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Biomedical subjects

S H Rosenberg

Publications and source records attributed to S H Rosenberg.

At least 19 recordsLinked to original sources
PubMed2007

Bcl-2 family proteins are essential for platelet survival.

Platelets are relatively short-lived, anucleated cells that are essential for proper hemostasis. The regulation of platelet survival in the circulation remains poorly understood. The process of platelet activation and senescence in vivo is associated with processes similar to those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, and cell shrinkage. ABT-737, a potent antagonist of Bcl-2, Bcl-X(L), and Bcl-w, induces apoptosis in nucleated cells dependent on these proteins for survival. In vivo, ABT-737 induces a reduction of circulating platelets that is maintained during drug therapy, followed by recovery to normal levels within several days after treatment cessation. Whole body scintography utilizing ([111])Indium-labeled platelets in dogs shows that ABT-737-induced platelet clearance is primarily mediated by the liver. In vitro, ABT-737 treatment leads to activation of key apoptotic processes including cytochrome c release, caspase-3 activation, and PS externalization in isolated platelets. Despite these changes, ABT-737 is ineffective in promoting platelet activation as measured by granule release markers and platelet aggregation. Taken together, these data suggest that ABT-737 induces an apoptosis-like response in platelets that is distinct from platelet activation and results in enhanced clearance in vivo by the reticuloendothelial system.

Animals↗
PubMed2001

New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models.

During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.

Animals↗
PubMed2001

A-204197, a new tubulin-binding agent with antimitotic activity in tumor cell lines resistant to known microtubule inhibitors.

Drug resistance is a prevalent problem in the treatment of neoplastic disease, and the effectiveness of many clinically useful drugs is limited by the fact that they are substrates for the efflux pump, P-glycoprotein. Because there is a need for new compounds that are effective in treating drug-resistant tumors, we tested A-204197 (4-[4-acetyl-4,5-dihydro-5-(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-N,N-dimethylbenzeneamine), a novel oxadiazoline derivative with antiproliferative properties, on cell lines that were either sensitive or resistant to known microtubule inhibitors. Cell lines that were resistant to paclitaxel, vinblastine, or colchicine were equally sensitive to A-204197 (proliferation IC50s ranging from 36 to 48 nM) despite their expression levels of P-glycoprotein. The effect of A-204197 on cell growth was associated with cell cycle arrest in G2-M, increased phosphorylation of select G2-M checkpoint proteins, and apoptosis. In competition-binding assays, A-204197 competed with [3H]-labeled colchicine for binding to tubulin (K(i) = 0.75 microM); however, it did not compete with [3H]-labeled paclitaxel. A-204197 prevented tubulin polymerization in a dose-dependent manner (IC50 = 4.5 microM) in vitro and depolymerized microtubules in a time-dependent manner in cultured cells. These findings indicate A-204197 is a promising new tubulin-binding compound with antimitotic activity that has potential for treating neoplastic diseases with greater efficacy than currently used antimitotic agents.

Antineoplastic Agents↗
PubMed2000

Modulation of drug resistance by alpha-tubulin in paclitaxel-resistant human lung cancer cell lines.

Beta(beta)-tubulin isotype variation has recently been implicated in the modulation of resistance to paclitaxel in human lung cancer cells and in primary human ovarian tumour samples. Whether alpha-tubulin is involved in drug resistance has not been reported. We have generated a paclitaxel-resistant cell line (H460/T800) from the sensitive human lung carcinoma parental cell line NCI-H460. The resistant cells are more than 1000-fold resistant to taxol and overexpress P-glycoprotein. Interestingly, H460/T800 cells also overexpress alpha- and beta-tubulin as detected by Western blot analysis. From Northern blot analysis, the mechanism of tubulin overexpression appears to be post-transcriptional. To understand whether alpha-tubulin plays a role in drug resistance, we transfected antisense human kalpha1 cDNA construct into the H460/T800 paclitaxel-resistant cells. The antisense clones displayed a reduced alpha-tubulin expression, and the cells were 45-51% more sensitive to paclitaxel and other known antimitotic drugs, compared with vector transfected controls. Complementary experiments of transfecting the sense kalpha1 cDNA into H460 cells conferred a 1.8- to 3.3-fold increase in the IC(50) of several antimitotic agents. Our study suggests that alpha-tubulin is one of the factors that contributes to drug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Rapid colchicine competition-binding scintillation proximity assay using biotin-labeled tubulin.

