Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One thousand twenty patients consecutively admitted because of a clinical suspicion of pancreatic cancer were investigated to evaluate the accuracy of simple clinical, laboratory, and ultrasonographic data in the diagnosis of pancreatic cancer. Age, weight loss, recent-onset diabetes mellitus, palpable abdominal mass or gallbladder, elevated serum bilirubin or alkaline phosphatase levels, and ultrasonography were significant criteria in discriminating 80 pancreatic cancers from 940 controls. The most sensitive criteria were ultrasonography (83%), weight loss (66%), and bilirubin level of > 3 mg/dl (61%); the most specific were ultrasonography (99%), recent-onset diabetes (97%), and a distended palpable gallbladder (94%). Only ultrasonography demonstrated an elevated positive predictive value (86%), while weight loss, elevated bilirubin and alkaline phosphatase, besides ultrasonography had an elevated negative predictive value (95%). These results show that advanced pancreatic cancer may be excluded with simple clinical and laboratory data; ultrasonography can confirm the diagnosis with a high degree of accuracy. We suggest that the results of any new diagnostic tests for pancreatic cancer be compared with these clinical findings.
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PMID:Clinical presentation and ultrasonography in the diagnosis of pancreatic cancer. 846 88

In the present study, epithelial cells in the bone marrow of 42 patients with pancreatic carcinoma were identified immunocytochemically with monoclonal antibodies (MAbs) CK2, KL1 and A45-B/B3 directed to epithelial cytokeratins (CK), using the alkaline phosphatase anti-alkaline phosphatase method. The specificity of the MAbs was demonstrated by negative staining of marrow from 25 non-carcinoma age-matched control patients. Analysis of bone marrow aspirates from cancer patients revealed CK-positive cells in 14 (58.3%) of 24 cancer patients treated with curative intent and 10 (55.6%) of 18 patients with extended disease. After a median follow-up of 15.6 months (range 3-31 months), 5 (35.7%) out of 14 patients who underwent complete surgical resection but had tumour cells in bone marrow presented with distant metastasis and 6 (42.9%) with local relapse as compared to none of 10 corresponding patients without such cells (P < 0.05). The described technique may help to identify patients with pancreatic cancer and potential high risk of early metastatic relapse. The results promise to be of important assistance in determining prognosis and consequences in therapy of early stage pancreatic cancer.
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PMID:Epithelial tumour cells in bone marrow of patients with pancreatic carcinoma detected by immunocytochemical staining. 866 55

We investigated the effect of 5-aza-2'-deoxycytidine (ADC) (a specific inhibitor of DNA methylation) on differentiation, Lewisy (Ley) antigen expression, and DNA fragmentation (a biochemical marker of apoptosis) in human pancreatic cancer MIA PaCa-2 cells. ADC markedly inhibited the growth of MIA PaCa-2 cells. Flow cytometric analysis showed that ADC suppressed the cell population in the G1 phase, but enhanced it in the G2/M phase. On the other hand, several markers of cell differentiation including morphological and biochemical alterations were distinctly induced in cells treated with ADC. Morphologically, the cells were enlarged and thinner than the untreated control cells, and intracellular alkaline phosphatase (ALP) activity was markedly increased. Additionally, biochemical markers of apoptosis including DNA fragmentation and Ley antigen expression were induced in association with the appearance of morphological and biochemical markers of differentiation (ALP). These results suggest that the hypomethylation of DNA is involved in the molecular mechanism of growth inhibition, induction of apoptosis, and differentiation in human pancreatic cancer MIA PaCa-2 cells.
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PMID:Induction of Ley antigen by 5-aza-2'-deoxycytidine in association with differentiation and apoptosis in human pancreatic cancer cells. 868 22

Minimal residual disease in patients with operable pancreatic carcinoma is frequently missed by current noninvasive tumour staging. We applied an immunocytochemical cytokeratin assay that allows identification of individual pancreatic carcinoma cells disseminated to bone marrow. Prior to therapy, bone marrow was aspirated from the upper iliac crest of 48 patients with ductal adenocarcinoma of the pancreas at various disease stages and an age-matched control group of 33 noncarcinoma patients. Tumor cells in cytologic bone marrow preparations were detected with monoclonal antibodies (mAbs) CK2, KL1, and A45-B/B3 to epithelial cytokeratins (CK) using the alkaline phosphatase antialkaline phosphatase method. CK-positive cells were found in 14 (48.4%) of 31 cancer patients treated with curative intent and in 10 (58.8%) of 18 patients with extended disease. The overall frequency of these cells was 1 to 83 per 5x10(5) mononuclear cells with no significant differences between patients at different tumor stages and lymph node involvement. After a median follow-up of 22.8 months (range 3-48 months), 6 (40.0%) of 15 patients who underwent complete surgical resection but had tumor cells in bone marrow presented with distant metastasis and 7 (46.7%) had local relapse compared to none of 12 corresponding patients without such cells (p<0.05). Univariate survival analyses revealed that the presence of CK-positive cells was predictive of reduced overall survival. In conclusion, anticytokeratin mAbs are reliable probes for the immunocytochemical detection of single pancreatic cancer cells disseminated to bone marrow. Thus the described technique may help identify patients with pancreatic cancer and at potentially high risk of early metastatic relapse. The results promise to be of important assistance for determining prognosis and the consequences in therapy of early stage pancreatic cancer.
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PMID:Micrometastases in bone marrow: prognostic indicators for pancreatic cancer. 1044 15

