PubMed Health⌕ Search

Biomedical subjects

W J Gullick

Publications and source records attributed to W J Gullick.

At least 109 records · Page 6Linked to original sources
PubMed1991

Gonadotrophin-releasing hormone: physiological significance and relevance to cancer.

Gonadotrophin releasing hormone (GnRH) is a decapeptide released by the hypothalamus. The binding of the peptide to pituitary receptors leads to the activation of second messenger systems. The physiological outcome of the exposure of pituitary cells to GnRH is the release of luteinising hormone (LH) and follicle-stimulating hormone (FSH). Continued exposure of these receptors to high concentrations of the peptide desensitises the receptor, thus inhibiting the release of gonadotrophins. This paradoxical effect has proved to be beneficial in the clinic where long-acting and enzyme-resistant analogues are used to inhibit the pituitary-gonadal axis, for example in the treatment of advanced prostatic cancer. In addition GnRH-analogues may affect tumour cells directly as observed in vitro. These direct effects have been described as inhibitory but recent data suggests that low concentrations of GnRH-analogues may stimulate short term growth of prostatic cancer cells in vitro. GnRH shares many other common characteristics with peptide growth factors, including common second messenger systems and receptor desensitisation on prolonged exposure to the ligand. It is possible that the direct inhibitory effects of GnRH-analogues are mediated through the desensitisation of tumour GnRH receptors, as suggested by recent observations. The nature and mechanism of the direct anti-tumour effect is important to understand and to promote the therapeutic efficacy of GnRH-analogues in the clinic.

Amino Acid Sequence↗
PubMed1991

c-erbB-2 protein overexpression in breast cancer is a risk factor in patients with involved and uninvolved lymph nodes.

The c-erbB-2 gene is overexpressed in about 20% of human breast cancers. Four hundred and eighty-three cases previously examined by immunohistochemical staining for c-erbB-2 expression were analysed to assess the risk associated with the elevated protein expression. Oncoprotein expression was correlated with increasing tumour grade but not with oestrogen receptor status, nodal involvement, tumour size or age. There was an increased risk of relapse and death associated with c-erbB-2 expression irrespective of nodal involvement. This marker thus appears to be a significant prognostic factor in the early as well as the late stages of breast cancer.

Adult↗
PubMed1991

c-erbB-2 oncoprotein expression in primary and advanced breast cancer.

Immunoreactivity for c-erbB-2 oncogene product expression has been investigated in patients with breast cancer using the polyclonal antibody 21N. Three series of patients were studied, 602 presenting with primary operable cancer, 57 with stage 3 and 123 with stage 4 disease. Representative tissue sections of each primary tumour were stained using a standard immunoperoxidase technique. Invasive tumour membrane immunoreactivity was assessed and identified in 15% of patients with primary operable cancer and 20% in the advanced breast cancer group. The results demonstrate a relationship between poorer survival and oncogene expression in all three patient groups. Patients in the primary operable cancer group with membrane oncoprotein expression had a poorer outcome, 35% 10-year survival, compared with those in which membrane expression was absent, 55% 10-year survival. The median survival of patients with stage 3 disease with c-erbB-2 membrane positivity was 17 months compared to 24 months with membrane negativity. In stage 4 disease median survival with membrane expression was 8.8 months compared to 19.7 months with no membrane expression. In addition in the series of primary cancers a correlation existed between histological grade and membrane immunoreactivity. Multivariate analysis showed histological grade to be a more powerful prognostic factor than c-erbB-2 protein expression. In conclusion, this study demonstrates, in a large series of patients presenting to one centre, that c-erbB-2 protein expression is a prognostic indicator in patients with primary operable and advanced breast disease.

Breast Neoplasms↗
PubMed1991

Expression of growth factor receptors in human brain tumours.

The expression of the EGF receptor, c-erbB-2 and PDGF receptor proteins has been studied in a series of human brain tumour biopsies and cell lines. Western blotting was used to determine the amount of protein present and their intrinsic and ligand promoted enzyme activities were studied by immunoprecipitation followed by autophosphorylation. EGF receptors were found to be expressed at very high levels in 40% of primary tumour biopsies, but at uniformly low levels in tumour derived cell lines. The c-erbB-2 protein was not detected in tumour biopsies, but was present at variable, but low levels in extracts of tumour cell lines. PDGF receptors were also found at moderate to low levels in both primary tumours and cell lines. The EGF receptor gene was amplified in four out of 14 primary tumours and this generally correlated with high levels of protein expression. The c-erbB-2 gene was not amplified. Employing the polymerase chain reaction and sequence specific oligonucleotides as probes there was no evidence of mutations in the c-erbB-2 gene transmembrane region. These results suggest that alterations of expression of the EGF receptor may play a role in human brain tumours. There was however no evidence for aberrant expression of the c-erbB-2 protein. Additional experiments are required to assess the influence of PDGF receptor expression in brain tumour cells.

