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N Robertson

Publications and source records attributed to N Robertson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Fused pyrazine mono-N-oxides as bioreductive drugs. III. Characterization of RB 90740 in vitro and in vivo.

RB 90740 is the lead compound in a series of aromatic mono-N-oxide bioreductive drugs. The compound shows considerably greater toxicity towards hypoxic verses aerobic mammalian cells in vitro. The differential in concentration required to give the same level of cell killing under these conditions ranges from 3.5 in a human bronchio-alveolar tumor cell line up to 120 in a rodent cell line defective in the repair of DNA strand breaks. The ability of RB 90740 to cause DNA strand breaks under hypoxic conditions was confirmed by alkaline sucrose gradient and pulsed field gel electrophoresis techniques. Despite these properties demonstrated in vitro, RB 90740 was shown not to be cytotoxic to hypoxic cells in experimental murine tumors in vivo. This may be due, in part, to the level of hypoxia (< 0.02% O2) necessary to produce toxicity in vitro.

Animals↗
PubMed1995

Multiple sclerosis in the north Cambridgeshire districts of East Anglia.

The Cambridgeshire multiple sclerosis register was established in 1989 and initially reported a prevalence of 130/10(5) population for south and east Cambridgeshire (south Cambs). This survey has now been extended to the northern county districts where there were 449 patients with multiple sclerosis in population of 378,959 on 1 July 1993 (118/10(5); 95% confidence interval (95% CI) 108-130). Four hundred and four had either definite or probable disease (107/10(5); 95% CI: 98-118). This matches the highest figures in the series of seven epidemiological surveys carried out in southern England over the past decade. Comparison with these and other studies indicates that no latitudinal gradient of disease is found in southern England despite spanning four degrees of latitude.

Adolescent↗
PubMed1995

Assessing the work of medical audit advisory groups in promoting audit in general practice.

Objectives--To determine the role of medical audit advisory groups in audit activities in general practice. Design--Postal questionnaire survey. Subjects--All 104 advisory groups in England and Wales in 1994. Main measures--Monitoring audit: the methods used to classify audits, the methods used by the advisory group to collect data on audits from general practices, the proportion of practices undertaking audit. Directing and coordinating audits: topics and number of practices participating in multipractice audits. Results--The response rate was 86-5%. In 1993-4, 54% of the advisory groups used the Oxfordshire or Kirklees methods for classifying audits, or modifications of them. 99% of the advisory groups collected data on audit activities at least once between 1991-2 and 1993-4. Visits, questionnaires, and other methods were used to collect information from all or samples of practices in each of the advisory group's areas. Some advisory groups used different methods in different years. In 1991-2, 57% of all practices participated in some audit, in 1992-3, 78%, and in 1993-4, 86%. 428 multipractice audits were identified. The most popular topic was diabetes. Conclusions--Advisory groups have been active in monitoring audit in general practice. However, the methods used to classify and collect information about audits in general practices varied widely. The number of practices undertaking audit increased between 1991-2 and 1993 1. The large number of multipractice audits supports the view that the advisory groups have directed and coordinated audit activities. This example of a national audit programme for general practice may be helpful in other countries in which the introduction of quality assurance is being considered.

England↗
PubMed1995

The T-cell receptor beta locus and susceptibility to multiple sclerosis.

Assessments of genetically determined variations in the T-cell antigen receptor in multiple sclerosis (MS) have yielded conflicting results. We used three restriction fragment length polymorphisms (RFLPs) and a polymorphic microsatellite repeat as markers for the T-cell receptor (TCR) beta locus (7q32-35) in multiplex MS families. Affected sibling-pair analysis of the RFLP data failed to show evidence for linkage (127 families) whereas analysis of the microsatellite data (86 families) provided weak evidence for linkage with a maximum lod score of 0.98 (p < 0.05). We repeated the analysis in those families (n = 53) in which the affected sibling pairs were concordant for the HLA haplotype DR15/DQ6. This altered the proportion of affected siblings sharing 0, 1, 2 RFLP haplotypes from 0.24, 0.50, and 0.26 (p = NS) before stratification to 0.16, 0.41, and 0.43 (p < 0.05) in the DR15/DQ6 positive pairs alone; for the microsatellite data, sharing altered from 0.16, 0.50, and 0.34 (p < 0.05) in all pairs to 0.07, 0.49, and 0.44 (p < 0.01) in the DR15/DQ6 concordant siblings.

