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S Eccles

Publications and source records attributed to S Eccles.

At least 19 recordsLinked to original sources
PubMed2005

Granisetron attenuates exercise-induced conditioned taste aversion in the rat.

A conditioned taste aversion (CTA) paradigm was used in the present study to investigate whether CTA produced by exercise could be attenuated by the 5-HT(3) receptor antagonist granisetron. Male Sprague-Dawley rats were randomly allocated to one of four groups (Ns=6) and were exposed to salty (0.128 M sodium chloride) or sour (0.00138M citric acid) solutions. Subjects were injected with either saline solution (1.0 ml, 0.9%) or granisetron (0.5mg/kg, IP) and were exposed to 30 min of forced wheel running exercise (70 revolutions/30min) 10 min after injection. Exercise induced CTA to both the salty (3.7 ml intake) and sour-flaroured (3.1ml intake) solutions as compared with no exercise (intake 14.0 and 13.7 ml), and administration of granisetron significantly attenuated the exercise-induced CTA to the salty- and sour-flavoured solutions.

Animals↗
PubMed2003

Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer.

Squamous cell carcinoma (SCC) of the oral tongue is characterized by a high propensity for cervical nodal metastasis, which affects the probability of regional control and survival. Until now, elective treatment of the clinically negative neck in early lesions (T(1-2)) of the oral tongue cancer remains controversial. This study attempted to identify predictive factor(s) for cervical nodal metastasis and treatment outcomes in patients with early stage SCC of the oral tongue treated primarily by surgery. Fifty patients with previously untreated Stage I/II primary tongue carcinomas with available archival specimens treated at the Royal Marsden Hospital between 1981 and 1998 were reviewed. Clinico-pathological features including age, gender, alcohol and tobacco consumption, tumour location, histological grade, tumour-stromal border, growth pattern, tumour thickness, and clinical stage were evaluated and the correlations with cervical metastases and outcome analysis were determined. The overall occult nodal metastatic rate was 40% (20/50). Tumour thickness exceeding 5 mm was statistically significantly correlated with cervical metastases (P = 0.003; relative risk = 2.429). No statistical correlation was observed between other clinico-pathological parameters and nodal metastasis. With a median follow-up of 98 months, 5-year actuarial overall, disease-specific (DSS), and relapse-free survival were 65.71, 67.77, and 68.18%, respectively. Univariate analysis for DSS showed poorer outcomes for patients with age > 60 years (P = 0.0423) and tumour thickness > 5 mm (P = 0.0067). The effect of tumour thickness was maintained (P = 0.005) on multivariate analysis. The present study indicates that the thickness of primary tumour has a strong predictive value for occult cervical metastasis and poor outcomes in patients with Stage I/II oral tongue SCC. Thus, elective neck treatment (surgery or irradiation) is indicated for tumours exceeding 5 mm thickness.

Adult↗
PubMed2000

Expression and regulation of c-ERBB ligands in human head and neck squamous carcinoma cells.

We recently reported that multiple c-erbB ligands differentially modulate in vitro proliferation, invasion and expression of matrix metalloproteinases in human head and neck squamous carcinoma cells (HNSCC). In order to evaluate further the importance of c-erbB ligands in tumor progression, the expression and regulation of this growth factor family in HNSCC cells was studied. We demonstrate that mRNAs for the 6 major c-erbB ligands, namely, epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), betacellulin (BTC), heparin-binding epidermal growth factor-like growth factor (HB-EGF), amphiregulin (AR) and heregulin (HRG), are expressed in a large panel of HNSCC cell lines. In addition to TGF-alpha, other ligands (notably BTC and HRG-beta1) are involved in the autocrine growth regulation of these cells. Each c-erbB ligand when applied exogenously, induced mRNA expression of both itself and the remaining family members and a differential response in the kinetics of induction was found. HB-EGF and HRG mRNAs were induced rapidly (within 1 hr) and to a greater extent (3.2-6.2- and 4.8-7. 3-fold increase) than TGF-alpha, BTC and AR mRNAs (1.6-2.7, 1.8-3.6- and 1.6-4.2-fold, respectively). This pattern was observed for all inducing ligands tested. Analysis of mRNA stability, and concurrent treatment with BTC (as an inducing ligand) and cycloheximide (to inhibit protein synthesis) suggested both transcriptional and post-transcriptional regulatory mechanisms. These results support and extend previous observations of c-erbB receptor signaling as a critical element in the pathogenesis and progression of HNSCC, and emphasize the role of autocrine ligand production.

