2-substituted piperazines as constrained amino acids. Application to the synthesis of potent, non carboxylic acid inhibitors of farnesyltransferase.
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Alkyl and Aryl Transferases↗
Biomedical subjects
S L Graham
Publications and source records attributed to S L Graham.
Farnesyltransferase inhibitors and anti-Ras therapy.
The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic precursor which requires posttranslational processing to attain biological activity; farnesylation of the cysteine residue present in the CaaX motif located at the carboxy-terminus of all Ras proteins is the critical modification. Once farnesylated and further modified, the mature Ras protein is inserted into the cell's plasma membrane where it participates in the signal transduction pathways that control cell growth and differentiation. The farnesylation reaction that modifies Ras and other cellular proteins having an appropriate CaaX motif is catalyzed by a housekeeping enzyme termed farnesyl-protein transferase (FPTase). Inhibitors of this enzyme have been prepared by several laboratories in an effort to identify compounds that would block Ras-induced cell transformation and thereby function as Ras-specific anticancer agents. A variety of natural products and synthetic organic compounds were found to block farnesylation of Ras proteins in vitro. Some of these compounds exhibit antiproliferative activity in cell culture, block the morphological alterations associated with Ras-transformation, and can block the growth of Ras-transformed cell lines in tumor colony-forming assays. By contrast, these compounds do not affect the growth or morphology of cells transformed by the Raf or Mos oncoproteins, which do not require farnesylation to achieve biological activity. The efficacy and lack of toxicity observed with FPTase inhibitors in an animal tumor model suggest that specific FPTase inhibitors may be useful for the treatment of some types of cancer.
Alkyl and Aryl Transferases↗
Farnesyltransferase inhibitors: a new class of cancer chemotherapeutics.
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Alkyl and Aryl Transferases↗
Activated protein C resistance--low incidence in glaucomatous optic disc haemorrhage and central retinal vein occlusion.
PURPOSE: Activated protein C (APC) resistance has recently been reported as conferring a sevenfold increase in the risk of venous thrombosis. It is linked to a genetic mutation in the factor V gene which occurs commonly (about 2% to 4% of the community have the mutation). Glaucoma patients with nerve fibre layer (NFL) haemorrhages on the optic disc and patients with central retinal vein occlusion (CRVO) were tested for APC resistance to determine if there was an association. METHODS: Twenty-three patients with glaucomatous NFL haemorrhages and 23 patients with CRVO were tested. The CRVO cases included 11 with relatively young age of onset (mean 45.1 +/- 6.9 years) without conventional vascular risk factors. Eighty randomly selected Red Cross blood donor samples and 33 staff members were tested as controls. Clotting times with and without exogenous APC were recorded and an APC ratio determined. Cases with APC resistance were tested to confirm that they had the factor V Leiden gene. RESULTS: No cases of APC resistance were identified in the glaucoma patients and only one of the younger CRVO patients tested positive, but four of 113 controls tested positive. The difference in prevalence between groups is not significant. The mean APC ratios for the three groups were very similar: NFL haemorrhages 5.46(+/- 1.62), CRVO 5.70(+/- 1.56), controls 5.34 ( +/- 1.19) p > 0.5. CONCLUSION: There was not clear association detected between glaucomatous NFL haemorrhages or CRVO and APC resistance in this sample of patients. This negative finding is important due its known association with venous thrombosis elsewhere in the body.
Adult↗
Geographical distribution of risk factors and incidence of invasive cervical cancer in south east China.
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Carcinoma, Squamous Cell↗
Contrast sensitivity for flickering and static letters and visual acuity at isoluminance in glaucoma.