Adult↗
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↗
PubMed1994

The role of DT-diaphorase in determining the sensitivity of human tumor cells to tirapazamine (SR 4233).

PURPOSE: To determine the dependency of the aerobic and hypoxic toxicity of tirapazamine on the intracellular activity of DT-diaphorase. METHODS AND MATERIALS: A panel of 18 human cell lines comprising predominantly small cell and nonsmall cell lung cancer and breast cancer lines were used. The activity of DT-diaphorase was determined in cytosolic preparations from cell lysates. The toxicity of tirapazamine was determined using the MTT assay after either 96 or 3 h aerobic exposure or 3 h treatment in hypoxia. RESULTS: The cell lines exhibited a 5000-fold range in DT-diaphorase activity. In toxicity experiments, values of IC50 range from 10.2-120 microM and from 155-1230 for 96 and 3 h aerobic exposures, respectively. In N2, IC50s ranged from 8-55 microM. None of the toxicity values correlate with activity of DT-diaphorase, neither did the ratio of aerobic:hypoxic toxicity (differential toxicity). CONCLUSION: The expression of DT-diaphorase in human tumor cells does not affect the toxicity of tirapazamine.

Antineoplastic Agents↗
PubMed1994

Suppression of Ras transformation by serum response factor.

Serum response factor (SRF) is a nuclear transcription factor that binds to the serum response element (SRE) found in the promoter regions of a number of growth factor-inducible genes, as well as muscle-specific genes. The smooth muscle alpha-actin promoter contains two SRE sequences that can bind to SRF. Its expression is repressed in Ras-transformed fibroblast cells and derepressed in revertant cells. In this study, we demonstrate that SRF can activate alpha-actin expression in Ras-transformed cells and that overexpression of SRF in Ras-transformed cells can revert their transformed phenotype. The ability of SRF to bind to the SRE was required for this effect, since mutations that inhibit DNA binding abolish SRF's ability to activate alpha-actin expression and suppress transformation by the ras oncogene. These results show that SRF, thought to be involved in stimulation of cell growth through activation of growth factor-inducible genes, can actually have the opposite effect and suggest a novel mechanism for suppression of transformation by Ras.

Actins↗
PubMed1994

Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis.

The observation of a multiple sclerosis (MS)-like illness in patients, particularly women, who carry the most common Leber's hereditary optic neuropathy mitochondrial DNA (mtDNA) mutation may indicate a contributory role for mitochondrial genes in genetic susceptibility to MS. We screened 307 unrelated MS patients, ascertained from population surveys, for the pathogenic Leber's hereditary optic neuropathy mutations at positions 11778 and 3460 of mtDNA, and also studied 20 patients with prominent and early optic nerve involvement. In addition, these 307 patients and 129 control subjects were investigated for the base change at position 13708, which has been suggested to play a role in the pathogenesis of Leber's hereditary optic neuropathy. Neither of the pathogenic mtDNA mutations occurred in the unselected MS patients. The 13708 base change was present in MS patients at a frequency similar to that in healthy control subjects. Three of the patients selected on the basis of severe optic nerve involvement had either the 11778 (one) or 3460 (two) mutations associated with Leber's hereditary optic neuropathy. All were women and none had affected relatives. We conclude that these mutations do not contribute to genetically determined susceptibility in typical MS patients, although a mitochondrial genetic component in the etiology of MS remains possible. A subgroup of MS patients, particularly females with severe bilateral visual failure due to optic neuropathy, may harbor a Leber's hereditary optic neuropathy mutation and we suggest that mtDNA analysis is appropriate in these patients.

Adult↗
PubMed1994

Factors affecting sensitivity to EO9 in rodent and human tumour cells in vitro: DT-diaphorase activity and hypoxia.

Twenty-three human tumour cell lines (lung, breast, and colon) and eight rodent cell lines were evaluated for their sensitivity to the quinone-based anticancer drug EO9 [3-hydroxymethyl-5-aziridinyl-1-methyl-2-(1H indole-4,7-dione)prop-beta-en-alpha-o1]. Sensitivity was compared with the intracellular levels of DT-diaphorase, and cell lines showing highest enzyme activity tended to be the most sensitive to EO9. The role of DT-diaphorase in determining drug sensitivity was confirmed by using the enzyme inhibitor dicoumarol, which protects cells containing high levels of DT-diaphorase from the cytotoxic action of EO9. Hypoxia increased the cytotoxicity of cells containing low but not high levels of DT-diaphorase, implying that both 1- and 2-electron reductive activation processes can be important for expression of EO9 toxicity. It is concluded that EO9 is a potentially useful agent in the enzyme directed approach to the use of bioreductive drugs in cancer therapy.