Amphiregulin↗
PubMed2000

Overexpression of epidermal growth factor receptor in human head and neck squamous carcinoma cell lines correlates with matrix metalloproteinase-9 expression and in vitro invasion.

Numerous reports have shown an association between overexpression of the epidermal growth factor receptor (EGFR), and poor prognosis in head and neck squamous cell carcinomas (HNSCC), however, the underlying mechanisms are still unclear. In the present study, we set out to determine whether EGFR expression was associated with in vitro invasive capacity in a panel of four established and ten newly derived HNSCC lines. Ten of the cell lines expressed high levels of EGFR as determined by a ligand-binding assay and dot blot analysis, whereas the remaining four showed weak overexpression or normal levels of EGFR. The ability of cells to invade through Matrigel was found to be higher in the EGFR overexpressing cell lines (p < 0. 0001). Expression levels of matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, MMP-13, MT1-MMP) and tissue inhibitors of MMP (TIMP-1, TIMP-2) were evaluated by semiquantitative RT-PCR, substrate zymography and western blot. We found a strong positive correlation between EGFR levels and the expression of MMP-9 mRNA (r(2) = 0.95; p < 0.0001), MMP-9 enzyme activity (r(2) = 0.8099; p < 0.0001) and an inverse correlation with TIMP-1 (r(2) = 0.48; p = 0.0059). In six selected HNSCC lines, in vitro invasion was assayed in the presence of an anti-EGFR monoclonal antibody, ICR62. A significant reduction of invasion in four selected EGFR-overexpressing cell lines was found with 30 nM ICR62 (from 50% to 70%; p < 0.001) but there was no effect in two cell lines with normal EGFR levels. Our results show that the in vitro invasive phenotype of HNSCC lines correlates with high EGFR and MMP-9 expression, and it is therefore suggested that the EGFR signaling pathway might play an important role in the invasive behavior of HNSCC via specific upregulation of MMP-9 and downregulation of TIMP-1.

Carcinoma, Squamous Cell↗
PubMed1999

In vivo efficacy of XR9051, a potent modulator of P-glycoprotein mediated multidrug resistance.

Overexpression of P-glycoprotein (P-gp) is a potential cause of multidrug resistance (MDR) in tumours. We have previously reported that XR9051 (N-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phe nyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-pipera zinylidene)methylbenzamide) is a potent and specific inhibitor of P-gp, which reverses drug resistance in several murine and human MDR cell lines. In this study we have evaluated the in vivo efficacy of this novel modulator in a panel of murine and human tumour models and examined its pharmacokinetic profile. Efficacy studies in mice bearing MDR syngeneic tumours (P388/DX Johnson, MC26) or human tumour xenografts (A2780AD, CH1/DOXr, H69/LX) demonstrated that co-administration of XR9051 significantly potentiated the anti-tumour activity of a range of cytotoxic drugs. This modulatory activity was observed following parenteral and oral co-administration of XR9051. In addition, the combination schedules were well-tolerated. Following intravenous administration in mice, XR9051 is rapidly distributed and accumulates in tumours and other tissues. In addition, the compound is well-absorbed after oral administration. These data suggest that XR9051 has the potential for reversing clinical MDR mediated by P-glycoprotien.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

c-erbB-2 as a target for immunotherapy.

