Biomedical subjects

D Perrin

Publications and source records attributed to D Perrin.

At least 19 recordsLinked to original sources

PubMed2006

Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta.

In human post-natal somatic cells, low global levels of DNA methylation have been associated with the hypomethylation of several repetitive elements, a feature that has been proposed to be a surrogate epigenetic marker. These data, mainly derived from the analysis of cancer cells, suggest a potential association between loss of cell-growth control and altered differentiation with hypomethylation of repetitive sequences. Partial hydatidiform moles (PHMs) can be used as an alternative model for investigating this association in a non-tumorigenic context. This gestational disease is characterized by abnormal overgrowth and differentiation of the placenta and spontaneous abortion. Here, we comprehensively analyse the DNA methylation of these trophoblastic tissues in both PHM and normal placenta at global and sequence-specific levels. Analysis of the global 5-methylcytosine content and immunohistochemistry indicate that PHM and normal placenta have identical global levels of DNA methylation. In contrast, bisulfite genomic sequencing shows that, whereas Alu, NBL2 and satellite 2 repetitive elements are equally methylated, LINE-1 sequences are hypermethylated in PHM tissues ( approximately 2-fold relative to normal placenta). Interestingly, altered demethylation is also found in triploid diandric embryos that originate from dispermic fertilization of an oocyte, a common event responsible for most PHMs. In conclusion, alterations of DNA methylation do not seem to be randomly distributed in PHM, as several repeated elements remain unaltered, whereas LINE-1 sequences are hypermethylated. In addition, our findings suggest that the hypomethylation of repetitive elements in cancer is directly linked to the neoplasic process and not a simple consequence of loss of growth control observed in most of the cancer cells.

Cell Differentiation↗

PubMed2006

BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine H3 receptor: Preclinical pharmacology.

Histamine H3 receptor inverse agonists are known to enhance the activity of histaminergic neurons in brain and thereby promote vigilance and cognition. 1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, hydrochloride (BF2.649) is a novel, potent, and selective nonimidazole inverse agonist at the recombinant human H3 receptor. On the stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding to this receptor, BF2.649 behaved as a competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity approximately 50% higher than that of ciproxifan. Its in vitro potency was approximately 6 times lower at the rodent receptor. In mice, the oral bioavailability coefficient, i.e., the ratio of plasma areas under the curve after oral and i.v. administrations, respectively, was 84%. BF2.649 dose dependently enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity, with an ED50 value of 1.6 mg/kg p.o., a response that persisted after repeated administrations for 17 days. In rats, the drug enhanced dopamine and acetylcholine levels in microdialysates of the prefrontal cortex. In cats, it markedly enhanced wakefulness at the expense of sleep states and also enhanced fast cortical rhythms of the electroencephalogram, known to be associated with improved vigilance. On the two-trial object recognition test in mice, a promnesiant effect was shown regarding either scopolamine-induced or natural forgetting. These preclinical data suggest that BF2.649 is a valuable drug candidate to be developed in wakefulness or memory deficits and other cognitive disorders.

Acetylcholine↗

PubMed2006

Hearts with concordant ventriculoarterial connections but parallel arterial trunks.

OBJECTIVES: To determine the characteristic morphological features of hearts with concordant ventriculoarterial connections and parallel arterial trunks, and to provide unequivocally a method to describe their anatomy. DESIGN, METHODS AND PATIENTS: The entire cardiac database and cardiac pathological archive at the Hospital for Sick Children, Toronto, Ontario, Canada, was interrogated to identify all patients with concordant ventriculoarterial connections and parallel arterial trunks. The clinical records, autopsy reports and actual cardiac specimens of those who underwent autopsy, were reviewed. RESULTS: 8 cases meeting our criteria were identified. The infundibular anatomy was variable, including four hearts with bilateral infundibulums, three with subpulmonary infundibulums and one with bilaterally absent infundibulums. Considerable variability was also found in the type of atrial arrangement, along with the morphology of the atrioventricular junctions. The most common findings were the usual atrial arrangement (n = 5), left juxtaposition of the right atrial appendages (n = 3), an atrial septal defect (n = 6), univentricular atrioventricular connection (n = 5), ventricular septal defect (n = 8) and pulmonary obstruction (n = 4). In addition, five specimens had either a single coronary artery or two coronary arteries arising from the anticipated right coronary aortic sinus. CONCLUSIONS: Concordant ventriculoarterial connections with parallel arterial trunks can be found in a variety of segmental combinations. An accurate diagnosis of these rare hearts can be achieved by detailed analysis of not only the ventriculoarterial connections but also the infundibular anatomy and the spatial relationship of the arterial trunks. Particular attention to the coronary arteries is warranted.