Animals↗
PubMed1994

Manipulation and exploitation of the tumour environment for therapeutic benefit.

We describe aspects of the tumour microenvironment that are available as targets for manipulation. In particular, the question asked is whether hypoxia in tumours is a problem to be overcome, or a physiological abnormality to be exploited? Bioreductive drugs require metabolic reduction to generate cytotoxic metabolites. This process is facilitated by appropriate reductases and the lower oxygen conditions present in solid tumours compared with normal tissues. Because of their specificity, bioreductive drugs are used to help answer this question. Other aspects of tumour physiology and biochemistry that may be exploited include tissue dependent reductase expression, pH and angiogenesis.

Antineoplastic Agents↗
PubMed1994

No linkage or association between multiple sclerosis and the myelin basic protein gene in affected sibling pairs.

Myelin basic protein was examined as a candidate gene for susceptibility to multiple sclerosis using two adjacent amplification fragment length polymorphisms (AmpFLPs), containing seven and six highly informative alleles respectively. No allelic association was found with multiple sclerosis, comparing 77 cases and 88 controls, and there was no evidence for linkage in 73 affected sibling pairs, using the methods of identity by descent and identity by state.

Adult↗
PubMed1992

Residential care for the long term mentally ill in Canterbury: options, costs and funding sources.

AIMS: To obtain estimates of the costs of the main options of care for the long term mentally ill and to compare different approaches to costing. METHOD: Resources used by samples of residents in extended hospital care (EC, n = 43), community staffed houses (SH, n = 30), boarding houses (BH, n = 43) and group homes (GH, n = 100) were identified and costed using both the expenditure and total resource concepts of cost estimation. RESULTS: Using the expenditure concept of cost SH was the most expensive at $773 per person per week, compared to $700 for EC, $189 for BH and $155 for GH. Using the resource cost approach, valuing all resources used, SH and EC were similar at $790, compared to $184 and $169 for BH and GH care. Nursing was the most costly input with striking differences between nursing costs in the four modes of care. CONCLUSIONS: The results indicate a gap in the spectrum of residential care options, between high and low cost care. Future funding arrangements will require improved linkage between needs assessment and resource provision.

Capital Financing↗
PubMed1992

The sensitivity of human tumour cells to quinone bioreductive drugs: what role for DT-diaphorase?

15 human tumour cell lines (lung, breast and colon) have been evaluated for their sensitivity to the quinone based anti-cancer drugs Mitomycin C, Porfiromycin, and EO9 (3-hydroxymethyl-5-aziridinyl-1-methyl-2-(IH-indole-4,7-dione)prop-beta- en-alpha-ol). Sensitivity has been compared with the intra-cellular levels of DT-diaphorase, an enzyme thought to be important in the reductive activation of these quinones. No correlation exists between levels of DT-diaphorase and sensitivity to Mitomycin C or Porfiromycin. However, for EO9 those cell lines showing highest levels of DT-diaphorase activity tend to be the most sensitive.

Antineoplastic Agents↗
PubMed1991

Monoclonal anti-idiotypic antibodies to human melanoma-associated proteoglycan antigen: generation and characterization of anti-idiotype antibodies.

We have characterized a number of monoclonal anti-idiotype antibodies (mAb2s) made against a monoclonal antitumor antibody, MEM136. The monoclonal antibody 1 (mAb1) MEM136 recognizes an epitope on human melanoma-associated proteoglycan and blocks melanoma cell interaction with basement membrane components in vitro. The anti-idiotype antibodies (Ab2s) made against MEM136 each cross-inhibited, to varying degrees, their binding to MEM136. Thus, the mAb2s recognized overlapping idiotopes on MEM136. In an attempt to identify potential internal image candidates we set up a cell migration inhibition assay. In this assay, migration of melanoma-associated proteoglycan-positive Colo38 cells was determined through a membrane barrier impregnated with Matrigel, which is composed of extracellular matrix components, i.e., collagen type IV, heparan sulfate, and laminin. Interestingly, only Ab2s IM06 and IM32 inhibited melanoma cell migration. Additional studies indicate that of eight mAb2s tested, only IM32 and IM06 induced anti-MPG responses in rabbits. The possibility that IM32 and IM06 bear images of melanoma cell surface-associated proteoglycan epitopes is discussed.

Antibodies, Anti-Idiotypic↗