The c-erbB-2 proto-oncogene encodes a 185 kDa transmembrane Type 1 tyrosine kinase receptor whose amplification and/or overexpression has been linked with poor prognosis in a variety of cancers. The oncoprotein has been suggested to play a key role in tumour cell invasion, motility and metastasis, and in responsiveness to therapeutic agents. Over-expression of c-erbB-2 therefore identifies an important subset of patients with a high probability of relapse, but low probability of response to certain conventional therapies. The cell surface location of the oncoprotein, its stability of expression and low levels in normal adult tissues render it an attractive target for immunotherapeutic intervention. Although a 'self' antigen, there is evidence that c-erbB-2 p185 can induce both humoral and cell-mediated immune responses in cancer patients. Approaches to exploit p185 as an immunotherapeutic target include vaccination with peptides, plasmid DNA or vectors (viruses/bacteria) carrying the gene; with cytokines, co-stimulatory factors and superantigens being evaluated as adjuvants. Many monoclonal antibody (mAb)-based strategies are also in clinical development. Monoclonal antibodies can serve multiple functions; direct inhibition of c-erbB-2 activity, recruitment of host effector mechanisms and direct or indirect delivery of toxic payloads. Clinical trials in patients with late stage disease have shown that many of these approaches are safe, feasible and relatively non-toxic, and, in some cases, objective responses have been seen. As with all immunotherapy, the greatest benefit is likely to be obtained in patients with minimal residual disease in an adjuvant setting; such studies are awaited with interest.

Journal Article↗
PubMed1996

Phase I trial and tumour localisation of the anti-EGFR monoclonal antibody ICR62 in head and neck or lung cancer.

The purpose of this study was to determine the effect of the first rat monoclonal antibody (MAb ICR62) to the epidermal growth factor receptor (EGFR) in a phase I clinical trial in patients with unresectable squamous cell carcinomas. This antibody effectively blocks the binding of EGF, transforming growth factor (TGF)-alpha and HB-EGF to the EGFR, inhibits the growth in vitro of tumour cell lines which overexpress the EGFR and eradicates such tumours when grown as xenografts in athymic mice. Eleven patients with squamous cell carcinoma of the head and neck and nine patients with squamous cell carcinoma of the lung, whose tumours expressed EGFR, were recruited. Groups of three patients were treated with 2.5 mg, 10 mg, 20 mg or 40 mg of ICR62 and a further eight patients received 100 mg. All patients were evaluated for toxicity using WHO criteria. Patients' sera were tested for the clearance of MAb ICR62 and the development of human anti-rat antibodies (HARA). No serious (WHO Grade III-IV) toxicity was observed in patients treated with up to 100 mg of antibody ICR62. Antibody ICR62 could be detected at 4 h and 24 h in the sera of patients treated with 40 mg or 100 mg of ICR62. Only 4/20 patients showed HARA responses (one at 20 mg, one at 40 mg and two at 100 mg doses) and of these only the former two were anti-idiotypic responses. In four patients receiving doses of ICR62 at 40 mg or greater, biopsies were obtained from metastatic lesions 24 h later and examined for the localisation of ICR62 using anti-rat antibody reagent. In these patients we showed the localisation of MAb ICR62 to the membranes of tumour cells; this appeared to be more prominent at the higher dose of 100 mg. On the basis of these data we conclude that MAb ICR62 can be administered safely to patients with squamous cell carcinomas and that it can localise efficiently to metastases even at relatively low doses.

Adult↗
PubMed1994

Differentiation or immune destruction: two pathways for therapy of squamous cell carcinomas with antibodies to the epidermal growth factor receptor.

We have carried out an immunohistochemical investigation of xenografts of epidermal growth factor receptor (EGFR)-overexpressing tumors that have been induced to regress by treatment with rat monoclonal antibodies (mAbs) to the human EGFR [ICR16 (IgG2a), ICR62 (IgG2b), and ICR64 (IgG1)]. When mice bearing xenografts of the HN5 squamous cell carcinoma were treated for 5 days with mAb ICR62 or ICR16, the antibodies were found to be localized uniformly on the tumor cell membranes. However, the foci of tumor cells that remained following treatment with ICR62 were smaller than with ICR16 and the former showed a more pronounced host mononuclear cell infiltrate. Examination of the few tumors that had not regressed completely and were still present as static nodules 77 days following the final treatment with anti-EGFR mAbs revealed significant levels of therapeutic mAb in the nonviable areas of the tumors. The microscopic areas of apparently viable tumor cells that did not stain when only secondary antibody was used stained positive when the sections were treated first with an anti-EGFR antibody. This suggests that loss of the target antigen was not a significant factor and that these residual cells might be eradicated by further treatment with mAb. Furthermore, the finding of keratinized areas in the tumors undergoing regression suggested that the carcinoma cells had undergone terminal differentiation following exposure to antibody. This possibility was supported by the finding that treatment of HN5 cells in vitro with mAbs ICR16, ICR62, or ICR64 resulted in the accumulation of cells in the G0-G1 phases of the cell cycle and expression of the terminal differentiation markers involucrin and cytokeratin 10. We found no evidence of apoptosis in such cells. We conclude that antibodies which block the binding of EGF and transforming growth factor alpha to the EGFR can inhibit the growth of EGFR-overexpressing tumors by directing terminal differentiation and that a further therapeutic benefit may be obtained via immunological mechanisms with rat IgG2b mAbs such as ICR62.

