N -arachidonoylethanolamine (anandamide) was the first endogenous cannabinoid receptor ligand to be discovered. Dual synthetic pathways for anandamide have been proposed. One is the formation from free arachidonic acid and ethanolamine, and the other is the formation from N -arachidonoyl phosphatidylethanolamine (PE) through the action of a phosphodiesterase. These pathways, however, do not appear to be able to generate a large amount of anandamide, at least under physiological conditions. The generation of anandamide from free arachidonic acid and ethanolamine is catalyzed by a degrading enzyme anandamide amidohydrolase/fatty acid amide hydrolase operating in reverse and requires large amounts of substrates. As for the second pathway, arachidonic acids esterified at the 1-position of glycerophospholipids, which are mostly esterified at the 2-position, are utilized for the formation of N -arachidonoyl PE, a stored precursor form of anandamide. In fact, the actual levels of anandamide in various tissues are generally low except in a few cases. 2-Arachidonoylglycerol (2-AG) was the second endogenous cannabinoid receptor ligand to be discovered. 2-AG is a degradation product of arachidonic acid-containing glycerophospholipids such as inositol phospholipids. Several investigators have demonstrated that 2-AG is produced in a variety of tissues and cells upon stimulation. 2-AG acts as a full agonist at the cannabinoid receptors (CB1 and CB2). Evidence is gradually accumulating and indicates that 2-AG is the most efficacious endogenous natural ligand for the cannabinoid receptors. In this review, we summarize the tissue levels, biosynthesis, degradation and possible physiological significance of two endogenous cannabimimetic molecules, anandamide and 2-AG.

Animals↗

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Design and anti-HIV-1 activity of hammerhead and hairpin ribozymes containing a stable loop.

Three ribozymes, a hairpin ribozyme (HR112) and two hammerhead ribozymes (RZ115 and RZ119) containing a 5'C(UUCG)G3' loop were designed to cleave the U5 region in the long terminal repeat (LTR) of HIV-1 RNA. The t1/2 values of chemically synthesized substrates mediated by three ribozymes were measured. The transformed CEM cells possessing these three ribozyme-encoding genes were challenged with a HIV-1IIIB strain, and two of these three ribozymes, HR112 and RZ119, were shown to possess strong anti-HIV-1 activity.

Anti-HIV Agents↗

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Evaluation of the maximal excretion rate of indocyanin green as a prognostic indicator in patients undergoing biliary decompression for obstructive jaundice.

To assess the postoperative outcome of jaundiced patients and to select the optimal timing for surgical intervention, indocyanin green (ICG) concentrations in the bile were measured after biliary decompression in patients with obstructive jaundice. The maximal excretion rate of ICG in the bile was calculated as a function of time (ICG Bmax). Among 59 patients with positive ICG Bmax values, morbidity was 15.2% and postoperative hospital mortality was 3.3%. However, the morbidity and mortality in nine patients with values between -0.5 and 0 were 88.8 and 44.4%, respectively. The 13 patients with in ICG Bmax below -0.5 had a 76.9% morbidity and a 61.5% mortality. The patients with ICG Bmax values below 0 showed a significantly higher morbidity and mortality than positive ICG Bmax patients. In patients showing ICG Bmax values below -0.5, surgery is contraindicated despite intensive postoperative care. The ICG Bmax value improved according to the increasing effect of biliary decompression. The index is useful not only as a prognostic index in the early phase of biliary decompression but also as an index of bile secretory capacity at a given time. By means of time course measurement of this index, the suitable time for operation can be determined. The ICG Bmax is a useful and reliable indicator in the assessment of hepatobiliary functional reserve in jaundiced patients after biliary decompression and prior to further surgical intervention.

Adult↗

PubMedDate not supplied

Two cases of Pneumocystis carinii pneumonia occurred in human immunodeficiency virus infected patients: supplemental treatment with aerosolised pentamidine isethionate.