We have developed a rapid [3H]colchicine competition-binding scintillation proximity assay (SPA) to evaluate antimitotic compounds that bind to the colchicine-binding site on tubulin. The premise of our assay is that compounds will compete with radiolabeled colchicine for the tubulin-binding domain. Biotin-labeled tubulin is incubated first with unlabeled compound and radiolabeled ligand. Streptavidin-labeled SPA beads are added, and the radiolabel associated with tubulin is directly counted with no separation steps. Under our experimental conditions, the dissociation constant of binding (Kd) for colchicine to tubulin was determined to be 1.4 microM, which was consistent with previously reported values. Assay validation was performed by competitively inhibiting [3H]colchicine binding to tubulin with known microtubule inhibitors and comparing their inhibition constants (Ki). Our SPA bead method is a powerful tool since it overcomes the disadvantage of traditional filtration techniques, as there are no separation steps. It is extremely easy to set up, multiple samples can be assayed and supply and labor costs are reduced because of the minimal volume and test reagents used.

Aminophenols↗
PubMed1999

Discovery of a series of cyclohexylethylamine-containing protein farnesyltransferase inhibitors exhibiting potent cellular activity.

Synthesis of a library of secondary benzylic amines based on the Sebti-Hamilton type peptidomimetic farnesyltransferase (FTase) inhibitor FTI-276 (1) led to the identification of 6 as a potent enzyme inhibitor (IC(50) of 8 nM) which lacked the problematic thiol residue which had been a common theme in many of the more important FTase inhibitors reported to date. It has previously been disclosed that addition of o-tolyl substitution to FTase inhibitors of the general description 2 had a salutary effect on both FTase inhibition and inhibition of Ras prenylation in whole cells. Combination of these two observations led us to synthesize 7, a potent FTase inhibitor which displayed an IC(50) of 0.16 nM for in vitro inhibition of FTase and an EC(50) of 190 nM for inhibition of whole cell Ras prenylation. Modification of 7 by classical medicinal chemistry led to the discovery of a series of potent FTase inhibitors, culminating in the identification of 25 which exhibited an IC(50) of 0.20 nM and an EC(50) of 4.4 nM. In vivo tests in a nude mouse xenograft model of human pancreatic cancer (MiaPaCa cells) showed that oral dosing of 25 gave rise to impressive attenuation of the growth of this aggressive tumor cell line.

Alkyl and Aryl Transferases↗
PubMed1999

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.

Alkyl and Aryl Transferases↗
PubMed1999

Potent and orally bioavailable noncysteine-containing inhibitors of protein farnesyltransferase.

Potent and orally bioavailable nonthiol-containing inhibitors of protein farnesyltransferase are described. Oral bioavailability was achieved by replacement of the pyridyl ether moiety of 1 with a 2-substituted furan ether to give 4. Potency was regained with 2,5-disubstituted furan ethers while maintaining the bioavailability inherent in 4. p-Chlorophenylfuran ether 24 is 0.7 nM in vitro (FTase) and is 32% bioavailable in the mouse, 30% bioavailable in rats, and 21% bioavailable in dogs.

Alkyl and Aryl Transferases↗
PubMed1999

Effect of novel CAAX peptidomimetic farnesyltransferase inhibitor on angiogenesis in vitro and in vivo.