Animals↗
PubMed1994

Immunotherapy with antibodies to the EGF receptor.

A series of rat monoclonal antibodies (MAbs) has been generated against the extracellular domain of the receptor for EGF which block the binding of EGF and TGF alpha to the receptor and inhibit the growth in vitro of a range of carcinoma cell lines that over-express the receptor for EGF. Some of these antibodies were able also to induce the complete regression of xenografts of EGFR-over-expressing tumours when treatment was started, either at the time of tumour inoculation or later when the tumours were established. The most effective of these antibodies was ICR62, which was also able to activate host immune effector functions. We conclude that antibodies which block growth-factor-ligand interaction can have a profound influence on the proliferative capacity of tumour cells in vivo and may have useful clinical application.

Animals↗
PubMed1994

Clinical radioimmunolocalization with a rat monoclonal antibody directed against c-erbB-2.

Lymph node status is still the single most important prognostic factor in breast cancer and surgery remains the only reliable means of providing this information. This study evaluates using a highly specific radiolabeled monoclonal antibody to provide equivalent information. The optimum labeling conditions for radiolabeling a monoclonal antibody against the gene product of the protooncogene c-erbB-2 with Tc99m were established. This immunoconjugate was next evaluated in a mouse model system and averaged 20% localization of the total injected dose per gram of tumor at 24 h. Ten patients have had this immunoconjugate, with planar and tomographic reconstructed images being obtained at 24 h. The resulting images were compared to histopathological examination of the surgical specimens. Three patients acted as normal controls, two patients were selected on the basis of inappropriate sampling of adjacent ductal carcinoma in situ, three patients demonstrated only moderate antigen expression, and two patients demonstrated excellent tumor localization in both breast primary and regional node metastases. The high specificity of this antibody, ease of labeling, and excellent localization performance with a good antigen target encourage the development of this system as a method of localization and a potential means of antibody-guided therapy.

Adult↗
PubMed1994

Biodistribution and kinetics of radiolabelled pyrrolidino-4-iodo-tamoxifen: prospects for pharmacokinetic studies using PET.

With a view to evaluating the role of PET imaging in early clinical studies of new anticancer drugs, we are investigating the recently developed antiestrogen compound pyrrolidino-4-iodo-tamoxifen (idoxifene). Preliminary experimental studies have been undertaken using [125,131I]idoxifene, following synthesis of a tributyl-stannyl-idoxifene precursor to facilitate radioiodination. We have investigated the tissue biodistribution and kinetics of [125I]idoxifene following i.v. infusion in hooded rats bearing the hormone-dependent transplantable mammary tumour OES.HR1. Clearance of idoxifene from the circulation is accompanied by an increase in uptake by tumour and uterus, to peak levels after 24 hours (0.33 +/- 0.037% dose/g (mean +/- 1 SD) and 0.40 +/- 0.033% dose/g, respectively). Highest uptake of idoxifene was found in the liver (11.0 +/- 0.8% dose/g), with a progressive fall after 24 hours consistent with hepatobiliary excretion of the radiotracer. No evidence of idoxifene metabolism was found in tissue extracts taken up to 48 hours. Whole body clearance of [131I]idoxifene was characterised by a single exponential decay (t1/2 = 140 hours) up to 350 hours post administration. We conclude that 124I-labelled idoxifene combined with PET imaging would facilitate human in vivo pharmacokinetic studies of this new anticancer drug and provide an opportunity to investigate relationships between drug uptake and tumour response.

Animals↗
PubMed1993

Radioimmunolocalisation in breast cancer using the gene product of c-erbB2 as the target antigen.