PURPOSE: Psychophysical testing was used to assess the effects of early glaucomatous damage on visual functions mediated by the magnocellular and parvocellular pathways. METHODS: We studied 57 eyes with early glaucoma, 92 eyes suspect for glaucoma, and 88 normal eyes. Tests were designed to target the functions of the magnocellular (M) or the parvocellular (P) pathways, and included measurements of contrast sensitivity for letter recognition, using both static presentation, and counterphase modulation at 25 Hz. We assumed that ability to perform the latter task would depend on the integrity of the M-cell pathway. To evaluate P-cell function we measured spatial acuity for a green letter presented against an isoluminant white background. Tests were carried out in the fovea, and at 3 degrees nasal, superior, temporal and inferior to the fovea. RESULTS: Glaucomatous eyes showed, on average, defects in almost all of the functions tested. Threshold elevations for static and isoluminant presentations were generally as large as those for flickering stimuli. The inferior paracentral part of the retina was generally more severely affected than the other locations tested. The defects observed in the suspect population were similar to, although smaller in magnitude than, those found in eyes with glaucoma. A discriminant analysis identified a subset of five tests, including P as well as M pathway tests, which was able to correctly classify 89% of normal and 79% of glaucomatous eyes. CONCLUSIONS: Putative M- and P-cell functions are both impaired at a relatively early stage of glaucoma. Deficits for both types of test are most severe in the inferior paracentral area of the retina (superior visual fields). Psychophysically based detection of the condition can benefit if results from different tests, done at different retinal locations, are combined.
Adult↗
Comparison of psychophysical and electrophysiological testing in early glaucoma.
PURPOSE: To compare the sensitivity and specificity of a wide range of psychophysical and electrophysiological tests in the detection of early glaucomatous damage. METHODS: Forty-three normals and 43 patients with early glaucoma, some still without field defects, were tested with differential light threshold perimetry, short-wavelength automated perimetry, high-pass resolution perimetry, motion detection, flicker contrast sensitivity, flickering and isoluminantly matched letter tests, and pattern and flash electroretinography, including photopic, scotopic, oscillatory potentials, and 30 Hz flicker. Receiver operating characteristic analysis was applied to continuous variables derived from each of the tests. RESULTS: Most parameters reflected glaucomatous loss to some degree, even though only single variables were analyzed separately in the receiver operating characteristic analysis. The pattern electroretinogram and some of the letter acuity tests had the best sensitivity and specificity, followed by short-wavelength automated perimetry and high-pass resolution-perimetry. Motion detection, flicker contrast, and flash electroretinogram parameters scored poorly. Six patients with normal results on the Humphrey field test had abnormal results on many of the other tests. CONCLUSIONS: Applying different psychophysical and electrophysiological tests may add to our ability to detect early glaucomatous damage.
Contrast Sensitivity↗
Pseudodipeptide inhibitors of protein farnesyltransferase.
A series of pseudodipeptide amides are described that inhibit Ras protein farnesyltransferase (PFTase). These inhibitors are truncated versions of the C-terminal tetrapeptide (CAAX motif) of Ras that serves as the signal sequence for PFTase-catalyzed protein farnesylation. In contrast to CAAX peptidomimetics previously reported, these inhibitors do not have a C-terminal carboxyl moiety, yet they inhibit farnesylation in vitro at < 100 nM. Despite the absence of the X residue in the CAAX motif, which normally directs prenylation specificity, these pseudodipeptides are greater than 100-fold selective for PFTase over type 1 protein geranylgeranyltransferase.
3T3 Cells↗
Development of inhibitors of protein farnesylation as potential chemotherapeutic agents.
Protein prenylation, adding either the 15-carbon isoprenoid farnesyl or the 20-carbon isoprenoid geranylgeranyl to cysteine residue(s) at or near the C-termini of proteins, is a recently identified post-translational modification that localizes some proteins to a membrane compartment. One of the most intensely studied prenylated proteins is Ras, a low molecular weight GTP-binding protein that plays an important role in the regulation of cell proliferation. Proteins encoded by ras genes with oncogenic mutations are capable of transforming cells in culture. Such mutated ras genes are frequently found in a wide variety of human tumors. Localization of the Ras oncoprotein to the cytoplasmic face of the plasma membrane via farnesylation is essential for efficient cell transforming ability. Thus, inhibition of the Ras farnesylation reaction is a possible anti-cancer strategy. Several strategies have been employed to inhibit Ras farnesylation, including inhibition of isoprenoid biosynthesis and inhibition of the enzyme which catalyzes the farnesylation reaction, farnesyl-protein transferase (FPTase). Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate limiting enzyme in isoprenoid biosynthesis, inhibit Ras farnesylation and block the growth of ras-transformed cells. However, antiproliferative effects do not result from specific inhibition of Ras farnesylation; they are also observed in cells transformed by raf, which is independent of Ras farnesylation. A more specific approach to inhibiting Ras farnesylation is to inhibit FPTase. Using random screening of natural products and a rational design approach, a variety of compounds that specifically inhibit FPTase have been isolated.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Interpretation of high-pass resolution perimetry with a probability plot.
