Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1835664 (TOC)
 2,763 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Frequent observations of allelic loss in chromosomal band 17q25.1 in a variety of human cancers have suggested that one or more tumor suppressor genes are normally present in this region. Moreover, a locus responsible for hereditary focal non-epidermolytic palmoplantar keratoderma (tylosis oesophageal cancer; TOC), a condition associated with esophageal cancer, has been mapped to the same band. During efforts to sequence, by shot-gun methods, a 1 Mb target region that we had defined as the DNA segment harboring the putative tumor suppressor gene(s) involved in these events, we identified a novel cDNA, DRHC (down-regulated in human cancers), that showed reduced expression in 28 of 95 (29%) cell lines derived from a variety of human cancers. The full-length cDNA, 6275 bp long, was expressed predominantly in thymus and brain. The predicted 1942-amino-acid product exhibited significant sequence homology to yeast enzymes belonging to the DEAD-helicase superfamily, and appeared to be a Uvr/Rep helicase with a DEXDc consensus domain. Transfection of a DRHC expression vector inhibited growth of cancer cells in liquid medium or soft agar. The results suggest that loss of expression of DRHC may play a role in human carcinogenesis.
 ...
PMID:Down-regulation in human cancers of DRHC, a novel helicase-like gene from 17q25.1 that inhibits cell growth. 1269 22

Reactive metabolites are widely accepted as playing a pivotal role in causing idiosyncratic adverse drug reactions (IDR). However, much is unknown about the biological mechanisms of IDR, although the initiating event in most cases is an attachment of a reactive intermediate to macromolecules leading to immune-mediated responses. Reactive metabolites are also involved in many mutagenesis/carcinogenesis events by reacting with DNA. Drug designers thus have reasons to make large efforts to avoid making test compounds having a liability to generate reactive metabolites. In this Perspective we argue for using structural alerts (SA) as the most straightforward way to link forecasting about chemical hazards of planned test compounds to the accumulated knowledge base. Although many SAs have been widely recognized and reviewed previously, there are also a lot of observations that have no readily discernible chemical interpretation. For drug designers to benefit from all published data, the knowledge has to be organized in a way that is readily searchable starting with a query structure. We propose that an increased number of structural alerts with more details should be applied to obtain improved decision support. The association of selected SAs with reference drugs, whose proposed or hypothesized activation mechanisms build the knowledge base, should be readily available in a format comprising of small summaries with included hyperlinks for quick access to the original literature, as outlined in the TOC illustration. Since some structural alerts are present in drugs that do not cause idiosyncratic adverse reactions or drug-drug interactions, it is important to elaborate on the reasons for this discrepancy as much as possible.
 ...
PMID:Systematic Approach to Organizing Structural Alerts for Reactive Metabolite Formation from Potential Drugs. 2974 1