Two cases of Pneumocystis carinii pneumonia occurred in human immunodeficiency virus infected patients who were diagnosed by the aspiration-lung-biopsy. They were treated with 4 mg/kg of pentamidine isethionate intravenously administered followed by pentamidine aerosol inhalation. Although clinical and laboratory findings were improved by the fifth or seventh day of intravenous therapy, substantial leukocytopenia, from 3,000/cmm to 600/cmm and from 2,700/cmm to 1,000/cmm, occurred. At this point, the method of pentamidine administration was switched to inhalation. Pentamidine 600 mg in 30 ml distilled water was aerosolised using ultrasonic nebuliser and exposed for a 30-minute period once daily. In both cases, chest x-rays showed improvements: The disappearance of P. carinii were obtained in two weeks. Mild coughing was the sole adverse reaction encountered during the course of aerosol inhalation.

Administration, Inhalation↗

PubMedDate not supplied

Three cases of acquired immunodeficiency syndrome complicated with toxic epidermal necrolysis.

Co-trimoxazole (trimethoprim-sulfamethoxazole) and pyrimethamine-sulfadoxine have been recommended for treatment and prophylaxis, respectively, of Pneumocystis carinii pneumonia (PCP). However, toxic epidermal necrolysis (TEN) occurred in three of four patients with acquired immunodeficiency syndrome (AIDS) during the course of treatment or prophylaxis of PCP with these agents. On the other hand, 14 patients with PCP treated with pentamidine never developed TEN. Because the incidence of adverse skin reactions is higher among patients with AIDS than those without AIDS, and TEN is a severe, potentially fatal skin reaction, sulfonamide-containing drugs should be given cautiously to patients with AIDS.

Acquired Immunodeficiency Syndrome↗

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Immunohistochemical detection of occult metastases in paraaortic lymph nodes in advanced gastric cancer.

Some Japanese surgeons have examined the utility of super-extended paraaortic lymphadenectomy (PAL) as part of the surgical treatment for advanced gastric cancer. However, therapeutic value of this PAL remains controvertial. The purpose of this study was to evaluate appropriate candidates who might benefit from PAL by the immunostaining with cytokeratin (CK) of the macroscopically intact paraaortic nodes. A total of 525 paraaortic nodes from 35 patients was serially sectioned and stained with hematoxylin-eosin (H&E) and CK staining. A total of 17 nodes (3.2%) from 7 patients (20.0%), among 525 macroscopically intact paraaortic nodes, was determined to be immunopositive for CK. In 4 patients, 8 H&E-positive nodes with metastases were all immunopositive and, in addition, 4 H&E-negative nodes were also immunopositive. Furthermore, 3 patients with H&E-negative nodes had five immunopositive nodes. Immunostaining with CK was useful for detection of occult metastases. Survival was prolonged in 3 of these 7 patients. The incidence of CK-positive nodes was significantly higher in patients with gross type of 3 or 4 gastric cancer and in patients with H&E-detected nodal metastasis within group 3 (N3) nodes. It seems that such patients would benefit from prophylactic PAL.

Aged↗

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Nuclear accumulation of p53 protein in gastric cancer strongly correlates with enlargement of nuclear area of cancer cells.

