A gene expression database for the molecular pharmacology of cancer.

We used cDNA microarrays to assess gene expression profiles in 60 human cancer cell lines used in a drug discovery screen by the National Cancer Institute. Using these data, we linked bioinformatics and chemoinformatics by correlating gene expression and drug activity patterns in the NCI60 lines. Clustering the cell lines on the basis of gene expression yielded relationships very different from those obtained by clustering the cell lines on the basis of their response to drugs. Gene-drug relationships for the clinical agents 5-fluorouracil and L-asparaginase exemplify how variations in the transcript levels of particular genes relate to mechanisms of drug sensitivity and resistance. This is the first study to integrate large databases on gene expression and molecular pharmacology.

Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner.

The effect of previous exposure to amphetamine (AMPH) in the ventral tegmental area (VTA) on the subsequent self-administration of cocaine was assessed. Rats in different groups were pre-exposed to three injections into the VTA of either saline (0.5 microl/side) or AMPH (2.5 microg/0.5 microl/side). Injections were given once every third day. Starting 7-10 days after the last pre-exposure injection, rats were trained to self-administer cocaine (0.3 mg/kg/infusion) under fixed ratio 1 and 2 (FR1 and FR2) schedules and then tested under a progressive ratio (PR) schedule of reinforcement for six consecutive days. No differences between groups were observed during self-administration training under the FR schedules of reinforcement. However, when tested under the PR schedule, VTA AMPH pre-exposed rats worked more and, as a result, obtained more infusions of cocaine than saline pre-exposed rats. Rats in a separate group pre-exposed to VTA AMPH but co-infused with the D(1)-like dopamine (DA) receptor antagonist SCH23390 (0.25 microg/0.5 microl/side) did not show enhanced cocaine self-administration. These rats, as well as others pre-exposed to VTA SCH23390 alone showed levels of cocaine self-administration similar to saline pre-exposed rats. Thus, in a manner paralleling the sensitization of AMPH-induced locomotion and nucleus accumbens DA overflow, previous exposure to AMPH in the VTA leads to enhanced intravenous self-administration of cocaine and activation of D(1) DA receptors in this site during pre-exposure is necessary for the production of this effect.

MedMiner: an Internet text-mining tool for biomedical information, with application to gene expression profiling.

The trend toward high-throughput techniques in molecular biology and the explosion of online scientific data threaten to overwhelm the ability of researchers to take full advantage of available information. This problem is particularly severe in the rapidly expanding area of gene expression experiments, for example, those carried out with cDNA microarrays or oligonucleotide chips. We present an Internet-based hypertext program, MedMiner, which filters and organizes large amounts of textual and structured information returned from public search engines like GeneCards and PubMed. We demonstrate the value of the approach for the analysis of gene expression data, but MedMiner can also be extended to other areas involving molecular genetic or pharmacological information. More generally still, MedMiner can be used to organize the information returned from any arbitrary PubMed search.

EDGAR: extraction of drugs, genes and relations from the biomedical literature.

EDGAR (Extraction of Drugs, Genes and Relations) is a natural language processing system that extracts information about drugs and genes relevant to cancer from the biomedical literature. This automatically extracted information has remarkable potential to facilitate computational analysis in the molecular biology of cancer, and the technology is straightforwardly generalizable to many areas of biomedicine. This paper reports on the mechanisms for automatically generating such assertions and on a simple application, conceptual clustering of documents. The system uses a stochastic part of speech tagger, generates an underspecified syntactic parse and then uses semantic and pragmatic information to construct its assertions. The system builds on two important existing resources: the MEDLINE database of biomedical citations and abstracts and the Unified Medical Language System, which provides syntactic and semantic information about the terms found in biomedical abstracts.

Blockade of D2 dopamine receptors in the VTA induces a long-lasting enhancement of the locomotor activating effects of amphetamine.

The present study examined the effects of pre-exposure to eticlopride, a D2 dopamine receptor antagonist, in the ventral tegmental area (VTA) on the subsequent locomotor activating effects of amphetamine (AMPH). Rats were pre-exposed to one of three doses of eticlopride (0.75, 3.0 or 12.0 microg/0.5 microl per side) or saline (0.5 microl/side) in the VTA, once every third day, for a total of three infusions. Locomotor activity was recorded for 2 h following each pre-exposure injection. The low and intermediate doses of eticlopride produced no effects, while the high dose decreased locomotor activity compared to saline controls. 10-14 days following the last pre-exposure injection, all rats were challenged with AMPH (1.0 mg/kg, ip) and locomotor activity was recorded. Rats pre-exposed to the low dose of eticlopride exhibited enhanced locomotor activity whereas those pre-exposed to the intermediate or high doses did not differ from saline pre-exposed controls, suggesting that blockade of D2 dopamine receptors in the VTA can lead to sensitized locomotor responding to AMPH. To investigate the possible mechanism by which the low dose of eticlopride induced sensitization, extracellular levels of dopamine were measured as increasing concentrations of eticlopride (0.1, 1.0, 10.0 and 100.0 micromol/l) were perfused through a microdialysis probe implanted in the VTA. Only the lowest eticlopride concentration elevated extracellular dopamine levels. Therefore, as in the case of AMPH-induced sensitization, the induction by eticlopride of sensitization to AMPH may be initiated by the ability of eticlopride to increase extracellular levels of dopamine in the VTA.