Aorta↗

PubMed2005

Characterisation of ionisation chambers for a mixed radiation field and investigation of their suitability as radiation monitors for the LHC.

Monitoring of the radiation environment is one of the key tasks in operating a high-energy accelerator such as the Large Hadron Collider (LHC). The radiation fields consist of neutrons, charged hadrons as well as photons and electrons with energy spectra extending from those of thermal neutrons up to several hundreds of GeV. The requirements for measuring the dose equivalent in such a field are different from standard uses and it is thus necessary to investigate the response of monitoring devices thoroughly before the implementation of a monitoring system can be conducted. For the LHC, it is currently foreseen to install argon- and hydrogen-filled high-pressure ionisation chambers as radiation monitors of mixed fields. So far their response to these fields was poorly understood and, therefore, further investigation was necessary to prove that they can serve their function well enough. In this study, ionisation chambers of type IG5 (Centronic Ltd) were characterised by simulating their response functions by means of detailed FLUKA calculations as well as by calibration measurements for photons and neutrons at fixed energies. The latter results were used to obtain a better understanding and validation of the FLUKA simulations. Tests were also conducted at the CERF facility at CERN in order to compare the results with simulations of the response in a mixed radiation field. It is demonstrated that these detectors can be characterised sufficiently enough to serve their function as radiation monitors for the LHC.

Computer-Aided Design↗

PubMed2004

Sub-chronic exposure to toluene at 40 ppm alters the monoamine biosynthesis rate in discrete brain areas.

Effects of long-term exposure to a sub-toxic concentration of toluene (40 ppm, 104 h per week, 16 weeks) have been studied on monoamine biosynthesis rate in rat. The activities of the rate limiting enzymes in catecholamine and 5-hydroxytryptamine biosynthesis tyrosine and tryptophan hydroxylase, respectively, were estimated in vivo by measuring the accumulation of l-dihydroxyphenylalanine and 5-hydroxytryptophan after pharmacological blockade of l-aromatic acid decarboxylases by NSD-1015 (100 mg kg(-1) ip). The sub-chronic exposure to toluene led to a significant and gender dependent alteration in both catecholamine and 5-hydroxytryptamine biosynthesis rate in brainstem catecholaminergic cell groups and hypothalamus. In females exposed to toluene, changes in tryptophan hydroxylation were found in rostral subset of A2C2 (+41%) and in A1C1 (+41%) while a decrease in A5 (-44%) and an increase in A2C2 (+28%) were found in tyrosine hydroxylation. In males, an increase in tryptophane hydroxylation was observed in rostral subset of A2C2 (+35%) while a decrease was observed in ventro-median hypothalamus (-17%). These results suggest that toluene exposure to a dose generally recognized as sub-toxic (40 ppm, no observed adverse effect level) leads to adverse effects on monoaminergic systems. Therefore, the neurotoxicity of toluene should be carefully re-evaluated taking into account not only the exposure level but also the duration.

5-Hydroxytryptophan↗

PubMed2004

Biological properties of acid etched titanium implants: effect of sandblasting on bone anchorage.

The SLA (sandblasted with large grit and acid etched) surface is a textured surface that has been documented to lead to a rapid and strong implant fixation. The purpose of the present study was to determine the contribution of sandblasting in addition to etching to implant anchorage. It was also aimed to determine if the pits carved during etching alone have a bone-interlocking capacity that leads to microanchorage between the implant and bone. SLA implants and machined-and-acid-etched (MA) implants were placed in the maxilla of Land Race pigs. After 10 weeks of healing, they were reverse torqued. The reverse torque of the SLA and MA implants was 157.29 +/- 38.04 N cm and 105.33 +/- 25.12 N cm, respectively. Sandblasting increased bone anchorage by 49.3%; the difference was statistically significant (p =.028). Bone was found attached to both surfaces; bone ingrowth was found in the pits of both surfaces. It is suggested that the two surfaces are able to generate bone interlocking and mechanical coupling at the interface. When finite-element modeling is performed with these surfaces, it is suggested that the bound mode be used instead of the slip mode.

Bone and Bones↗

PubMed2003

Resistance to obesity in Lou/C rats prevents ageing-associated metabolic alterations.