The nuclear area (NA) of cancer cells have been reported to be a useful prognostic indicator in various tumors. However, this image analysis of cancer nucleus has only rarely been applied to gastric adenocarcinoma. Moreover, it remains to be shown what types of biological factors influence this nuclear feature. In this study, we analyzed the area of cancer nuclei in tumors from 97 patients with advanced gastric cancer (t3, n0, stage II) by using hematoxylin and eosin stained slides with a computer-assisted image-analysis system. The morphometric data were compared with clinicopathological and biological status of the tumors. The mean NA of 50 tumors with venous invasion (50 microm2) was significantly larger than that of 47 tumors without venous invasion (38 microm2, p<0.0001). There was a significant correlation between the NAs of cancer cells and the p53 labeling indices of tumors (p=0.0012) and Ki-67 labeling indices of tumors (p=0.0324). However, no significant correlation was detected between the NAs of cancer cells and other factors, such as, tumor size, DNA ploidy pattern, expression of vascular endothelial growth factor (VEGF), or microvessel density of tumors. The five-year survival rate of 49 patients with large nuclear area (NA > or =41 microm2, 63%) was significantly lower than that of 48 patients with small nuclear area (NA <41 microm2, 78%, p=0.043). Data from computerized morphometry are objective and can be obtained rapidly by conventional microscopic analysis. The NA of cancer cells in advanced gastric cancer appears to predict the ability to invade the microvessels in the gastric wall. This nuclear morphological feature strongly correlated with p53 accumulation in the nuclei of gastric adenocarcinoma.

Cell Nucleus↗

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The expression of thymidine phosphorylase and its correlation with angiogenesis in gastric adenocarcinoma.

BACKGROUND: It has been recently reported that thymidine phosphorylase (dThdPase) is identical to platelet-derived endothelial cell growth factor (PD-ECGF). dThdPase is known to be one of the angiogenic factors. Expression of dThdPase has been detected both in cancer cells and in stroma cells. However, the role of dThdPase, in cancer cells and in stroma cells regarding, neovascularization in gastric adenocarcinoma is still unclear. In this study, we analyzed the correlation between dThdPase activity and neovascularization in gastric cancer. MATERIALS AND METHODS: We obtained fresh samples (tumors and adjacent normal mucosas) from 67 patients with gastric cancer who underwent gastrectomy between 1993 and 1994. The dThdPase activity was analyzed by the ELISA (enzyme-linked immunosorbent assay) method and by the immunohistochemical staining. Microvessel density (MVD) and vascular endothelial growth factor expression of tumors were analyzed by immunohistochemical staining. RESULTS: The dThdPase activity of tumors (117 +/- 98 U/mg protein) was significantly higher than that of normal mucosas (46 +/- 36 U/mg protein, P < 0.0001). The expression of dThdPase was detected by immunostaining in stroma cells but not in mucosal cells in normal tissues. Based on the immunostaining results, 16 tumors expressed dThdPase both in cancer cells and stroma cells. The mean dThdPase activity and the mean MVD of these 16 tumors were significantly higher than those of 15 tumors with expression of dThdPase only in the stroma cells, and than those of 36 tumors with expression of dThdPase in neither the cancer cells or the stroma cells. The MVD of tumors strongly correlated with the dThdPase activity of tumors detected by the ELISA method (P < 0.0001). CONCLUSIONS: The total amount of dThdPase produced by cancer cells and stroma cells may influence tumor angiogenesis in gastric cancer.

Adenocarcinoma↗

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Prognostic benefit of extended radical lymphadenectomy for patients with gastric cancer.

BACKGROUND: The therapeutic value of extensive gastric lymphadenectomy in gastric cancer is controversial. We retrospectively investigated the effect of extended lymphadenectomy on survival in 882 patients with gastric cancer. MATERIALS AND METHODS: From 882 patients who underwent gastrectomy, D0 or D1 lymphadenectomy was performed on 137 patients, D2 lymphadenectomy on 524 and D3 lymphadenectomy on 221. Curative gastrectomy was performed on 771 patients and the 5-year survival rate of patients had undergone D0 or D1 lymphadenectomy (D1 group) and that of patients who had undergone D2 lymphadenectomy (D2 group) was compared with that of patients had undergone D3 lymphadenectomy (D3 group). RESULTS: In each stage, the 5-year survival rates of patients who had undergone curative operations (n = 771) were compared among the D1, D2 and D3 groups. The 5-year survival rates were as follows: Stage I: n = 510, 89.3% (D1 group: n = 91, 85.8%; D2 group: n = 384, 90.3%; D3 group: n = 35, 88.1%; p = 0.539), Stage II: n = 83, 77.8% (D2 group: n = 35, 82.7%; D3 group: n = 48, 74.3%; p = 0.601), Stage III: n = 133, 50.2% (D2 group: n = 46, 39%; D3 group: n = 87, 56.1%; p = 0.027), Stage IV: n = 45, 8.9% (D2 group: n = 10, 0%; D3 group: n = 35, 11.4%; p = 0.588). Postoperative complications were detected in 10.4% of the cases and the in-hospital mortality rate was 2.4%. The postoperative morbidity rate of the D3 group (15.8%) was significantly higher than that of the other groups (D1 group: 7.3% and D2 group: 9%; p = 0.008). However, the in-hospital mortality rate of the D3 group (1.4%) was not different from that of the other groups (D1 group: 3.7% and D2 group: 2.5%; p = 0.374). CONCLUSION: These results indicate that D3 lymphadenectomy might be performed as safely as D1 or D2 lymphadenectomy on patients with gastric cancer. In addition, D3 lymphadenectomy might provide a survival benefit for patients with Stage III or Stage IV gastric cancer.