Brain Neoplasms↗
PubMed1991

Comparison of epidermal growth factor receptor expression in lung cancer by immunohistochemical staining of both frozen and formalin fixed specimens.

Two monoclonal antibodies used to investigate the expression of the epidermal growth factor receptor (EGF-R) in 45 lung cancers were compared. The R1 antibody recognises the extracellular domain portion of the receptor and the F4 is directed against the cytoplasmic portion. The reactivities of the two antibodies have been compared in fresh frozen tumour specimens. In addition the staining activity of the F4 antibody (the first to EGF-R which can be used in archival material) was compared using frozen and paraffin sections from the same series of tumours. Comparisons of the numbers of cells staining with the R1 and F4 antibody showed only slight discrepancy when fresh material was examined. The discrepancy that existed could be explained by the heterogeneity of the tumours. Very similar results were obtained using the F4 antibody on paraffin embedded and fresh non-small cell lung cancer material. We conclude that the expression EGF-R can be detected reliably by the F4 antibody in both the fresh frozen and formalin fixed, paraffin embedded material and could be useful in assessing the clinical importance of EGF-R in archival tumour material.

Cytological Techniques↗
PubMed1990

The partial purification and characterization of GnRH-like activity from prostatic biopsy specimens and prostatic cancer cell lines.

We have investigated the possibility of the secretion of gonadotrophin-releasing-hormone (GnRH)-like peptides by prostatic cancer cells in culture and their presence in cytosolic preparations from human prostatic biopsy specimens. A GnRH-specific radioimmunoassay showed GnRH-like activity in concentrated cytosolic preparations and conditioned media from DU 145, an androgen-insensitive human prostatic cell line and from LNCaP, an androgen-responsive prostatic cancer cell line. GnRH immunoreactivity in culture media correlated directly with cell numbers. HPLC demonstrated that this GnRH-like material co-migrated with synthetic GnRH. This homology between synthetic GnRH and partially purified prostatic GnRH was confirmed following V8 protease and trypsin digestion which resulted in similar alterations in HPLC characteristics. The mean content of GnRH-like activity/g specimen tissue was significantly more in malignant tissue (88.5 +/- 80.5 fmol) than in benign (29.6 +/- 22 fmol), though more specimens of benign tissue were positive (37/54) than malignant tissue (6/22). This observation, taken with an earlier finding of GnRH-specific receptors in a hormone-sensitive cell line and human cancer specimens provides supportive evidence for the autocrine hypothesis of cell regulation.

Gonadotropin-Releasing Hormone↗
PubMed1990

Bradykinin receptors undergo ligand-induced desensitization.

Bradykinin binds to specific cell surface receptors on Rat13 fibroblasts with a high affinity (2.1 nM). Prolonged exposure of cells to the ligand causes a concentration-dependent decline in surface levels of the 2.1 nM receptor from 40,000 receptors per cell to undetectable levels with a t1/2 of approximately 2 h. The decline occurs in parallel with the appearance of an equal number of lower affinity binding sites (40 nM), suggesting that ligand exposure causes desensitization by an alteration in receptor affinity. The affinity change is characterized by a faster rate of ligand dissociation while the rate of association remains unaltered. The observed desensitization is dependent on the presence of active cellular metabolism since (i) it does not occur in whole cells maintained at 4 degrees C and (ii) membranes prepared from Rat13 cells retain their high-affinity sites at 37 degrees C despite extensive ligand exposure.

Animals↗
PubMed1990

c-erbB-2 oncoprotein expression in primary human tumors.

Using a specific antiserum (21N) to the c-erbB-2 oncoprotein, a total of 405 primary malignant human tumors arising in the breast (n = 191), lung (n = 110), colon/rectum (n = 23), bladder (n = 48), prostate (n = 23), and skin (n = 10) were stained immunohistochemically to detect those tumors that over-expressed this putative transmembrane receptor. Malignant cells showed intense positivity for this oncoprotein in 17% of the breast carcinomas, 4% of the colorectal tumors, 2% of the bladder tumors, and 1% of the nonsmall cell lung carcinomas. No positive staining was evident in the prostate, skin, or small cell lung carcinomas. This study shows that over-expression of the c-erbB-2 oncoprotein is common in breast cancer but relatively rare in the other malignancies studied. In addition, this oncoprotein can be identified readily in routine paraffin-embedded tissue.

Breast Neoplasms↗
PubMed1990

The role of the epidermal growth factor receptor and the c-erbB-2 protein in breast cancer.

