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S L Graham

Publications and source records attributed to S L Graham.

At least 19 recordsLinked to original sources
PubMed2001

Evaluation of farnesyl:protein transferase and geranylgeranyl:protein transferase inhibitor combinations in preclinical models.

Farnesyl:protein transferase (FPTase) inhibitors (FTIs) were originally developed as potential anticancer agents targeting the ras oncogene and are currently in clinical trials. Whereas FTIs inhibit the farnesylation of Ha-Ras, they do not completely inhibit the prenylation of Ki-Ras, the allele most frequently mutated in human cancers. Whereas farnesylation of Ki-Ras is blocked by FTIs, Ki-Ras remains prenylated in FTI-treated cells because of its modification by the related prenyltransferase, geranylgeranyl:protein transferase type I (GGPTase-I). Hence, cells transformed with Ki-ras tend to be more resistant to FTIs than Ha-ras-transformed cells. To determine whether Ki-ras-transformed cells can be targeted by combining an FTI with a GGPTase-I inhibitor (GGTI), we evaluated potent, selective FTIs, GGTIs, and dual prenylation inhibitors (DPIs) that have both FTI and GGTI activity. We find that in human PSN-1 pancreatic tumor cells, which harbor oncogenic Ki-ras, and in other tumor lines having either wild-type or oncogenic Ki-ras, treatment with an FTI/GGTI combination or with a DPI blocks Ki-Ras prenylation and induces markedly higher levels of apoptosis relative to FTI or GGTI alone. We demonstrate that these compounds can inhibit their enzyme targets in mice by monitoring pancreatic and tumor tissues from treated animals for inhibition of prenylation of Ki-Ras, HDJ2, a substrate specific for FPTase, and Rap1A, a substrate specific for GGPTase-I. Continuous infusion (72 h) of varying doses of GGTI in conjunction with a high, fixed dose of FTI causes a dose-dependent inhibition of Ki-Ras prenylation. However, a 72-h infusion of a GGTI, at a dose sufficient to inhibit Ki-Ras prenylation in the presence of an FTI, causes death within 2 weeks of the infusion when administered either as monotherapy or in combination with an FTI. DPIs are also lethal after a 72-h infusion at doses that inhibit Ki-Ras prenylation. Because 24 h infusion of a high dose of DPI is tolerated and inhibits Ki-Ras prenylation, we compared the antitumor efficacy from a 24-h FTI infusion to that of a DPI in a nude mouse/PSN-1 tumor cell xenograft model and in Ki-ras transgenic mice with mammary tumors. The FTI and DPI were dosed at a level that provided comparable inhibition of FPTase. The FTI and the DPI displayed comparable efficacy, causing a decrease in growth rate of the PSN-1 xenograft tumors and tumor regression in the transgenic model, but neither treatment regimen induced a statistically significant increase in tumor cell apoptosis. Although FTI/GGTI combinations elicit a greater apoptotic response than either agent alone in vitro, the toxicity associated with GGTI treatment in vivo limits the duration of treatment and, thus, may limit the therapeutic benefit that might be gained by inhibiting oncogenic Ki-Ras through dual prenyltransferase inhibitor therapy.

Alkyl and Aryl Transferases↗
PubMed2001

Design and biological activity of (S)-4-(5-([1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino]methyl)imidazol-1-ylmethyl)benzonitrile, a 3-aminopyrrolidinone farnesyltransferase inhibitor with excellent cell potency.

The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.

Alkyl and Aryl Transferases↗
PubMed2001

Diaryl ether inhibitors of farnesyl-protein transferase.

Imidazolemethyl diaryl ethers are potent inhibitors of farnesyl-protein transferase. The SNAr displacement reaction used to prepare these diaryl ethers was amenable to rapid parallel synthesis of FPTase inhibitors. The use of a broad range of commercially available phenols quickly identified compounds which proved active in cells.

Alkyl and Aryl Transferases↗
PubMed2001

2-Arylindole-3-acetamides: FPP-competitive inhibitors of farnesyl protein transferase.

A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.

Alkyl and Aryl Transferases↗
PubMed2001

Anions modulate the potency of geranylgeranyl-protein transferase I inhibitors.