AIMS/HYPOTHESIS: Ageing is associated with metabolic alterations characterised by changes in energy expenditure, obesity, leptin and insulin resistance. The Lou/C rat, an inbred strain of Wistar origin, is presented as both an obesity-resistant rat and a model of healthy ageing. METHODS: To characterise the mechanisms underlying obesity resistance in Lou/C rat, we measured food intake and energy expenditure by indirect calorimetry at 1, 6, 12, 18, and 24 months of age. Moreover, plasma insulin and leptin concentrations were assessed by radioimmunoassay in Lou/C and Wistar rats throughout their life span. RESULTS: Compared to Wistar rats, Lou/C rats presented a higher food intake only at 24 months of age and they had a higher energy expenditure at 6 and 12 months of age (+21% and +14%, respectively). Plasma insulin concentration increased markedly in 18- and 24-month-old Wistar rats, but remained stable during ageing in Lou/C rats. From the age of 6 months, the plasma leptin concentrations in Wistar rats were higher than in Lou/C rats of the same age (four-, seven-, five- and threefold higher at 6, 12, 18, 24 months of age, respectively). CONCLUSION/INTERPRETATION: Compared to Wistar rats, Lou/C rats did not develop insulin resistance as confirmed by a higher glucose infusion rate during the hyperinsulinaemic-euglycaemic clamp. These data provide evidence that insulin resistance is associated with the excess of adipose tissue in Wistar rats. Not only Lou/C rats present a higher median life span than Wistar rats (+20%), but they also show a healthy ageing process considering fat accretion and insulin resistance.

Aging↗

PubMed2003

Neurochemical development of the brainstem catecholaminergic cell groups in rat.

The postnatal development of tyrosine hydroxylase activity has been studied in the brainstem catecholaminergic cell groups (A1C1, A2C2, A5, A6, A7), involved in cardiorespiratory control. In rat, at birth and at postnatal days P3, P7, P14, P21 ant P68, we used a microdissection technique followed by in vivo measurement of the tyrosine hydroxylase (TH) activity, the rate-limiting enzyme in catecholamine synthesis. There is two successive marked increases in TH activity: at P3 in every catecholaminergic cell groups (A1C1, +225%; A2C2, +300%; A5, +190%; A6, +205% compared to birth) and during the third postnatal week with a peak of TH activity at P14 (A6, +90% above the P7 level) or at P21 (A1C1, +715%; caudal A2C2, +585%; rostral A2C2, +15%; A5, +445%; A7, +180% compared to P7). The data suggest the existence of two temporal windows during the neurochemical development of the catecholaminergic cell groups, which correspond to two metabolic transitions. The first one could be related to the intra-, extrauterine transition and the second one, to a deep energetic phase of maturation in the rat brain, closely related to the maturation of cardiorespiratory processes.

Animals↗

PubMed2002

Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development.

Vinflunine, the most recent Vinca alkaloid in clinical development, demonstrated superior antitumour activity to other Vincas in preclinical tumour models. This study aimed to define its molecular mechanisms of cell killing in both parental sensitive and vinflunine-resistant P388 leukaemia cells. Vinflunine treatment of these cells resulted in apoptosis characterized by DNA fragmentation and proteolytic cleavage of poly-(ADP-ribose) polymerase. Apoptosis-inducing concentrations of vinflunine caused c-Jun N-terminal kinase 1 stimulation, as well as caspases-3/7 activation. This activation of caspases and the induction of apoptosis could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. Interestingly, the apoptosis signal triggered by vinflunine in these P388 cells was not mediated through Bcl-2 phosphorylation. In addition, when vinflunine resistance was developed in P388 cells, it was associated with resistance to vinflunine-induced apoptosis, as reflected by a loss of capacity to induce DNA fragmentation and PARP degradation, and characterized by increased levels of Bcl-2 and Bfl-1/A1. Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms.

Animals↗

PubMed2002

Influence of tropolone on Poria placenta wood degradation.

