Biomedical subjects

Gordon C Tucker

Publications and source records attributed to Gordon C Tucker.

10 recordsLinked to original sources

PubMed2006

Blockade of alpha v beta3 and alpha v beta5 integrins by RGD mimetics induces anoikis and not integrin-mediated death in human endothelial cells.

Alpha v integrins are thought to play an important role in tumor angiogenesis. However, discrepancies between findings with Arg-Gly-Asp (RGD) mimetics, which block angiogenesis in animal models, and knockout mice, in which loss of some alpha v integrins enhances tumor angiogenesis, raise questions concerning the function of these integrins and the precise role of alpha v substrate mimetics in antiangiogenic therapies. We have examined the effects of a novel non-peptide RGD mimetic, S 36578-2, on human endothelial cells to elucidate its antagonist activity and to identify possible agonist functions. S 36578-2 is highly selective for alpha v beta3 and alpha v beta5 integrins and induces detachment, caspase-8 activation, and apoptosis in human umbilical endothelial cells (HUVECs) plated on vitronectin. Importantly, the compound has no effect on the morphology or survival of cells plated on interstitial matrix components such as fibronectin, and it does not potentiate the apoptotic process in suspended cells. Identical results were obtained with a cyclic RGD peptide with similar target specificity. In microvascular endothelial cells, S 36578-2-induced death was also linked to its antiadhesive effect, with established lines markedly more resistant than primary cultures to the antiadhesive and proapoptotic effects. Altogether, these findings have important implications for the development of this class of antiangiogenics.

Anoikis↗

PubMed2006

Integrins: molecular targets in cancer therapy.

Integrins are cell surface adhesion molecules coupling the extracellular environment to the cytoskeleton as well as receptors for transmitting signals important for cell migration, invasion, proliferation, and survival. At least six integrin inhibitors are being evaluated in clinical trials for cancer. Currently, patients with melanoma and glioblastoma multiforme benefit from Vitaxin (MedImmune, Gaithersburg, MD) or cilengitide treatment, respectively. Many phase II trials are being or have been conducted with these two compounds (the most advanced). Surprisingly, despite the broad theoretical impact of such molecules on integrin function, and thus on pathology, the clear identification of discrete clinical niches for their use remains to be defined. Possible reasons for this are discussed in this review. The parallel development of integrin antagonists as imaging tools for patient selection may accelerate the discovery of new avenues for their use.

Antibodies, Monoclonal↗

PubMed2004

Novel RGD-like molecules based on the tyrosine template: design, synthesis, and biological evaluation on isolated integrins alphaVbeta3/alphaIIbbeta3 and in cellular adhesion tests.

RGD (Arg-Gly-Asp) peptidomimetics have been designed for covalent anchorage on biomaterials. The tyrosine template was thus equipped with (i) a basic side chain of various flexibility, (ii) an acidic side chain, which incorporated the XPS fluorine tag, and (iii) a spacer-arm terminated by a primary amine for surface grafting. The most active compounds showed IC50 values in the nanomolar range versus isolated human integrins alphaVbeta3 and alphaIIbbeta3. Preincubation of CaCo2 cells with soluble peptidomimetics (2 and 19a) prevented cellular adhesion on culture plates coated with vitronectin. On the other hand, peptidomimetics (19a and 19b) immobilized on a poly(ethylene)terephthalate membrane (PET) promoted CaCo2 cells adhesion. A modeling study at the ab initio level in MINI-1' basis allowed to compare the various synthetic ligands of integrins and to propose novel pharmacophore structures.

Biomimetic Materials↗

PubMed2004

Synthesis of N,N'-disubstituted 3-aminobenzo[c] and [d]azepin-2-ones as potent and specific farnesyl transferase inhibitors.

A structure-activity study was performed by synthesis on N,N'-disubstitution of 3-aminobenzo[c] and [d]azepin-2-one 2 and 3 to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities.

Alkyl and Aryl Transferases↗

PubMed2003

Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors.

The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.

Administration, Oral↗

PubMed2003

Parallel liquid synthesis of N,N'-Disubstituted 3-amino azepin-2-ones as potent and specific farnesyl transferase inhibitors.

