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E Maxwell

Publications and source records attributed to E Maxwell.

18 recordsLinked to original sources
PubMed2001

The farnesyl transferase inhibitor SCH 66336 induces a G(2) --> M or G(1) pause in sensitive human tumor cell lines.

SCH 66336 is a potent farnesyl transferase inhibitor (FTI) in clinical development. It efficiently prevents the membrane association of H-ras, but not K- or N-ras. Yet, in soft agar, it reverts the anchorage-independent growth of human tumor cell lines (hTCLs) harboring H-ras, K-ras, and N-ras mutations, implying that blocking farnesylation of proteins besides ras may be responsible for this effect. Experiments show that SCH 66336 altered the cell cycle distribution of sensitive human tumor cells in two distinct ways. Most sensitive hTCLs accumulated in the G(2)-->M phase after the FTI treatment, but those with an activated H-ras accumulated in G(1) phase, suggesting that the biological effects induced by FTIs in cells with an activated H-ras are distinct from other sensitive cells. A careful genotypic comparison of the hTCLs revealed that those cells with wild-type p53 are especially sensitive to the FTIs. In these cells p53 and its downstream target gene p21(Cip1) are induced after treatment with SCH 66336 for 24 h. These data suggest that cell cycle effects, either G(1) or G(2)-->M accumulation, and p53 status are important for mediating the effects of FTIs on tumor cells.

3T3 Cells↗
PubMed2001

Raised white cell count in a sick adult.

A 57 year old man presents to the emergency department in acute pulmonary oedema. Examination reveals evidence of left heart failure, 1-2 cm cervical, axillary and inguinal lymph nodes and mild splenomegaly. A full blood examination is listed in Table 1.

Humans↗
PubMed2000

A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5.

HIV-1 entry into CD4(+) cells requires the sequential interactions of the viral envelope glycoproteins with CD4 and a coreceptor such as the chemokine receptors CCR5 and CXCR4. A plausible approach to blocking this process is to use small molecule antagonists of coreceptor function. One such inhibitor has been described for CCR5: the TAK-779 molecule. To facilitate the further development of entry inhibitors as antiviral drugs, we have explored how TAK-779 acts to prevent HIV-1 infection, and we have mapped its site of interaction with CCR5. We find that TAK-779 inhibits HIV-1 replication at the membrane fusion stage by blocking the interaction of the viral surface glycoprotein gp120 with CCR5. We could identify no amino acid substitutions within the extracellular domain of CCR5 that affected the antiviral action of TAK-779. However, alanine scanning mutagenesis of the transmembrane domains revealed that the binding site for TAK-779 on CCR5 is located near the extracellular surface of the receptor, within a cavity formed between transmembrane helices 1, 2, 3, and 7.

Amides↗
PubMed2000

Type 2B von Willebrand's disease in thirteen individuals from five unrelated Australian families: phenotype and genotype correlations.

Type 2B von Willebrand's disease (VWD) is due to a qualitative defect in von Willebrand factor (VWF) in which there is an increased affinity for the platelet glycoprotein Ib-IX-V receptor complex. Spontaneous binding of type 2B VWF to platelets and subsequent clearance from the plasma is thought to account for the characteristic phenotype of type 2B VWD. These gain-of-function mutations are due to single amino substitutions that are clustered within the functionally important A1 domain of VWF. We describe 13 individuals from five unrelated families in Australia with type 2B VWD, report their phenotypic abnormalities, and delineate their causative mutations. We confirm that the mutation Arg543Trp is also particularly common among families with type 2B VWD in Australia.

Amino Acid Substitution↗
PubMed1999

Integrin alpha(v)beta(3)-mediated activation of apoptosis.

The alpha(v)beta(3) integrin mediates endothelial cell binding to the extracellular matrix and transduces an intracellular signal promoting survival of endothelial cells and various tumor cells. While the alpha(v)beta(3) integrin-mediated survival signal has been shown to be adhesion dependent, a thorough analysis has not been performed comparing the biochemical effects of antagonist binding to alpha(v)beta(3) integrin with the effects induced by the growth of cells in suspension. In this study we demonstrate that expression of alpha(v)beta(3) integrin in human embryonic kidney 293 cells transfers the alpha(v)beta(3) integrin survival pathway to an epithelial cell line. Furthermore, we show that alpha(v)beta(3) integrin-expressing cells respond differently to alpha(v)beta(3) integrin-specific antagonist treatment and growth in suspension conditions. Treatment with the alpha(v)beta(3) antagonist echistatin resulted in an apoptotic response occurring prior to cell detachment and was not observed in either suspended cells or antagonist-treated suspended cells. These data suggest that the death induced by antagonist binding to alpha(v)beta(3) integrin results in an apoptotic signal with different kinetics than the apoptotic signal induced by matrix detachment (anoikis). Since aberrant alpha(v)beta(3) integrin expression in tumor models is thought to play a role in tumor cell survival, these data have implications for the use of alpha(v)beta(3) antagonists as anti-tumor agents.