BACKGROUND: The interpretation of high-pass resolution perimetry (HRP) fields can be difficult. An age-related probability plot was derived from a known data base to determine whether this improved specificity and sensitivity in early glaucoma detection. METHODS: Forty glaucoma patients with minor field loss and 40 normals of equivalent age and sex underwent HRP. All had previous Humphrey field data available for comparison. The detection of previously confirmed field defects by HRP was examined using different parameters. RESULTS: Using the age-corrected 95% confidence levels gave the best results, with sensitivity of 82.5% (33/40) and specificity of 85% (34/40). Using the contour plot yielded lower sensitivity (67.5%), while subjectively "eyeballing" the ring printout gave higher sensitivity (90%), but led to poor specificity (72.5%). CONCLUSION: The use of a probability plot enhances the performance of HRP. A certain proportion of cases may be missed using one criterion alone, but combining the information with other indices can increase the yield.
Adult↗
Effect of repeat use and coating defects of gold foil electrodes on electroretinogram recording.
Qualitative defects and resistances in 94 used gold foil electrodes were examined. The electrodes were divided into four groups of varying resistances and gold coating defects. Ten were randomly selected from each group to measure standard photopic electroretinograms (ERGs) in a normal subject. Ten new electrodes were used as controls. There was no significant difference among the electrode groups for ERG peak implicit times or amplitudes, although a slightly greater amplitude variability was observed for the groups with more defects. Provided the resistance of the electrode is low ( < 5 omega), its reuse at least for ganzfeld ERGs appears warranted regardless of apparent coating defects.
Electric Impedance↗
Flash and pattern electroretinogram changes with optic atrophy and glaucoma.
We investigated recent reports that, contrary to common belief, glaucoma can affect flash as well as pattern electroretinograms. An extensive flash and pattern electroretinogram test protocol was used in a large sample of glaucoma patients and age-matched controls who were either visually normal or had other optic nerve diseases. All electroretinogram parameters were reduced and delayed in normal people > 55 years of age. The effect did not increase in later decades. In patients aged < or = 55 years, flash electroretinograms showed mild reductions and delays from optic atrophy alone. Glaucomatous ERG changes were larger and increased with disease severity. Pattern electroretinograms and oscillatory potentials were almost equally reduced in optic atrophy and all degrees of glaucoma. Mildly affected patients > 55 years of age had similar electroretinogram change to age-matched normals in most conditions. Advanced glaucoma patients showed similar differences from normal irrespective of age. This suggests that direct diagnostic application of these results to older patients will be difficult, that the ERG changes in glaucoma cannot be attributed simply to optic atrophy and that additional widespread outer retinal damage occurs in glaucoma.
Age Factors↗
Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip.
PURPOSE: Hypoperfusion of the optic nerve head may be among the significant factors relating to glaucoma damage. The physiologic nocturnal blood pressure "dip" may be exaggerated in some patients and may compromise local vascular supply. METHODS: Twenty-four-hour ambulatory blood pressure recording was performed on 38 patients with normal-tension glaucoma and on 46 with primary open-angle glaucoma. Eleven control subjects of similar age also were tested. The means of the systolic and diastolic blood pressures, mean arterial pressure, and pulse pressure for 24 hours, taken during the daytime (6 AM-10 PM) and night (10 PM-6 AM) periods were determined. The percentage nocturnal dip for each patient was calculated. A masked assessment of Humphrey visual fields for progression or stability was done on those 52 patients who had numerous fields plotted for more than 2 years. RESULTS: The results of the control subjects confirmed that the authors' technique produces values similar to cardiologic studies from large healthy populations. The mean results from all the authors' patients with glaucoma were within the ranges reported for control subjects in the literature. The blood pressure parameters of the normal-tension glaucoma and primary open-angle glaucoma groups did not differ significantly. All nocturnal pressure parameters (except pulse pressure) were lower in the 37 patients with progressive field defects compared with the 15 patients whose pressure parameters were stable, whereas the systolic, diastolic, and mean arterial pressure dips were significantly larger (systolic dip, P = 0.001). CONCLUSION: The nocturnal reduction in blood pressure may be an additional risk factor in patients with glaucoma.