The reductive conversion of ribonucleotides to deoxyribonucleotides by ribonucleotide reductase (RR) is a crucial and rate-controlling step in the pathway leading to the biosynthesis of DNA, since deoxyribonucleotides are present in extremely low levels in mammalian cells. Mammalian ribonucleotide reductase (RR) is composed of two dissimilar proteins, often referred to as R(1), which contains polythiols and R(2), which contains non-heme iron and a free tyrosyl radical. Both the R(1) and R(2) subunits contribute to the active site of the enzyme. Currently, there are two broad classes of RR inhibitors. The first class includes nucleoside analogs which bind to the R1 subunit of the enzyme, several of which are in development. Among those, Gemcitabine and MDL 101,731 have demonstrated impressive efficacy against various solid tumors. Gemcitabine has now been approved for the treatment of pancreatic cancer and non-small cell lung cancer. The most promising second class of inhibitors of RR includes HCTs [alpha--(N)-heterocyclic carboxaldehyde thiosemicarbazones, e.g., 3-AP and 3-AMP], which exert enzyme inhibitory effect through high affinity binding with non-heme iron. Based on the clinical success achieved by Gemcitabine, it seems reasonable that a strong inhibitor of RR, which is essential for cellular replication, would be a useful addition to the existing therapeutic agents against cancer. In this chapter, we wish to report several highly efficient syntheses for both 3-AP and 3-AMP based upon palladium mediated Stille/Suzuki/Heck coupling reactions. Based upon the in vivo efficacy profile observed with these two agents, 3-AP was chosen over 3-AMP as the candidate for further optimization with the intention to improve its biological and pharmaceutical properties. In this vein, we have completed the synthesis of two water soluble phosphate containing prodrugs and one disulfide-linked prodrug of 3-AP. As expected, bioconversion study using either alkaline phosphatase or glutathione showed that these prodrugs were indeed converted to the parent 3-AP. When evaluated against the murine M-109 lung carcinoma as well as the B16-F10 murine melanoma xenograft models, the newly prepared phosphate prodrugs displayed improved efficacy and safety profiles than that found with the parent. More significantly, the ortho-phosphate prodrug 21 demonstrated impressive antitumor effect using once-a-day dosing regimen. In summary, the results disclosed herein demonstrated that some of 3-AP prodrugs prepared indeed demonstrated improved pharmaceutical, biological and toxicity profiles over the parent 3-AP. Efforts directed towards further optimization of 3-AP prodrugs as novel anticancer agents is clearly warranted.
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PMID:Syntheses and antitumor activities of potent inhibitors of ribonucleotide reductase: 3-amino-4-methylpyridine-2-carboxaldehyde-thiosemicarba-zone (3-AMP), 3-amino-pyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) and its water-soluble prodrugs. 1117 70

With the advances of videolaparoscopic surgery, this approach had become the treatment of choice for cholelithiasis. However, about 5% to 10% may present common bile duct lithiasis. Most surgeons have still difficulties to deal with this situation and do prefer resolve with open surgery or with further endoscopic approach. We present a case of a 60-year-old man, with 18 months history of right upper quadrant pain, weight loss and jaundice. He was referred with diagnostic of pancreatic cancer. Laboratory investigation showed increased bilirubin (10 mg/dL), alkaline phosphatase and GGT. Abdominal ultrasound showed atrophic gallbladder with dilated intra and extrahepatic biliary tree. Computerized tomography scan disclosed enlarged biliary tree with 3 cm stone in the distal common bile duct. The patient underwent a laparoscopic cholecystectomy followed by choledochotomy and retrieval of the large stone. A latero-lateral choledochoduodenum anastomosis was then performed to decompress the biliary tree. The patient had an uneventful recovery being discharged at the 6th postoperative day. Laparoscopic management of choledocholithiasis is feasible in many patients, specially those with dilated biliary tree. The retrieval of stones may be followed by biliary drainage with T-tube. In some elderly patients with chronically dilated common bile duct, as in the present case, a choledochoduodenal anastomosis is the procedure of choice.
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PMID:[Laparoscopic treatment of common bile duct lithiasis]. 1123 72