We have identified and characterized potent and specific inhibitors of geranylgeranyl-protein transferase type I (GGPTase I), as well as dual inhibitors of GGPTase I and farnesyl-protein transferase. Many of these inhibitors require the presence of phosphate anions for maximum activity against GGPTase I in vitro. Inhibitors with a strong anion dependence were competitive with geranylgeranyl pyrophosphate (GGPP), rather than with the peptide substrate, which had served as the original template for inhibitor design. One of the most effective anions was ATP, which at low millimolar concentrations increased the potency of GGPTase I inhibitors up to several hundred-fold. In the case of clinical candidate l-778,123, this increase in potency was shown to result from two major interactions: competitive binding of inhibitor and GGPP, and competitive binding of ATP and GGPP. At 5 mm, ATP caused an increase in the apparent K(d) for the GGPP-GGPTase I interaction from 20 pm to 4 nm, resulting in correspondingly tighter inhibitor binding. A subset of very potent GGPP-competitive inhibitors displayed slow tight binding to GGPTase I with apparent on and off rates on the order of 10(6) m(-)1 s(-)1 and 10(-)3 s(-)1, respectively. Slow binding and the anion requirement suggest that these inhibitors may act as transition state analogs. After accounting for anion requirement, slow binding, and mechanism of competition, the structure-activity relationship determined in vitro correlated well with the inhibition of processing of GGPTase I substrate Rap1a in vivo.

Adenosine Triphosphate↗
PubMed2001

3,8-Diazabicyclo[3.2.1]octan-2-one peptide mimetics: synthesis of a conformationally restricted inhibitor of farnesyltransferase.

A new synthesis of the 3,8-diazabicyclo[3.2.1]octan-2-one framework is described. Transannular enolate alkylation of piperazinone derivatives provides a flexible route to highly constrained bicyclic peptidomimetic synthons with substitution at the Calpha position. The chemistry was used to produce a conformationally constrained farnesyltransferase inhibitor, which aided the elucidation of enzyme-bound conformation.

Alkyl and Aryl Transferases↗
PubMed2001

Central corneal thickness, tonometry, and ocular dimensions in glaucoma and ocular hypertension.

PURPOSE: To assess possible correlations between central corneal thickness, tonometry, and ocular dimensions. PATIENTS AND METHODS: One hundred seventeen eyes of 117 patients who were not taking any intraocular pressure-lowering medications were studied prospectively. Forty-one patients had ocular hypertension; 13 patients had primary open-angle glaucoma; and 10 patients had normal-pressure glaucoma. Twenty-three healthy eyes were included. Thirty glaucoma suspects (10 patients monitored for possible normal-pressure glaucoma and 20 patients with intermittent ocular hypertension) were included for correlation analysis. Tonometry was performed with Goldmann applanation and pneumotonometry, and central corneal thickness, anterior chamber depth, lens thickness, and axial length were measured ultrasonically. RESULTS: Central corneal thickness was lowest in eyes with normal-pressure glaucoma (538 +/- 51 microm), highest in eyes with ocular hypertension (570 +/- 32 microm), and intermediate and similar in eyes with primary open-angle glaucoma and healthy eyes (547 +/- 34 microm and 554 +/- 32 microm, respectively). These differences were significant (P = 0.028). Goldmann applanation tonometry and central corneal thickness were weakly correlated (r = 0.12, P = 0.205), with a 0.2-mm Hg change per 10-microm variation in central corneal thickness. Pneumotonometry measurements were more strongly correlated with central corneal thickness (r = 0.21, P < 0.05). Lens thickness was strongly correlated with age (r = 0.57, P < 0.001). Anterior chamber depth was negatively correlated with lens thickness and age (r = -0.29, P < 0.005 and r = -0.25, P < 0.01). Axial length was correlated with anterior chamber depth and age (r = 0.5, P < .001 and r = -0.19, P < 0.05). CONCLUSION: Eyes diagnosed as having ocular hypertension have thicker corneas and eyes labeled as having normal-pressure glaucoma have thinner corneas, when compared with healthy eyes or eyes with primary open-angle glaucoma. The effect of central corneal thickness on Goldmann applanation tonometry accuracy appears to be small and usually not clinically relevant. When corneal thickness is markedly different from normal, the clinician may need to factor this into diagnosis and management.

Aged↗
PubMed2001

Triangular wire.

Explore the source record for details and available documents.