Aged↗
Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice.
For Ras oncoproteins to transform mammalian cells, they must be post-translationally modified with a farnesyl group in a reaction catalysed by the enzyme farnesyl-protein transferase (FPTase). Inhibitors of FPTase have therefore been proposed as anti-cancer agents. We show that L-744,832, which mimics the CaaX motif to which the farnesyl group is added, is a potent and selective inhibitor of FPTase. In MMTV-v-Ha-ras mice bearing palpable tumours, daily administration of L-744,832 caused tumour regression. Following cessation of treatment, tumours reappeared, the majority of which regressed upon retreatment. No systemic toxicity was found upon necropsy of L-744,832-treated mice. This first demonstration of anti-FPTase-mediated tumour regression suggests that FPTase inhibitors may be safe and effective anti-tumour agents in some cancers.
Alkyl and Aryl Transferases↗
Incomplete Reiter's syndrome with focal involvement of the posterior segment.
PURPOSE: To describe an unusual variant of Yersinia-induced, HLA-B27 associated incomplete Reiter's syndrome with focal involvement of the posterior segment. METHODS: Review of case records of a patient presenting with incomplete Reiter's syndrome which included a reactive arthritis with keratoconjunctivitis and anterior uveitis. RESULTS: The uveitis progressed to involve the posterior segment with a vitritis and two transient white retinal spots. After resolving, a retinal pigment epithelial (RPE) defect persisted at the site of one of the lesions. CONCLUSIONS: While involvement of the anterior segment of the globe in Reiter's disease is well recognised, a review of the literature reveals that focal posterior involvement is a rare feature in either Reiter's syndrome or the reactive arthritis group.
Adult↗
Pseudopeptide inhibitors of Ras farnesyl-protein transferase.
Inhibitors of Ras farnesyl-protein transferase are described. These are reduced pseudopeptides related to the C-terminal tetrapeptide of the Ras protein that signals farnesylation. Deletion of the carbonyl groups between the first two residues of the tetrapeptides either preserves or improves activity, depending on the peptide sequence. The most potent in vitro enzyme inhibitor described (IC50 = 5 nM) is Cys [psi CH2NH]Ile[psi CH2NH]Phe-Met (3). To obtain compounds able to suppress Ras farnesylation in cell culture, further structural modification to include a homoserine lactone prodrug was required. Compound 18 (Cys[psi CH2NH]Ile[psi CH2NH]Ile-homoserine lactone) reduced the extent of Ras farnesylation by 50% in NIH3T3 fibroblasts in culture at a concentration of 50 microM. Structure-activity studies also led to 12 (Cys[psi CH2NH]Val-Ile-Leu), a potent and selective inhibitor of a related enzyme, the type-I geranylgeranyl protein transferase.
Alkyl and Aryl Transferases↗
Synthesis and biological activity of ras farnesyl protein transferase inhibitors. Tetrapeptide analogs with amino methyl and carbon linkages.
Replacement of the central amino methylene linkage of C[psi CH2NH]A[psi CH2NH]AX tetrapeptide inhibitors with carbon tethers led to compounds with potency in the nanomolar range. Some of the more potent olefinic compounds inhibit Ras processing in intact v-ras transformed NIH 3T3 cells with IC50 values in the 0.1 to 1 microM range, and inhibit selectively the anchorage-independent growth of H-ras transformed Rat1 cells at 10 microM.
3T3 Cells↗