Annexin A5↗
PubMed1999

The CC-chemokine RANTES increases the attachment of human immunodeficiency virus type 1 to target cells via glycosaminoglycans and also activates a signal transduction pathway that enhances viral infectivity.

We have studied the mechanisms by which the CC-chemokine RANTES can enhance the infectivities of human immunodeficiency virus type 1 (HIV-1) and other enveloped viruses, when present at concentrations in excess of 500 ng/ml in vitro. Understanding the underlying mechanisms might throw light on fundamental processes of viral infection, in particular for HIV-1. Our principal findings are twofold: firstly, that oligomers of RANTES can cross-link enveloped viruses, including HIV-1, to cells via glycosaminoglycans (GAGs) present on the membranes of both virions and cells; secondly, that oligomers of RANTES interact with cell-surface GAGs to transduce a herbimycin A-sensitive signal which, over a period of several hours, renders the cells more permissive to infection by several viruses, including HIV-1. The enhancement mechanisms require that RANTES oligomerize either in solution or following binding to GAGs, since no viral infectivity enhancement is observed with a mutant form of the RANTES molecule that contains a single-amino-acid change (glutamic acid to serine at position 66) which abrogates oligomerization.

Animals↗
PubMed1999

Drinking and flying: a structural model.

BACKGROUND: Under a recent revision of the European Joint Aviation Authorities operations regulations it has been prohibited to act as a crew member of an aircraft with a BAC of greater than 0.02%. METHODS: This survey of UK Civil Aviation Authority pilots suggests that over 50% of respondents may have flown an aircraft with a BAC of greater than this prescribed amount. RESULTS: Professional pilots were found to be heavier drinkers than private pilots and were also more likely to infringe the 0.02% BAC rule. CONCLUSION: Analysis of the data using path analysis suggests that professional pilots may be more prone to offending as a result of training in a "drinking culture" and as a response to commercial pressures in the industry.

Adult↗
PubMed1997

Biochemical characterization of the binding of echistatin to integrin alphavbeta3 receptor.

Echistatin is a 49-amino-acid peptide belonging to the family of disintegrins that are derived from snake venoms and are potent inhibitors of platelet aggregation and cell adhesion. Integrin alphavbeta3 receptor plays a critical role in several physiological processes such as tumor-induced angiogenesis, tumor cell metastasis, osteoporosis and wound repair. In this study, we have characterized the binding of echistatin to purified integrin alphavbeta3 receptor and the form expressed on human embryonic kidney 293 cells. We show that both purified and membrane-bound integrin alphavbeta3 binds to echistatin with a high affinity, which can be competed efficiently by linear and cyclic peptides containing the RGD sequence. Previous studies have shown that alphavbeta3 binds to vitronectin in a nondissociable manner, whereas an RGD-containing peptide derived from vitronectin binds in a dissociable manner with a Kd of 9.4 x 10(-7) M. Our studies indicate that radiolabeled echistatin binds to alphavbeta3 in a nondissociable manner, similar to native echistatin. However, echistatin does not support the adhesion of 293 cells expressing alphavbeta3 receptor because of poor binding to plastic dishes and is a potent antagonist of the adhesion of these cells to vitronectin. These studies demonstrate that echistatin binding to alphavbeta3 is of high affinity and irreversible similar to vitronectin and provides an alternate ligand for high-throughput screening for alphavbeta3 antagonists.

Cell Adhesion↗
PubMed1996

Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism.

