Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colon cancer exhibits inherent insensitivity to chemotherapy by mechanisms that are poorly characterized. We have shown that human colon cancer cells are efficient in drug conjugation catalyzed by UDP-glucuronosyltransferases (UGTs) and now report on the role of glucuronidation in de novo resistance to two topoisomerase I inhibitors. Identification of the UGT responsible for glucuronidation of SN-38 and the anthraquinone NU/ICRF 505 was achieved by first using a panel of human cDNA-expressed isozymes to measure conjugating activity. HT29 colon cancer cells were then probed by reverse transcriptase-PCR, Western Blot analysis, and liquid chromatography with mass spectrometry for their profile and activity of UGT isozymes and screened for effective inhibitors of glucuronidation. Expression analysis was also conducted in colon cancer biopsies and paired adjacent normal colon specimens. UGT1A9 was identified as the isozyme catalyzing biotransformation of the two compounds in HT29 cells and propofol as an effective competitive inhibitor of this metabolism. Inhibition of glucuronidation resulted in up to a 5-fold enhancement in drug activity. The majority of colon cancer biopsies studies expressed UGT protein at levels greater than in HT29 cells but with marked interpatient variations and proficiently glucuronidated the two anticancer drugs. A range of UGT aglycones were capable of modulating glucuronidation in the biopies with octylgallate being 10-fold more potent (ID(50) 24 microM) than propofol. In a subset of tumors (33%), UGT protein levels and activity exceeded that of paired normal colon. Glucuronidation may represent a mechanism of intrinsic drug resistance in colon cancer open to modulation by a range of food additives and proprietary medicines.
 ...
PMID:Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives. 1467 8

Colon cancer detection at an early stage and identifying susceptible individuals can result in reduced mortality from this prevalent cancer. Genetic events leading to the development of this cancer involve a multistage progression of adenoma polyps to invasive metastatic carcinomas. Currently, there is no satisfactory screening method that is highly specific, sensitive, or reliable. Dietary patterns associated with the greatest increase in colon cancer risk are the ones that typify a diet rich in fat and calories, and low in vegetable, fruits, and fibers. Genetic susceptibility to environmental carcinogenesis must be factored into the risk assessment for this cancer. Many genes have been shown to be associated with increased expression and mutations in colorectal cancer patients. These genes have been reviewed; it is hoped that by carefully selecting a number of them, a molecular approach that is suitable for arriving at a tumorigenic expression index is developed, which will reliably detect this cancer at an early stage (i.e., before it metastasizes), especially in exfoliated samples (e.g., stool and blood), so that appropriate intervention strategies can be implemented. Illustrated herein is the utility of employing real-time reverse transcriptase polymerase chain reaction (RT-PCR) to quantitatively measure gene expression, and develop an index that is specific for this cancer, which if perfected may result in a reliable and sensitive screening technique for colorectal cancer detection.
 ...
PMID:Colon cancer: prevalence, screening, gene expression and mutation, and risk factors and assessment. 1584 22

Colon cancer (CC) is a leading cause of cancer mortality. Novel biomarkers are needed to identify CC patients at high risk of recurrence and those who may benefit from therapeutic intervention. The aim of this study is to investigate if miR-21 expression from RNA isolated from formalin-fixed paraffin-embedded (FFPE) tissue sections is associated with prognosis and therapeutic outcome for patients with CC. The expression of miR-21 was measured by quantitative reverse transcriptase-polymerase chain reaction in a Japanese cohort (stage I-IV, n = 156) and a German cohort (stage II, n = 145). High miR-21 expression in tumors was associated with poor survival in both the stage II/III Japanese (p = 0.0008) and stage II German (p = 0.047) cohorts. These associations were independent of other clinical covariates in multivariable models. Receipt of adjuvant chemotherapy was not beneficial in patients with high miR-21 in either cohort. In the Japanese cohort, high miR-21 expression was significantly associated with poor therapeutic outcome (p = 0.0001) and adjuvant therapy was associated with improved survival in patients with low miR-21 (p = 0.001). These results suggest that miR-21 is a promising biomarker to identify patients with poor prognosis and can be accurately measured in FFPE tissues. The expression of miR-21 may also identify patients who will benefit from adjuvant chemotherapy.
...
PMID:High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer. 2412 31