Lymph node status is still the single most important prognostic factor in breast cancer. Axillary surgery remains the only reliable means of providing this information. This pilot study evaluates using a highly specific radiolabelled monoclonal antibody to provide equivalent information by a non-invasive technique. After optimisation of labelling conditions, our first antibody, ICR12 (against the gene product of c-erbB-2) was evaluated in a mouse model system. Twenty-four hours post i.v. injection the mice were killed and their organs, blood and tumours harvested for counting. Tumour localisation was four times greater than that into normal tissues, reaching 20% injected dose per gram of tumour. Eight patients have had this Tc99m-ICR12. Patient selection was by immunocytochemical staining of fine needle aspirates from the patient's own breast cancer. After intravenous administration of the immunoconjugate, tomographic images were obtained at 24 h. These results were compared to the subsequent histopathological examinations. Three patients acted as normal controls, one patient was negative due to inappropriate sampling, and two patients had strong membrane staining and provided excellent tumour localisation to both breast primary and regional node metastases. A further two patients only had moderate antigen expression on staining and did not localise well. The good performance of this radiolabelled antibody with patients that strongly stain for the antigen encourages the development of this system as both a method of staging breast cancer and a potential means of immunotherapy in this subgroup of patients.

Adult↗
PubMed1993

Proliferative behaviour of an oestrogen sensitive rat mammary tumour: evidence for a paracrine interaction between tumour and stroma.

An oestrogen-sensitive rat mammary tumour (OES HR1) has been grown in normal female rats and in female and male rats supplemented with oestrone. In some rats, after the tumour was established, both exogenous and endogenous sources of oestrogen were removed--a treatment which inhibited further growth of the tumour. The proliferative characteristics of the tumours were measured by injecting the rats with deoxybromouridine (BrdU) 4 h before removing the tumour. Extracted nuclei were reacted with anti-BrdU and the labelling index and DNA content measured by flow cytometry. A correlation between the number of (diploid) host cells present and the number of (aneuploid) tumour cells in S-phase of the cell cycle was observed. This result suggests that there are paracrine interactions between tumour and host cells. We also observed that, on oestrogen ablation, the labelling index was significantly reduced while the percentage of cells in S-phase changed far less. The demonstration that there are cells in S-phase which are not proliferating highlights a possible problem with the measurement of proliferation in human tumours from a DNA histogram.

Aneuploidy↗
PubMed1993

Immunotherapy of human tumour xenografts overexpressing the EGF receptor with rat antibodies that block growth factor-receptor interaction.

Athymic mice bearing xenografts of human tumours that overexpress the receptor (EGFR) for EGF and TGF alpha have been used to evaluate the therapeutic potential of three new rat monoclonal antibodies (mAbs) directed against two distinct epitopes on the extracellular domain of the human EGFR. The antibodies, ICR16 (IgG2a), ICR62 (IgG2b) and ICR64 (IgG1), have been shown (Modjtahedi et al., 1993) to be potent inhibitors of the growth in vitro of a number of human squamous cell carcinomas because they block receptor-ligand interaction. When given i.p. at 200 micrograms dose, the three antibodies were found to induce complete regression of xenografts of the HN5 tumour if treatment with antibody commenced at the time of tumour implantation (total doses: ICR16, 3.0 mg; ICR62, 1.2 mg; ICR64, 2.2 mg). More importantly when treatment was delayed until the tumours were established (mean diam. 0.5 cm) both ICR16 and ICR62 induced complete or almost complete regression of the tumours. Furthermore, treatment with a total dose of only 0.44 mg of ICR62 was found to induce complete remission of xenografts of the breast carcinoma MDA-MB 468, but ICR16 was less effective at this dose of antibody and only 4/8 tumours regressed completely. ICR16 and ICR62 were poor inhibitors of the growth in vitro of the vulval carcinoma A431, but both induced a substantial delay in the growth of xenografts of this tumour and 4/8 tumours regressed completely in the mice treated with ICR62 (total dose 2.2 mg). Although ICR16 and ICR64 were more effective than ICR62 as growth inhibitors in vitro, ICR62 was found to be substantially better at inducing regression of the tumour xenografts due perhaps to additional activation of host immune effector functions by the IgG2b antibody. We conclude that these antibodies may be useful therapeutic agents that can be used alone without conjugation to other cytotoxic moieties.

Animals↗