Adult↗

PubMedDate not supplied

Bioadhesive peptides as potential anticancer drug carriers: activation via isopeptide deblocking by proteases.

BACKGROUND: Bioadhesive peptides are potentially useful as anticancer drug carriers, if the bioadhesivity becomes active only at the tumor site. We propose that this function can be achieved by the prodrug strategy using proteases in tumors. MATERIALS AND METHODS: A laminin fragment peptide, Ac-AASIKVAVSADR-NH2 (5), and its derivatives, Ac-AASIK(L) VAVSADR-NH2 (6), Ac-AASIDpm(NH2)VAVSADR-NH2 (7) and Ac-AASIDpm(L)(NH2)VAVSADR-NH2 (8), were synthesized and tested for their bioadhesive activity with 6 cancer cell lines. RESULTS: The strength of the binding was in the order of 5 >> 7 > or = 8 > or = 6. The attachment of mouse whole blood cells to peptide 6-coated surface was also weaker than to 5-coated surface. The Leu isopeptide linkage in 6 was enzymatically cleaved by the cells. CONCLUSION: The present results suggest that isopeptide 6, working as a prodrug form for the bioadhesive peptide 5, could serve as an anticancer drug carrier for tumor targeting.

Adhesiveness↗

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Pharmacokinetics of hypotonic cisplatin chemotherapy administered into the peritoneal and the pleural cavities in experimental model.

The pharmacokinetics of intraperitoneal (i.p.) and intrapleural (i.pl.) hypotonic cisplatin (CDDP) were compared under the same experimental conditions. The same dose of CDDP was administered in hypotonic (62 mOsm/L) and isotonic (308 mOsm/L) solutions to the peritoneal and pleural cavities of Ehrlich carcinoma cell bearing mice. The intracellular amount of platinum increased for more than 60 minutes after an i.pl. injection of the hypotonic solution of CDDP, whereas it increased for up to 30 minutes after an i.p. injection. Although hypotonic conditions augmented the amount of platinum taken-up by Ehrlich cells, the amount was significantly greater in the pleural cavity than in the peritoneal cavity. In Donryu rats, the levels of platinum in the i.p. and i.pl. fluids decreased rapidly after injection of hypotonic solution as compared with isotonic solution. The extent of this decrease was greater in the peritoneal cavity than in the pleural cavity. In the hypotonic condition, the area under the curve of concentration versus time (AUC) for platinum of i.pl. fluid was greater than that of i.p. fluid. When i.p. and i.pl. hypotonic CDDP were administered, the osmolarity of the fluid returned rapidly to the isotonic level, with equilibration in 30 or 180 minutes respectively. The lower osmolarity continued for a longer duration in the pleural cavity than in the peritoneal cavity. These results indicate that the pleural cavity may require a smaller amount of CDDP to achieve the same effect on intracellular uptake of platinum than the peritoneal cavity.

Animals↗