Fenton reactions are believed to play important roles in wood degradation by brown rot fungi. In this context, the effect of tropolone (2-hydroxycyclohepta-2,4,6-trienone), a metal chelator, on wood degradation by Poria placenta was investigated. Tropolone (50 micro M) strongly inhibits fungal growth on malt agar, but this inhibition could be relieved by adding iron salts. With an experimental system containing two separate parts, one supplemented with tropolone (100 micro M) and the other not, it was shown that the fungus is able to reallocate essential minerals from the area where they are available and also to grow in these conditions on malt-agar in the presence of tropolone. Nevertheless, even in the presence of an external source of metals, P. placenta is not able to attack pine blocks impregnated with tropolone (5 mM). This wood degradation inhibition is related to the presence of the tropolone hydroxyl group, as shown by the use of analogs (cyclohepta-2,4,6-trienone and 2-methoxycyclohepta-2,4,6-trienone). Furthermore, tropolone possesses both weak antioxidative and weak radical-scavenging properties and a strong affinity for ferric ion and is able to inhibit ferric iron reduction by catecholates, lowering the redox potential of the iron couple. These data are consistent with the hypothesis that tropolone inhibits wood degradation by P. placenta by chelating iron present in wood, thus avoiding initiation of the Fenton reaction. This study demonstrates that iron chelators such as tropolone could be also involved in novel and more environmentally benign preservative systems.

Antioxidants↗

PubMed2001

Direct photocleavage of HIV-DNA by quinacridine derivatives triggered by triplex formation.

Amino-p-quinacridine compounds (PQs) have been shown to stabilize strongly and specifically triple-helical DNA. Moreover, these derivatives display photoactive properties that make them efficient DNA cleavage agents. We exploited these two properties (triplex-specific binding and photoactivity) to selectively cleave a double-stranded (ds)DNA sequence present in the HIV-1 genome. Cleavage was first carried out on a linearized plasmid (3300 bp) containing the HIV polypurine tract (PPT) that allowed targeting by a triplex-forming oligonucleotide (TFO). PQ(3)(), the most active compound of the series, efficiently cleaved double-stranded DNA in the vicinity of the PPT when this sequence had formed a triplex with a 16-mer TFO. Investigation of the cleavage at the molecular level was addressed on a short DNA fragment (56 bp); the photoinduced cleavage by PQ(3)() occurred only in the presence of the triple helix. Nevertheless, unusual cleavage patterns were observed: damage was observed at guanines located 6-9 bp away from the end of the triple helical site. This cleavage is very efficient (up to 60%), does not require alkaline treatment, and is observed on both strands. A quinacridine-TFO conjugate produced the same cleavage pattern. This observation, along with others, excludes the hypothesis of a triplex-induced allosteric binding site of PQ(3 )()adjacent to the damaged sequence and indicates that PQ(3 )()preferentially binds in the vicinity of the 5'-triplex junction. Irradiation in the presence of TFO-conjugates with acridine (an intercalative agent) and with the tripeptide lys-tryp-lys led to a complete inhibition of the photocleavage reaction. These results are interpreted in terms of competitive binding and of electron-transfer quenching. Together with the findings of simple mechanistic investigations, they led to the conclusion that the photoinduced damage proceeds through a direct electron transfer between the quinacridine and the guanines. This study addresses the chemical mechanism leading to strand breakage and characterizes the particular photosensitivity of the HIV-DNA target sequence which could be an oxidative hot spot for addressed photoinduced strand scission by photosensitizers.

Aminoacridines↗

PubMed2000

The quantitative oxidation of methionine to methionine sulfoxide by peroxynitrite.

Both peroxynitrous acid and peroxynitrite react with methionine, k(acid) = (1.7 +/- 0.1) x 10(3) M(-1) s(-1) and k(anion) = 8.6 +/- 0.2 M(-1) s(-1), respectively, and with N-acetylmethionine k(acid) = (2.8 +/- 0.1) x 10(3) M(-1) s(-1) and k(anion) = 10.0 +/- 0.1 M(-1) s(-1), respectively, to form sulfoxides. In contrast to the results of Pryor et al. (1994, Proc. Natl. Acad. Sci. USA 91, 11173-11177), a linear correlation between k(obs) and [met] was obtained. Surprisingly, for every two sulfoxides and nitrites formed, one peroxynitrite is converted to nitrate. Thus, methionine also catalyzes the isomerization of peroxynitrite to nitrate. Neither the pH nor the concentration of methionine affected the distribution of the yields of nitrite, nitrate, and methionine sulfoxide, which were the only products detected. No products other than nitrite, nitrate, and methioninesulfoxide could be detected. The reactions of methionine and N-acetylmethionine with peroxynitrous acid and peroxynitrite are simple bimolecular reactions that do not involve an activated form of peroxynitrous acid or of peroxynitrite. Nitrite, produced together with methionine sulfoxide, or present as a contamination in the peroxynitrite preparation, is not innocuous, but oxidizes methionine by one electron, which leads to the formation of methional and ethylene.