Interleukin-10 (IL-10) is a recently described pleiotropic cytokine secreted mainly by type 2 helper T cells. Previous studies have shown that IL-10 suppresses cytokine expression by natural killer (NK) and type 1 T cells, thus down-regulating cell-mediated immunity and stimulating humoral responses. We here report that injected IL-10 protein is an efficient inhibitor of tumor metastasis in experimental (B16-F10) and spontaneous (M27 and Lox human melanoma) metastasis models in vivo at doses that do not have toxic effects on normal or cancer cells. Histological characterization after IL-10 treatment confirmed the absence of CD8+ and CD4+ T cells and macrophages at the sites of tumor growth, but abundant NK cells were localized at these sites. This unexpected finding was confirmed by showing that IL-10 inhibits most B16-F10 and Lox metastases in mice deficient in T or B cells (SCID and nu/nu mice), but not in those deficient in NK cells (beige mice or NK cell-depleted mice). However, IL-10 downregulation of pro-inflammatory cytokine production and/or recruitment of additional effector cells may also be involved in the anti-tumor effect at higher local concentrations of IL-10, since transfected B16 tumor cells expressing high amounts of IL-10 were rejected by normal, nu/nu, or SCID mice at the primary tumor stage, and there was still a 33% inhibition of tumor metastasis in beige mice.

Animals↗
PubMed1995

Antitumor effect of keto-diepoxides isolated from the fungus Nattrassia mangiferae.

A novel keto-diepoxide Sch 49209 and its derivative Sch 50672, produced by the fungus Nattrassia mangiferae, inhibited tumor cell invasion through an artificial basement membrane. These compounds, at nontoxic concentrations, inhibited invasion of HT-1080 cells in a dose-dependent manner. The IC50 values for Sch 49209 and Sch 50672 were 0.75 and 8 microM, respectively, when cells were incubated with drugs for 5 h. Sch 49209 inhibited both tumor cell invasion and cell motility to the same extent under conditions that did not cause any apparent cytotoxicity. Sch 4209 and Sch 50672, however, inhibited the growth of ras-transformed cells in a semisolid medium in a 5-day culture with IC50 values of 0.6 and 2.4 microM, respectively. They also inhibited the anchorage-dependent growth of pT24 cells in vitro with IC50 values of 0.5 and 0.9 microM for Sch 40209 and Sch 50672, respectively. Using the murine lung epidermoid carcinoma M27 cells implanted SC in mice as a model, we found both Sch 49209 and Sch 50672 inhibited the growth of this tumor at doses ranging from 2 to 10 mg/kg. These compounds also decreased the formation of spontaneous lung metastasis in this model. Sch 50672 inhibited the growth of human tumor xenografts, SW620 and A431, in athymic mode mice. Our data suggest that keto-diepoxides inhibit tumor growth and metastasis and that this activity may be due, in part, to anti-invasive activity.

Animals↗
PubMed1969

Cutis laxa.

Explore the source record for details and available documents.

Child, Preschool↗
PubMedDate not supplied

Efficacy of p53 adenovirus-mediated gene therapy against human breast cancer xenografts.

In response to DNA damage, p53 protein accumulates in the cell nucleus causing cells to undergo DNA repair or apoptosis, programmed cell death. Reintroduction of wild-type p53 into tumors with null or mutant p53 offers a novel strategy for controlling tumor growth, by inducing apoptotic death in neoplastic cells. The efficacy of a replication-deficient p53 adenovirus construct was tested against three human breast cancer cell lines expressing mutant p53, MDA-MB-231, -468, and -435. 231 and 468 cells were both highly transduced at a multiplicity of infection of 10. By contrast, 435 cells were rarely transduced. p53 adenovirus-mediated gene therapy was highly effective against 231 and 468 tumor xenografts in nude mice. At a total dose of 2.2 x 10(9) cellular infectious units (CIU), inhibition of 231 tumor growth was 86% (P < or = .01). Thirty-seven percent of that growth inhibition was due to p53, while 49% was adenovirus-specific. Inhibition of 468 tumor growth was 74% (P < or = .001). Forty-five percent of that inhibition was p53-specific, while 28% was adenovirus-specific. The ED50 values for 231 tumors and 468 tumor growth inhibition were 3 x 10(8) CIU and 2 x 10(8) CIU, respectively. Injection of p53 Ad into 231 or 468 tumors induced apoptosis. By contrast, growth inhibition in 435 tumors treated with p53 adenovirus was not significant, probably due to low adenovirus transduction. 231 and 435 cells both expressed high levels of alpha v, beta 1, beta 3, and beta 5 integrin subunits, ruling out lack of the appropriate integrins as the reason for the low infection rate in 435 cells. Our results demonstrate the ability of wild-type p53 to curtail cancerous cell growth in vivo in tumors expressing mutant p53. The ability of beta-gal Ad to infect tumor cells in vitro was generally predictive of in vivo p53 Ad efficacy.

Adenoviridae↗