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Biomedical subjects

Hilary Thomas

Publications and source records attributed to Hilary Thomas.

At least 19 recordsLinked to original sources
PubMed2006

Receptor tyrosine kinase (RTK) inhibition is effective in chemosensitising EGFR-expressing drug resistant human ovarian cancer cell lines when used in combination with cytotoxic agents.

This study has focused on the use of RTK inhibitors in the treatment of ovarian cancer. We have used the human ovarian cancer cell line PEO1 alongside two in-house derived drug resistant variants: PEO1CarboR (8-fold acquired resistance to carboplatin and cisplatin) and the Pgp expressing PEO1TaxR (15-fold acquired resistance to paclitaxel). These variant cell lines were shown to have a higher expression of EGFR 1.6- and 2.0-fold increase, respectively, compared with the parental cell line. We have shown that the RTK inhibitor GW282974A (an analogue of GW2016; lapatinib) is effective in chemosensitisation of drug resistant EGFR over-expressing cells giving rise to a synergistic effect when used in combination with either cisplatin or paclitaxel in chemosensitivity assays. These effects were also seen at the level of apoptosis using the Annexin V assay and expression levels of the IAP Survivin. A reduction in the downstream signalling effector phosphorylated ERK was seen in both resistant cell lines when GW282974A was used in combination with either cisplatin or paclitaxel. This reduction was not so apparent in cells treated with the single agent GW282974A or cytotoxic agent. Interestingly, we did not show evidence for an enhanced sensitivity to the RTK inhibitor in our EGFR expressing resistant lines versus parental PEO1 cells. However, the paclitaxel resistant cell line appeared more sensitive to the chemosensitising effects of GW282974A, in line with its increased EGFR expression. Our data suggest that RTK inhibition is effective in circumvention of tumour cell drug resistance that occurs in conjunction with EGFR overexpression.

Antineoplastic Agents↗
PubMed2006

Responses of human colorectal tumor cells to treatment with the anti-epidermal growth factor receptor monoclonal antibody ICR62 used alone and in combination with the EGFR tyrosine kinase inhibitor gefitinib.

The anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab has been approved for the treatment of patients with metastatic colorectal cancer. However, there is currently no reliable marker for response to therapy with the EGFR inhibitors. In this study, we investigated the sensitivity of 10 human colorectal tumor cell lines (DiFi, CCL218, CCL221, CCL225, CCL227, CCL228, CCL231, CCL235, CCL244, and HCT-116) to treatment with our anti-EGFR monoclonal antibody, ICR62, and/or the EGFR tyrosine kinase inhibitor, gefitinib. Of the cells examined, only DiFi contained high levels of constitutively active EGFR and were highly sensitive to treatment with both ICR62 (IC(50) = 0.52 nmol/L) and gefitinib (IC(50) = 27.5 nmol/L). In contrast, the growth of other tumor cell lines, which contained low levels of the EGFR, HER-2, and pAkt but comparable or even higher basal levels of phosphorylated mitogen-activated protein kinase (pMAPK), were relatively resistant to treatment with both inhibitors. Both ICR62 and gefitinib induced EGFR down-regulation, reduced the basal levels of pEGFR at five known tyrosine residues, pMAPK, and pAkt, and increased the sub-G(1) population in DiFi cells. However, treatment with a combination of ICR62 and gefitinib neither sensitized colorectal tumor cells that were insensitive to treatment with the single agent nor enhanced the growth-inhibitory effect of the single agent in DiFi cells. These results indicate that basal levels of pMAPK and pAkt are not good indicators of response to the EGFR inhibitors in colorectal cancer cells and dual targeting of the EGFR by a combination of ICR62 and gefitinib is not superior to treatment with a single agent.

Antibodies, Monoclonal↗
PubMed2006

On happiness.

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Happiness↗
PubMed2006

On feedback.

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Feedback↗
PubMed2006

Coexpression of the IGF-IR, EGFR and HER-2 is common in colorectal cancer patients.

Signalling via the insulin-like growth factor-I receptor (IGF-IR) has been associated with resistance to anti-epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)-based therapies in the experimental system, but the coexpression and clinical significance of the IGF-IR, EGFR and HER-2 in cancer patients remains unclear. IGF-IR, EGFR, and HER-2 status was assessed retrospectively in tumour specimens from 87 Dukes' C colorectal cancer patients using immunohistochemistry. Sections were scored by the percentage of positive cells (membrane and cytoplasmic) and intensity of staining. The association between receptor coexpression and clinicopathological parameters and overall survival were evaluated using univariate and multivariate (Cox) analysis. Overall, 93, 83 and 89% of the cases expressed IGF-IR, EGFR and HER-2, respectively. While 60% of the cases expressed membranous IGF-IR, the expression of EGFR and HER-2 was predominantly cytoplasmic. Coexpression of the IGF-IR, EGFR and HER-2 was present in tumours from 75% of the patients. No significant association was found between the expression or coexpression of total IGF-IR, EGFR and HER-2 and clinicopathological parameters or overall survival. Our results indicate that coexpression of IGF-IR, EGFR and HER-2 is common in Dukes' C colorectal cancer, warranting further investigation on the co-targeting of such receptors in colorectal cancer patients.

Aged↗
PubMed2005

On Kaiser.

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Diffusion of Innovation↗
PubMed2005

Dilemmas in decision-making about resuscitation--a focus group study of older people.

Cardiopulmonary resuscitation (CPR) may be used by default on patients suffering a cardiac arrest in hospital in the UK unless there is an order that specifies otherwise in the patient's notes. Guidelines recommend that the decision involves competent and willing patients or, in the case of incapacitation, their families. In practice, patient autonomy is often compromised. Ideally, discussion of preferences for end-of-life care should take place prior to hospitalisation. The majority of research on this topic has been conducted on hospitalised patients, so little is known about the views of older, but healthy, people about resuscitation decision-making. The present study was designed to address this gap. A series of eight focus groups involving a total of 48 participants over the age of 65 was conducted to explore people's views about the factors guiding resuscitation decision-making. A qualitative analysis, which emphasised the dilemmatic nature of resuscitation decision-making, identified two broad thematic dilemmas that subsumed six specific themes which contribute to resolving the dilemmas: quality of life (medical condition, mental versus physical incapacity, age and ageing, and burden), and the involvement of others (doctors and families) versus loss of autonomy. The dilemma underlying quality of life is that an acceptable quality of life after CPR cannot be assured. The dilemma underlying the involvement of others is that individual autonomy may be lost. The themes and subthemes provide the basis for guiding these difficult discussions in advance of serious illness.

Advance Care Planning↗