Aldehydes↗

PubMed2000

F 11782, a novel epipodophylloid non-intercalating dual catalytic inhibitor of topoisomerases I and II with an original mechanism of action.

F 11782, a novel epipodophylloid, proved a potent inhibitor of the catalytic activities of both topoisomerases I and II. Unlike classical inhibitors such as camptothecin or etoposide, F 11782 did not stabilise cleavable complexes induced by either topoisomerases I or II nor did it preferentially inhibit the religation step of the catalytic cycle of either enzyme. F 11782 neither intercalated DNA nor bound in its minor groove, and showed only weak inhibition of the ATPase activity associated with topoisomerase II. F 11782 appeared to act by inhibiting the binding of topoisomerases I and II to DNA in a manner dependent both on drug and enzyme concentrations, via a mechanism not previously described or shared by other known topoisomerase 'poisons' or inhibitors. In contrast, F 11782 had only a weak effect or none at all on various other DNA-interacting enzymes. In conclusion, F 11782, as a non-intercalating, specific catalytic inhibitor of both topoisomerases I and II with an original mechanism of action, may be considered to represent the first of a new class of topoisomerase-interacting agents.

Adenosine Triphosphatases↗

PubMed2000

Tomorrow's anticancer agents: inhibitors of Ras farnesylation.

The purpose of this chapter is to concentrate on what can be considered as definite milestones on the way from examples of inhibitors of farnesyl-protein transferase (FPTase) to candidate drugs actually being considered for or already being evaluated in clinical trials. Emphasis will be placed on results obtained using experimental tumour models in vivo, with a detailed discussion of these results and of the questions which remain to be studied or are still unanswered. The data discussed here are almost exclusively based on published reports, with only brief reference, in the chapter "use of the FPTase inhibitors in the clinic", to some of the newer compounds reported on during recent meetings, details of which have not yet appeared in the peer-reviewed literature. For those requiring a more extensive review of the catalogue of FPTase inhibitors now discovered, some excellent reviews have been committed to this purpose [1-3].

Alkyl and Aryl Transferases↗

PubMed2000

Exhaled carbon monoxide in mechanically ventilated critically ill patients: influence of inspired oxygen fraction.

OBJECTIVE: To assess the feasibility of exhaled carbon monoxide (CO) measurements in mechanically ventilated critically ill adult patients and to determine the influence of inspired oxygen fraction on this measurement. DESIGN: Prospective physiologic study. SETTING: Medical ICU in a community hospital. PATIENTS: The study was performed on nine mechanically ventilated patients with varying diagnoses. MEASUREMENTS AND RESULTS: Carbon monoxide concentration was determined with an infrared CO analyzer on exhaled breath collected at the outlet of the ventilator. We assessed the stability of exhaled carbon monoxide concentration over a 4-hour period and determined its course during a 7-hour period after inspired oxygen fraction had been abruptly increased from baseline to 1. Carbon monoxide was detected in exhaled breath in each patient at a higher concentration than in inspired gas (0.64 +/- 0.1 ppm vs 0.25 ppm, approximately). Exhaled carbon monoxide did not vary during a 4-hour period in five hemodynamically stable patients. When inspired oxygen fraction was increased from baseline (0.52 +/- 0.04) to 1, exhaled carbon monoxide concentration increased abruptly from baseline (0.63 +/- 0.13 ppm) to a peak value of 1.54 +/- 0.16 ppm within 15 min and returned slowly to baseline values within 7 h. CONCLUSION: CO was easily detected in the exhaled breath of mechanically ventilated patients and CO lung excretion was markedly but transiently dependent on inspired oxygen fraction. Other studies are warranted in order to determine the different factors that might influence CO lung excretion in critically ill patients.

Aged↗

PubMed2000

F 11782, a dual inhibitor of topoisomerases I and II with an original mechanism of action in vitro, and markedly superior in vivo antitumour activity, relative to three other dual topoisomerase inhibitors, intoplicin, aclarubicin and TAS-103.