Ras oncogenes can contribute to tumour development by stimulating vascular endothelial growth factor (VEGF)-dependent angiogenesis. The effect of Ras on angiogenesis may be affected by farnesyltransferase inhibitors (FTI) since farnesylation of Ras is required for its biological activity. In this paper we evaluated the effect of A-170634, a novel and potent CAAX FTI on angiogenesis. Human umbilical vein endothelial cell (HUVEC) tube formation and VEGF secretion were used to assess the effect of A-170634 on angiogenesis in vitro. In vivo, nude mice were injected with the K-ras mutant colon carcinoma cell line HCT116 and treated subcutaneously with A-170634 using osmotic minipump infusion for 10 days. The effect of A-170634 on corneal angiogenesis in vivo was assessed using pellets containing hydron, VEGF, A-170634 or vehicle. In vitro, A-170634 selectively inhibited farnesyltransferase activity over the closely related geranylgeranyltransferase I, inhibited Ras processing, blocked anchorage-dependent and -independent growth of HCT116 K-ras mutated cells, decreased HUVEC capillary structure formation, decreased VEGF secretion from tumour cells and HUVEC growth stimulating activity in a dose-dependent manner. In vivo, tumour growth was decreased by 30% and vascularisation in and around the tumours was reduced by 41% following drug-treatment with no apparent toxicity to the animals. VEGF-induced corneal neovascularisation was reduced by 80% following A-170634 treatment for 7 days. The data presented here demonstrated that A-170634 was a potent and selective peptidomimetic CAAX FTI with anti-angiogenic properties. These results implied that A-170634 may affect tumour growth in vivo by one or more antitumour pathways.

Alkyl and Aryl Transferases↗
PubMed1999

Synergistic effect of paclitaxel and 4-hydroxytamoxifen on estrogen receptor-negative colon cancer and lung cancer cell lines.

Antiestrogen tamoxifen (Tam) is the most prescribed drug for the treatment of estrogen receptor (ER)-positive breast cancers. It is also used in long-term clinical trials with encouraging preliminary results as a chemopreventive agent for breast cancer. The effect of Tam on ER-negative cancers, however, is unclear. Here we reported that paclitaxel and 4-hydroxytamoxifen (4-HT) have a synergistic cytotoxic effect on the ER-negative colon cancer cell line HCT15, which is refractory to paclitaxel alone. Our results showed that 4-HT at submicromolar concentrations effectively enhanced the antiproliferative effect of paclitaxel. In addition, at 1/10 of the paclitaxel concentrations used for HCT15, 4-HT and paclitaxel also showed synergistic effect on NCI H460, an ER-negative lung cancer cell line. For both cell lines, the effective concentration for paclitaxel to inhibit cell growth was 1 log lower in the combination treatment than the concentration used in the single treatment. Cell cycle analysis showed that the combination of paclitaxel and 4-HT increased the G2/M population and resulted in the increase of apoptosis in both cell lines. Enhanced early release of cytochrome c from mitochondria may be the apoptotic pathway activated in the combination treatment in HCT15 cells.

Adenocarcinoma↗
PubMed1995

Renin inhibitors.

Explore the source record for details and available documents.

Angiotensin II↗
PubMed1994

Renin inhibitors: C-terminal oxetanes as potent transition-state mimics.

A novel transition-state mimic containing a C-terminal oxetane has been developed. Renin inhibitors incorporating this fragment exhibit enhanced potency against human plasma renin at physiological pH. The binding affinity of this new species has allowed size reductions at other sites.

Dipeptides↗
PubMed1993

Studies directed toward the design of orally active renin inhibitors. 1. Some factors influencing the absorption of small peptides.

A systematic evaluation of structure-absorption relationships using a high throughput intraduodenal rat screening model has led to the delineation of a set of structural parameters that appear to govern bioavailability in a series of peptide-based renin inhibitors. Optimum structures, exemplified by 25 and 41, incorporated a single, solubilizing substituent at the C- or N-terminus combined with a lipophilic P2-site residue. Both inhibitors gave unprecedented plasma drug levels upon intraduodenal administration to monkeys, and the calculated bioavailability for 41 (14 +/- 4%) is the highest reported for any peptidic renin inhibitor.

Animals↗
PubMed1993

Studies directed toward the design of orally active renin inhibitors. 2. Development of the efficacious, bioavailable renin inhibitor (2S)-2-benzyl-3- [[(1-methylpiperazin-4-yl)sulfonyl]propionyl]-3-thiazol-4-yl-L-alanine amide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (A-72517).

Employing a set of empirical guidelines for the design of well-absorbed renin inhibitors, we have followed two strategies to improve potency while maintaining bioavailability. One process involved incorporation of an extended N-terminal residue bearing a weakly basic substituent and is exemplified by compound 25. The other approach centered on the inclusion of an N-terminal sulfonamide and culminated in the discovery of inhibitor 32 (A-72517). Both 25 and 32 showed excellent bioavailability in the rat and ferret (> 25%) and, while subject to hepatic elimination in the monkey, were efficacious in this species.

Animals↗