A rapid structure-activity study was performed by parallel liquid synthesis on N,N'-disubstitution of 3-amino azepin-2-one to afford potent and specific farnesyl transferase inhibitors with low nM enzymatic and cellular activities. The activities of the selected compounds were validated in vivo, and compounds 41a and 44a presented significant antitumour activity.

Alkyl and Aryl Transferases↗

PubMed2003

Decrease in survival threshold of quiescent colon carcinoma cells in the presence of a small molecule integrin antagonist.

The role of adhesion molecules, such as alphav integrins, in the control of the survival of quiescent tumor cells is unclear. We used S 34961, a novel small molecule alphav integrin antagonist, to investigate the role of integrin-signaling in the survival of populations of quiescent human HT-29 and HCT 116 colon carcinoma cells. S 34961 at 1 microM induced detachment, but cells retained viability, existing as clusters. Nonligated beta-integrins may recruit and activate caspase-8 [J Cell Biol 155:459-470, 2001]. However, congruent with the absence of apoptosis, no activation of caspase-8 in these cells was detected after incubation with S 34961. A rapid (2 h) change in conformation of the N terminus of proapoptotic Bak was observed before detachment, together with a decrease in phosphorylation of focal adhesion kinase (2 h) and subsequent (8 h) decreases in phosphorylation of extracellular signal-regulated kinase-1/2 and Akt. Together, these results suggested that although treatment with S 34961 has no effect on survival per se, it may reduce the survival threshold of the tumor cells, with Bak in an activated state. Indeed, concomitant incubation of S 34961 with 10 microM U-0126 (a mitogen-activated protein kinase kinase inhibitor) was found to lead to apoptosis (at 24 h), whereas U-0126 alone had no effect. Together, these observations could guide the use of combination therapy with integrin antagonists in the clinic.

Apoptosis↗

PubMed2003

Alpha v integrin inhibitors and cancer therapy.

Recent gene disruption experiments have suggested that targeting the alpha v integrins (cell surface adhesion and signaling receptors) to prevent tumor progression can result in different outcomes depending on the strategy. Nevertheless, two alpha v binding antagonists have made their way to the clinic in the oncology field; both Vitaxin, a humanized antibody, and cilengitide, a cyclic peptide mimicking the RGD ligand recognition peptidic domain common to alpha v integrin ligands, are in phase II clinical trials. This year, development of another peptidic inhibitor was initiated. This review questions whether companies are reluctant to propose small synthetic heterocyclic inhibitors as successors to peptide-derived agents with better pharmacokinetics and oral bioavailability. Is this class of compounds immediably flawed like the platelet alpha IIb beta 3 oral antagonists? Tentative answers are provided in this review following description of the lead compounds and the rationale for their use as cancer treatments, imaging agents or drug targeting vectors.

Animals↗

PubMed2002

Substituted benzocyloheptenes as potent and selective alpha(v) integrin antagonists.

A novel series of potent and specific alpha(v) integrin antagonists has been obtained by aminoalkyl substitutions on benzocyloheptene acetic acids as a rigid GD bioisostere. The preferred compounds 1-2, 1-3 and 1-8, showed nano- to subnanomolar IC(50) values on alpha(v)beta(3) and alpha(v)beta(5) integrins, with favorable pharmacokinetics.

Animals↗

PubMed2002

Inhibitors of integrins.

The inhibition of integrins--cell surface receptors with a crucial role in angiogenesis, tumour cell survival, invasion and metastases--has centred on the alpha(v)beta3 integrin. Work has culminated in two antagonists that are in clinical trials as cancer therapeutics. Other integrins appear to be candidate targets in the light of gene knockout studies. Surprisingly, genetic alpha(v)beta3 ablation did not confirm the pertinence of the use of alpha(v)beta3 antagonists. However, these apparent discrepancies could be explained by the new finding that this integrin has a role as a cell survival sensor, limiting rather than promoting angiogenesis. Accumulating data on the role of integrins and the mechanism of action of pharmacological antagonists will help to develop and apply an efficient anti-integrin therapy in cancer.

Animals↗