Recent studies have emphasized the importance of patient selection for the surgical resection of pancreatic adenocarcinoma based on reproducible prognostic factors. The aim of the study was to investigate the prognostic factors affecting long-term survival in patients with resectable and nonresectable pancreatic cancer and to evaluate their prognostic value. Forty six patients (25 women, 21 men, aged 44-80) with ductal adenocarcinoma of the pancreas were reviewed. Primary tumor size and regional enlargement of lymph nodes was assessed with enhanced CT scan. 13 patients were treated conservatively, 9 with standard Whipple procedure (pancreatoduodenectomy) and 24 - with palliative surgery. Survival probabilities were computed using univariate Kaplan-Meier analysis. Log-rank test was used to compare survival between groups. Overall median survival was 6 months with a 4 years survival of 2.2%. There was no difference in survival time (ST) between patients aged 65 years or younger and older (p=0.71). MeanST in patients after Whipple procedure was 10.3, after palliative surgery - 9.4 and after conservative treatment - 4.4 months (p<0.05). Thirty-day surgical mortality was 9.4%. ST was significantly longer in patients with tumors 3 cm or less of diameter compared with larger ones (p<0.05). Presenting signs and symptoms, like jaundice, diabetes, alkaline phosphatase, aspartate and alanine aminotransferase elevation and history of cholecystectomy did not have any significant impact on survival. The only significant independent factors improving survival were: operative treatment and tumor size smaller than 3 cm.
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PMID:Prognostic factors in the operative and palliative treatment of pancreatic cancer. 1462 94

Pancreatic cancer is one of the tumors with the highest mortality, poorly responding to available chemotherapeutic agents. The objective of this study was to study the anticancer effects of all-trans retinoid acid, a functional form of vitamin A, on pancreatic cancer cells. Human pancreatic cancer MiaPaCa-2 cells were treated with 1, 5, 10, 20, 30, 40 and 50 microM ATRA for 1, 2, 3, 4, 5 or 6 d, respectively. Cell growth was determined by MTT viability assay. The cell cycle distribution and the alkaline phosphatase (ALP) activity were analyzed by flow cytometry and chemical analyzer, respectively. The results show that ATRA significantly inhibited the growth of MiaPaCa-2 cells at 40 and 50 microM. ATRA arrested pancreatic cancer cells at G0/G1 phase. The sub-G1 peak and DNA fragmentation were observed. There were time and dose dependent increases in alkaline phosphatase activity (ALP), an indicator of cell differentiation, upon treatment with ATRA when compared to controls. In conclusion, ATRA has an inhibitory effect on the cell growth of MiaPaCa-2, and its tumor suppressive effect is by means of cell cycle arrest and apoptosis induction.
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PMID:The effects of all-trans-retinoic acid on cell cycle and alkaline phosphatase activity in pancreatic cancer cells. 1701 84

Granulocytic sarcoma mimicking a synchronous second primary neoplasm (SPN) constitutes a diagnostic and therapeutic challenge particularly in elderly patients. We report on a 75-year-old female presenting with a Core-binding Factor (CBF) AML of M4eo subtype. The patient also had jaundice, highly elevated bilirubin, lipase, alkaline phosphatase (AP), CA 19-9, and a pancreatic mass highly suspicious of infiltrating pancreatic carcinoma. However, a biopsy demonstrated granulocytic sarcoma. Since the patient had no comorbidities and had been in excellent performance status until the diagnosis of AML, induction chemotherapy was initiated, with subsequent normalization of bilirubin, CA 19-9, lipase and AP. Complete hematologic remission of AML was attained and the pancreatic mass could not be detected anymore. Retrospective analysis of the c-kit protooncogene did not disclose activating mutations of exons 8 or 17. Following one consolidation treatment, the patient remained in excellent health until relapse occurred 7 months later and she succumbed to AML. In conclusion, AML can rarely mimic the clinical picture of pancreatic cancer. The initially good response of this CBF leukemia highlights the principal usefulness of aggressive induction chemotherapy also in older AML patients, if they are carefully selected not only according to biological risk factors such as cytogenetics, but also to "host factors" (good performance status, lack of comorbidities, etc.).
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PMID:Granulocytic sarcoma of Core-binding Factor (CBF) acute myeloid leukemia mimicking pancreatic cancer. 1845 26

Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA 19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA 19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer.
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PMID:Modelling prognostic factors in advanced pancreatic cancer. 1923 30


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