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C Robson

Publications and source records attributed to C Robson.

8 recordsLinked to original sources
PubMed1998

Chemical synthesis and biological properties of novel fluorescent antifolates in Pgp- and MRP-overexpressing tumour cell lines.

We have synthesised a series of fluorescent analogues of methylbenzoprim, a diaminopyrimidine antifolate which we have previously shown to exhibit in vivo antitumour activity in a methotrexate (MTX) "transport-resistant" tumour cell line. The analogues bear the dansyl, nitrobenzoxodiazole or methoxycoumarin fluorophores. The cytotoxicity of the compounds was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay against two human lung cancer cell lines, together with their multidrug resistant (MDR) sublines. H69/P is a small cell line and its multidrug resistant subline H69/LX4 overexpresses P-glycoprotein (Pgp). COR-L23/P is a large cell line and its multidrug resistant subline COR-L23/R overexpresses the multidrug resistance associated protein (MRP). IC50 values for the compounds (i.e. concentration to reduce cell growth by 50%) in the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay ranged from 0.20 to 0.81 microM in the H69 parental line and from 0.83 to 5.10 microM in the COR-L23 parent line. The MDR sublines both showed clear cross-resistance to each of the compounds, with resistance factors (ratio of IC50 value in resistant vs parental cell line) ranging from 16 to 137 in H69/LX4 and from 5 to 16 in COR-L23/R. For compounds (10) and (11) where drug accumulation was studied using flow cytometry, resistance was associated with an approximately 10-fold reduction in cellular drug accumulation over a period of 30 min. The drug resistance modifiers verapamil (used at 6.6 microM) and cyclosporin A (used at 4.2 microM) were tested for their ability to sensitise the resistant lines. Whereas verapamil showed little activity, cyclosporin A partially restored the activity of compound (10), and fully restored the activity of compound (11) in H69/LX4 cells. This sensitisation of H69/LX4 by cyclosporin A was associated with a partial restoration of the drug accumulation deficit in this line. Hence, these novel lipophilic antifolates appear to be substrates for both the P-glycoprotein and MRP resistance mechanisms. Therefore, although they have been designed to overcome one mechanism of methotrexate resistance, namely impaired drug transport, this has been achieved only at the cost of rendering them susceptible to alternative mechanisms.

4-Chloro-7-nitrobenzofurazan↗
PubMed1998

Mechanism of gram-positive shock: identification of peptidoglycan and lipoteichoic acid moieties essential in the induction of nitric oxide synthase, shock, and multiple organ failure.

The incidence of septic shock caused by gram-positive bacteria has risen markedly in the last few years. It is largely unclear how gram-positive bacteria (which do not contain endotoxin) cause shock and multiple organ failure. We have discovered recently that two cell wall fragments of the pathogenic gram-positive bacterium Staphylococcus aureus, lipoteichoic acid (LTA) and peptidoglycan (PepG), synergize to cause the induction of nitric oxide (NO) formation, shock, and organ injury in the rat. We report here that a specific fragment of PepG, N-acetylglucosamine-beta-[1--> 4]-N-acetylmuramyl-L-alanine-D-isoglutamine, is the moiety within the PepG polymer responsible for the synergism with LTA (or the cytokine interferon gamma) to induce NO formation in the murine macrophage cell line J774.2. However, this moiety is also present in the PepG of the nonpathogenic bacterium Bacillus subtilis. We have discovered subsequently that S. aureus LTA synergizes with PepG from either bacterium to cause enhanced NO formation, shock, and organ injury in the rat, whereas the LTA from B. subtilis does not synergize with PepG of either bacterium. Thus, we propose that the structure of LTA determines the ability of a particular bacterium to cause shock and multiple organ failure (pathogenicity), while PepG acts to amplify any response induced by LTA.

Animals↗
PubMed1997

Nonclassical 2,4-diamino-5-aryl-6-ethylpyrimidine antifolates: activity as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents.

Twelve novel 2,4-diamino-5-(4'-benzylamino)- and 2,4-diamino-5[4'-(N-methylbenzylamino)-3'-nitrophenyl]-6-ethylp yrimidines bearing 4-substituents on the benzylamino or N-methylbenzylamino aryl ring were synthesized and evaluated as nonclassical inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase (DHFR). Compounds were prepared by reaction of 2,4-diamino-5-(4'-chloro-3'-nitrophenyl)- (8) or 2,4-diamino-5-(4'-fluoro-3'-nitrophenyl)-6-ethylpyrimidine (15) with the appropriate 4-substituted (CO2H, CO2Me, SO2NH2, dioxolan-2-yl, CHO, dimethyloxazolin-2-yl) benzylamine or N-methylbenzylamine derivative. Compounds 25-29 were synthesized from 2,4-diamino-5-{4'-[N-(4"-carboxybenzyl)amino]-3'-nitrophenyl}-6- ethylpyrimidine (10) and the corresponding amine (NH3, MeNH2, Me2NH, piperidine, diethyl L-glutamate) via isobutyl mixed anhydride coupling; hydrolysis of the diethyl L-glutamate 29 afforded the L-glutamate analogue 30. The compounds exhibited potent inhibitory activity against T. gondii (IC50 values 0.0018-0.14 microM) and rat liver (IC50 values 0.0029-0.27 microM) DHFR, with a 4-substituent invariably enhancing binding to both enzymes relative to the unsubstituted benzoprim (5) or methylbenzoprim (6). Modest selectivity for T. gondii enzyme was observed with several analogues, whereas all of the compounds were relatively weak inhibitors of P. carinii DHFR and exhibited no selectivity. Selected analogues were evaluated for in vivo antitumor activity against the methotrexate-resistant M5076 murine reticulosarcoma, with 2,4-diamino-5-{4'-[N-[4"-(N"-methylcarbamoyl)benzyl]-N- methylamino]-3'-nitrophenyl}-6-ethylpyrimidine (14) (Ki for rat liver DHFR = 0.00035 +/- 0.00029 nM) combining significant antitumor activity with minimal toxicity.

Animals↗
PubMed1984

Issues in the development of language intervention programmes.

An attempt has been made in this paper to address some issues involved in the development of language intervention programmes. The relative neglect of 'language' in the paper is justified by the importance of more general issues. After cursory attention to prescriptiveness in programmes, the concentration has been on the 'training of the trainers' and the need for an adequate and effective instructional model. Particular attention is given to evaluation and the need for a design which while acknowledging the practicalities of life in the field can nevertheless assist in determining the effects of the intervention (with a nod in the direction of casting the net sufficiently wide to encompass possible unintended effects). Finally, there is discussion of implementation, covering guidelines to bear in mind the developing the intervention and stressing that without successful implementation even the most effective programme fails, as it disappears like water in to the sands of the desert.

Child↗