Humans↗
PubMed2001

Electroencephalogram-based scaling of multifocal visual evoked potentials: effect on intersubject amplitude variability.

PURPOSE: The interindividual variability of the visual evoked potential (VEP) has been recognized as a problem for interpretation of clinical results. This study examines whether VEP variability can be reduced by scaling responses according to underlying electroencephalogram (EEG) activity. METHODS: A multifocal objective perimeter provided different random check patterns to each of 58 points extending out to 32 degrees nasally. A multichannel VEP was recorded (bipolar occipital cross electrodes, 7 min/eye). One hundred normal subjects (age 58.9 +/- 10.7 years) were tested. The amplitude and inter-eye asymmetry coefficient for each point of the field was calculated. VEP signals were then normalized according to underlying EEG activity recorded using Fourier transform to quantify EEG levels. High alpha-rhythm and electrocardiogram contamination were removed before scaling. RESULTS: High intersubject variability was present in the multifocal VEP, with amplitude in women on average 33% larger than in men. The variability for all left eyes was 42.2% +/- 3.9%, for right eyes 41.7% +/- 4.4% (coefficient of variability [CV]). There was a strong correlation between EEG activity and the amplitude of the VEP (left eye, r = 0.83; P < 0.001; right eye, r = 0.82; P < 0.001). When this was used to normalize VEP results, the CVs dropped to 24.6% +/- 3.1% (P < 0.0001) and 24.0% +/- 3.2% (P < 0.0001), respectively. The gender difference was effectively removed. CONCLUSIONS: Using underlying EEG amplitudes to normalize an individual's VEP substantially reduces intersubject variability, including differences between men and women. This renders the use of a normal database more reliable when applying the multifocal VEP in the clinical detection of visual field changes.

Adult↗
PubMed2000

Objective perimetry in glaucoma.

PURPOSE: Objective perimetry in glaucoma is described using the multifocal pattern visually evoked potential (VEP). A multichannel recording technique was used to improve signal detection in healthy volunteers and assess its ability to detect glaucoma and early changes in patients with suspected glaucoma. DESIGN: Prospective, case-control study. PARTICIPANTS: Thirty healthy volunteers, 30 patients with suspected glaucoma, and 30 patients with glaucomatous visual field defects were tested. METHOD: The VEP was recorded using cortically scaled, multifocal, pseudorandomly alternated pattern stimuli with the VERIS system (Electro-Diagnostic Imaging, Inc., San Francisco, CA). An array of four bipolar occipital electrodes provided four differently oriented channels for simultaneous recording. Signals were compared for different locations within the field up to 26 degrees of eccentricity. Healthy volunteers, patients with suspected glaucoma, and glaucoma patients with established visual field defects were tested, and results were compared with Humphrey visual fields (Humphrey Systems, Dublin, CA) performed on the same day. For reproducibility, five healthy volunteers were each tested on four separate days. The patients with suspected glaucoma and the established glaucoma patients were analyzed for intereye asymmetry of signals, and these data were compared with the asymmetry values of the healthy volunteers. RESULTS: Multiple recording channels significantly enhanced the recording of signals from parts of the visual field not reliably sampled with a single channel technique in all healthy volunteers, particularly along the horizontal meridian (P: < 0.001). Signal amplitude did not decline with age in healthy volunteers. Recordings showed good reproducibility within individuals. In all 30 glaucoma patients, the Humphrey visual field defects were well demonstrated by the VEP, and topographic location was strongly correlated (r(s) = 0.79). Despite large interindividual variations in amplitude, scotomas were well demonstrated when compared with normal values. In the patients with suspected glaucoma, smaller changes in signal amplitude could be identified in parts of the field still normal on perimetry using intereye asymmetry analysis. CONCLUSIONS: The multifocal, multichannel VEP can objectively detect glaucomatous visual field defects. The nasal step region can be more reliably tested using multiple channels. Asymmetry analysis has the potential to detect early defects. This technique represents a significant step toward the clinical application of objective perimetry in glaucoma.

Adult↗
PubMed2000

Multifocal pattern electroretinogram does not demonstrate localised field defects in glaucoma.

