction of oxidized LDL-induced synthesis of cholesteryl ester and thereby caused a reduced accumulation of lipid droplets in macrophage J774.
Animals↗
Inhibition of the uptake of oxidized low-density lipoprotein in macrophage J774 by the antibiotic ikarugamycin.
The antiprotozoal antibiotic ikarugamycin was found to significantly inhibit oxidized low-density lipoprotein(LDL)-induced accumulation of cholesteryl ester in macrophage J774 at a concentration over 1-4 microM. Cholesteryl ester synthesis from [14C]oleate in the macrophages was similarly inhibited by the antibiotic, while the synthesis of triacylglycerol and polar lipids was not affected. The internalization of oxidized [125I]LDL in macrophages was reduced to 50% by 2 microM ikarugamycin, while cell-surface binding of oxidized [125I]LDL, lysosomal hydrolysis of the internalized oxidized [125I]LDL and microsomal acyl-coenzyme A:cholesterol acyltransferase was not detectably inhibited by 5 microM ikarugamycin. The results demonstrated that ikarugamycin inhibited cholesteryl ester accumulation in macrophage J774 by specifically inhibiting the uptake of oxidized LDL.
Adenosine Triphosphate↗
Augmenting effect of sizofiran on the immunofunction of regional lymph nodes in cervical cancer.
The immunomodulating effect of sizofiran on regional lymph nodes (RLN) was studied in cervical cancer and benign gynecologic tumors comparatively between treated patients (sizofiran intramuscularly (1) 1 day (20 mg) before and (2) 8 days (20 mg) and 1 day (20 mg) before surgery; n = 34) and untreated patients (n = 21). The RLN (internal iliac lymph nodes) were dissected surgically, and freshly obtained mononuclear (MN) cells were studied to observe interleukin-2 (IL-2) production and lymphokine-activated killer cell and natural-killer cell activities. The infiltration of surface phenotype of MN cells into RLN was determined semiquantitatively by immunohistochemistry. Sizofiran augmented IL-2 production of RLN, which was accompanied by a marked increase in the number of cells stained with anti-Leu-3a and IL-2 receptor. This effect was found more often in Stage Ib disease than in Stage 0, and it was not observed in benign tumors. These results suggest that stimulation with some antigens (e.g., cancer antigen in the current study) is necessary to induce immunoaugmentation by sizofiran which has no antigenicity. The augmenting effect was seen even in lymph nodes involved by advanced cervical cancer. Therefore, sizofiran was found to be a potent biologic response modifier in patients with cervical cancer.
Adjuvants, Immunologic↗
Maintenance of the activation of peritoneal macrophages in patients with ovarian cancer by sizofiran and recombinant interferon-gamma.
Four patients with ovarian cancer received 20 mg of sizofiran, a beta-1,3-glucan (molecular weight: 450,000), intramuscularly one day before and 4, 7, 11, 14, 18 and 21 days after second look laparotomy and recombinant interferon-gamma (rIFN-gamma) intraperitoneally on the day of second look laparotomy and 4, 7, 11, 14, 18 and 21 days thereafter. The peritoneal cavity was washed with physiological saline and peritoneal macrophages (M phi) were isolated. The number of M phi increased 30-1600 times during the treatment period. The concentrations of interleukin-1, interferon-gamma, tumor necrosis factor and prostaglandin E2 were also found increased in the supernatant fluid of M phi cultured for 24 hours with 10 micrograms/ml of lipopolysaccharide. The present study demonstrated that the activation of peritoneal M phi could be maintained and its number was increased by repeated dosing of sizofiran and rIFN-gamma in combination every three or four days in patients with ovarian cancer. Peritoneal M phi thus activated may exert an antitumor effect on ovarian cancer.
Adult↗
Interferon-alpha, interferon-gamma and sizofiran in the adjuvant therapy in ovarian cancer--a preliminary trial.
The study included 24 cases of negative second-look laparotomy (SLL) after operation on ovarian cancer. 12 cases were treated with sizofiran and recombinant interferon-gamma before and after SLL and then with human lymphoblastoid interferon-alpha. The remaining 12 cases (controls) were followed up without any drug therapy after SLL. There were no recurrences in the treated group, but in 3 cases of the control group. Also significant difference in survival was noted in the treated group.
Adult↗
Characterization of a murine monoclonal antibody, 5D-4, reacting with pancreatic cancers and islets of Langerhans.
A murine monoclonal antibody (5D-4) was prepared by immunizing mice ip with human pancreatic cancer cell line (AsPC-1). The 5D-4 MAb reacted immunohistochemically with pancreatic and gastrointestinal tract tumors as well as pancreatic islets, and to a less extent with normal tissues. The 5D-4 MAb reacted not only with ca 50 KDa and 30 KDa solubilized protein from AsPC-1 cells by Western blot analysis but also with human insulin in a competition RIA. Double immunoperoxidase staining showed that the 5D-4 MAb cross-reacted with insulin but did not react with glucagon, somatostatin or pancreatic polypeptide. Immunoelectron micrograph of Langerhans island double-stained with the 5D-4 MAb and anti-insulin Ab revealed that the 5D-4 Mab recognized human insulin and ca 50 KDa and 30 KDa antigens in B-cells of islets of Langerhans. Thus, the 5D-4 Mab may be useful for the diagnosis of islet cell tumors as well as pancreatic cancers.
Animals↗
GC/MS analysis of urine in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
A patient with 3-hydroxy-3-methylglutaric aciduria was diagnosed using gas chromatography mass spectrometry. The patient had severe metabolic acidosis, hypoglycemia and hyperammonemia and excreted abnormal amounts of 3-methylglutaconic, 3-hydroxy-3-methylglutaric, 3-methylglutaric, 3-hydroxyisovaleric and glutaric acids in the urine. 3-Hydroxy-3-methylglutaric acid appeared as two peaks on the chromatogram after trimethylsilylation. One was a tri-trimethylsilyl and the other a di-trimethylsilyl derivative. 3-Methylglutaconic acid appeared as three peaks: cis-, trans- and cyclic cis-isomers. The structure of these derivatives was elucidated by deuterium-labeled trimethylsilyl derivatization. The di-trimethylsilyl derivative of 3-hydroxy-3-methylglutaric acid and the cyclic cis-isomer of 3-methylglutaconic acid do not appear to have been previously described. After treatment with leucine restriction milk, the excretion of leucine catabolites decreased but 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids continued to be excreted at abnormally high levels. It is concluded that these two metabolites are necessary for the chemical diagnosis of HMG-CoA lyase deficiency. This patient is the first case of HMG-CoA lyase deficiency to be reported in Japan.
Acidosis↗