PURPOSE: F 11782 (2",3"-bis pentafluorophenoxyacetyl-4",6"-ethylidene-beta-D-glucoside of 4'-phosphate-4'-dimethylepipodophyllotoxin, di-N-methyl glucamine salt) is a newly synthesized dual catalytic inhibitor of topoisomerases I and II with major in vivo antitumour activity. In this study, we compared and contrasted F 11782 with three other known inhibitors of both these nuclear enzymes, namely aclarubicin. intoplicin and TAS-103, and established its novel mechanism of action. METHODS: In vitro growth-inhibitory effects against a panel of murine and tumour cell lines were measured by cell counting, clonogenicity or tetrazolium metabolic dye (MTT) assays. In vivo antitumour activities were evaluated against two murine tumour models (i.v. P388 leukaemia and s.c. B16 melanoma). Finally, interactions with either DNA or DNA-topoisomerases were determined using various methodologies: DNA-intercalator displacement, pBR322 DNA relaxation, kDNA decatenation, topoisomerase II extractability measurements, stabilization of topoisomerase-induced cleavable complexes (CC) in vitro and in cells, and gel retardation assays. RESULTS: F 11782 had a different profile of sensitivities and proved generally less cytotoxic than the other dual inhibitors tested in vitro, while showing significantly superior antitumour activity in vivo. F 11782, which did not stabilize CC either in vitro or in cells, was the only compound of this series capable of inhibiting the catalytic activity of both DNA-topoisomerases without interacting with DNA, and of completely impairing the binding of these nuclear proteins to DNA. Moreover, only cotreatment of cells in vitro with F 11782 enhanced the cytotoxic activity of etoposide. CONCLUSION: These results emphasize the novel mechanism of action of F 11782 vis-a-vis the other dual inhibitors of topoisomerases I and II and so augur well for its future clinical development.

Aclarubicin↗

PubMed2000

Viral genome organizer: a system for analyzing complete viral genomes.

The viral genome organizer (VGO) is designed to simplify the characterization and annotation of complete viral genomes (particularly those of large poxviruses) and to help researchers discover new genes and detect gene fragmentation. VGO is based on Genotator [Harris, N.L., 1997. Genome Res. 7, 754-762], an annotation workbench designed for the analysis of eukaryotic genomic sequences. VGO automates a number of database search routines (FASTA, BLASTP, PSI-BLAST and TBLASTN), processes the results through a multiple-alignment viewer (MView; [Brown, N.P., Leroy, C., Sander, C. , 1998. Bioinformatics 14, 380-381]) and serves to manage the hundreds of DNA, protein and database search results files that must be organized when dealing with large complete poxviral genomes. It also directs the generation a self-dotplot of the genome by Dotter [Sonnhammer, E.L.L., Durbin, R., 1995. A dot-matrix program with dynamic threshold control suited for genomic DNA and protein sequence analysis. Gene 167: GC1-10. http://www.sanger.ac. uk/Software/Dotter/] to uncover repeated genes and sequences and provides Internet links to programs for generation of restriction maps and analysis of potential PCR primers. The user-friendly graphical interface displays DNA and protein sequences, links to search results, ORFs, stop-start codons, restriction sites and flags of database searches. Currently, VGO and associated programs run in an X-windows environment on commonly available UNIX machines.

Databases, Factual↗

PubMed2000

Inhibition of RAS-targeted prenylation: protein farnesyl transferase inhibitors revisited.

The ras oncogene and its 21 kD protein product, Ras, has emerged during the last decade as a potentially exploitable target for anticancer drug development. The knowledge that Ras was readily prenylated by protein farnesyl transferase (PFTase) and that inhibition of this prenylation had functional consequences for the transformed phenotype that expressed oncogenic Ras provided the rational for the development of PFTase inhibitors. The initial enthusiasm for this approach seemed justified by the early identification of PFTase inhibitors that were able potently and specifically to block Ras processing, signalling and transformation in transformed and tumour cell lines in vitro and in certain selected animal models. More recently the recognition that geranylgeranyl transferase (GGTase) I might also be a therapeutic target is being actively researched. The last couple of years though have proved remarkable with the disclosure of a series of structurally-diverse molecules, whose major in vivo preclinical activites have been well documented against experimental animal tumours, and culminating this year in preliminary reporting of their Phase I clinical evaluations. Nevertheless, during the research and development phases of PFTase inhibitors as pharmaceutical agents for clinical use, there have been several unexpected findings which have raised intriguing and potentially crucial questions about their activities. This review aims to highlight and offer new insights into many of these issues and to bring into perspective concerns arising from basic research, as well as from clinical studies. There seems little doubt that these inhibitors of RAS-targeted prenylation represent a new generation of anticancer drugs for the preclinical researcher, whether they can be successfully exploited in clinical practice should be resolved early in the next millenium.

Alkyl and Aryl Transferases↗