PURPOSE: To determine if a multifocal PERG could be recorded in normals, and to examine changes in the multifocal PERG in glaucoma patients. To compare the ability of multifocal PERG and multifocal VEP responses in the same individuals to identify localised field defects in glaucoma. METHODS: Using the VERIS Scientific system multifocal PERGs were recorded from 19 sites of the visual field according to pseudo-random binary m-sequence. Twenty normals and 15 glaucoma subjects were tested. Multifocal pattern VEPs were also recorded in the glaucoma cases using a cortically scaled stimulus. RESULTS: The second order kernel of the PERG shows a consistent signal. The overall PERG amplitude decreases with age in normals. In glaucoma the PERG amplitude was reduced across the field, but reductions did not correspond to the area of the scotoma. The VEP showed localised signal reductions in all 15 cases of glaucoma. CONCLUSION: A multifocal PERG can be recorded in normals. However it did not reflect localised ganglion cell losses, whereas the multifocal pattern VEP recorded to a very similar stimulus in the same individual did show losses in the scotoma area.

Adult↗
PubMed2000

Objective VEP perimetry in glaucoma: asymmetry analysis to identify early deficits.

PURPOSE: The multifocal visual evoked potential (VEP) shows markedly symmetrical responses between the two eyes of control subjects. Patients with glaucoma and patients considered at high risk for glaucoma were examined to determine if VEP asymmetry could be identified and used for diagnosis and detection of early damage. METHODS: Multifocal pattern VEP recordings were performed using a single channel bipolar occipital electrode position and the Visual Evoked Response Imaging System (VERIS). There were 125 subjects: 24 control subjects, 70 patients with glaucoma, and 31 patients considered at high risk for glaucoma. A between-eye relative asymmetry coefficient (RAC) was determined for each of the 60 test points in the VEP field. The RAC for patients with glaucoma and patients considered at risk for glaucoma were compared with values from control subjects. Correlation between Humphrey thresholds and RAC scores was performed. RESULTS: Patients with glaucoma and patients considered at risk for glaucoma both showed significantly larger mean quadrant RAC values. When point by point analysis was performed, 69 out of 70 scotomas were identified with a cluster of at least 3 points of P < 0.05. For those considered at high risk for glaucoma, 10 out of 31 patients had abnormal areas in the VEP field. There was a strong correlation (r = 0.82) between quadrantic RAC mean values and Humphrey quadrant threshold scores in an asymmetric glaucoma subgroup. Abnormal VEP responses were identified in parts of the visual field that were still normal on perimetry. CONCLUSIONS: Asymmetry analysis correctly identifies patients with glaucomatous field loss and shows abnormalities in many patients considered at high risk for glaucoma who still have normal fields. Asymmetry analysis is able to identify objectively the extent of glaucomatous damage and may be able to detect changes before subjective field loss occurs.

Adolescent↗
PubMed2000

Comparison of the Humphrey swedish interactive thresholding algorithm (SITA) and full threshold strategies.

PURPOSE: To compare the Swedish interactive thresholding algorithm (SITA) strategy with the full threshold strategy in routine clinical practice. METHODS: Using the Humphrey visual field analyzer model 750 (Allergan Humphrey, San Leandro, CA), 108 subjects were tested with 24-2 SITA (version A9) and 24-2 full threshold strategies. Test results were compared for time taken and reliability and on the basis of seven criteria of abnormality. RESULTS: The SITA required on average 48.8% less time than the full threshold strategy. Patient reliability parameters were somewhat better with SITA. There was a strong correlation between mean deviation and pattern standard deviation. Average threshold sensitivity at each point was increased by 1.31 dB with SITA, but greater differences were seen at points with lower sensitivity. Using the full threshold strategy as our standard for comparison, the sensitivity of SITA varied from 83.0% to 93.2% in detecting the variously defined abnormalities. Fields shown as normal with full threshold strategy corresponded with those found to be normal with SITA in 79.0 to 96.3% cases depending on criteria for abnormality. There were a few cases in which SITA suggested an early abnormality but results of full threshold testing remained normal. On average, the size and depth of scotomas decreased slightly with SITA, but this difference was not statistically significant. Of the 70 patients surveyed about their preference, 65 (92.9%) preferred SITA. CONCLUSION: Full threshold and SITA strategies are comparable in detecting glaucomatous defects. The SITA strategy requires significantly less time to perform and is a satisfactory alternative to full threshold algorithms in clinical practice for diagnosis and management of glaucoma.

Adult↗