Breast cancer cells are derived from epithelial cells lining the ducts of the breast. One of the fundamental characteristics that distinguish tumour cells from normal cells is that cancer cells grow in an apparently unregulated way. Understanding the mechanisms that regulate the growth and differentiation of normal breast epithelial cells and the differences between these systems in cancer cells is one of the central goals of research into the cell biology of breast cancer.

Breast Neoplasms↗
PubMed1990

NCL-CB11, a new monoclonal antibody recognizing the internal domain of the c-erbB-2 oncogene protein effective for use on formalin-fixed, paraffin-embedded tissue.

The c-erbB-2 proto-oncogene encodes a 190 k Mr protein representing a putative growth factor receptor with considerable homology to the EGF receptor. Gene amplification and overexpression of the oncogene protein have been demonstrated in a variety of tumours including breast cancer, where it is associated with a poor prognosis. In this study we have produced and characterized a mouse monoclonal antibody, designated NCL-CB11, to the c-erbB-2 protein. NCL-CB11 was generated to a synthetic peptide sequence corresponding to a site of predicted antigenicity near the C-terminus of the internal domain of the protein. NCL-CB11 produces intense membrane-associated immunohistochemical staining in a proportion of human cancer cells. The specificity of the antibody is supported by Western blotting and immunoprecipitation studies. Reactivity with an internal site of the protein is confirmed by the necessity of cell permeabilization for reactivity in fluorescence-activated cell sorter (FACS) analysis. A high degree of correlation between immunohistochemical staining using NCL-CB11, and c-erbB-2 gene amplification has been observed. NCL-CB11 should prove to be a valuable reagent for investigations into the pathological significance of c-erbB-2 protein expression.

Animals↗
PubMed1990

The c-erb B-2 proto-oncogene in human pancreatic cancer.

The c-erb B-2 oncogene encodes a 190 kD transmembrane growth factor receptor which is closely related to the EGF receptor and has been found to be amplified and overexpressed in a number of human adenocarcinomas, particularly of the breast. We have analysed, by immunocytochemistry using the 21N antibody, expression of c-erb B-2 in a retrospective series of pancreatic adenocarcinoma, chronic pancreatitis, and examples of histologically normal pancreas. In three cases (21 per cent) of chronic pancreatitis, there were focal areas of cytoplasmic immunoreactivity in regenerating epithelium. In 15 cases (17 per cent) of pancreatic adenocarcinoma, cytoplasmic immunoreactivity was seen, while in two cases (2 per cent) strong membrane staining of tumour cells was seen which could be blocked by peptide controls. c-erb B-2 immunoreactivity was also demonstrated using a second antibody, 20N, which recognizes another peptide sequence of the c-erb B-2 protein. There was no relationship between immunoreactivity and histological subtype or grade, but there was absolute concordance between staining in primary and metastatic deposits. Since the rat homologue (neu) of the c-erb B-2 oncogene may be activated by a specific point mutation in its transmembrane region, we have analysed 23 cases from this series for mutations by polymerase chain reaction amplification and sequence-specific oligonucleotide hybridization. We were unable to identify activity mutations in this series. These data suggest that there is abnormal expression of c-erb B-2 oncogene in nearly 20 per cent of cases although mutational activation of this gene is not seen in human pancreatic adenocarcinoma.

Adenocarcinoma↗
PubMed1990

c-erbB-2 oncogene expression in ovarian cancer.

One hundred and four common epithelial malignancies of the ovary were stained for c-erbB-2 using an affinity-purified polyclonal antibody 21N. Twenty-three out of 104 (22.1 per cent) showed cytoplasmic staining alone. Nine out of 104 (8.7 per cent) showed both membrane and cytoplasmic staining. In a multivariate Cox analysis with other known risk factors the relative risk for cytoplasmic staining alone was 1.456 (chi 2 = 1.71, P greater than 0.1) and for membrane and cytoplasmic staining 0.316 (chi 2 = 7.95, P less than 0.005). These results do not support an adverse prognostic effect of c-erbB-2 in our patients.

Aged↗
PubMed1990

Immunohistochemical demonstration of c-erbB-2 protein in mammary ductal carcinoma in situ.

The presence of the c-erbB-2 protein, demonstrated immunohistochemically with antibody 21N, has been studied in 72 cases of pure mammary ductal carcinoma in situ. Sixty-one percent of cases showed positive staining. The protein was always present in large-cell comedo type of ductal carcinoma in situ, and never in small-cell cribriform/micropapillary type of ductal carcinoma in situ. When nuclear size was measured, staining was associated with tumors containing cells with large nuclei measuring up to 20 mu, and was never present in lesions containing cells with small nuclei measuring 10 mu or less. In tumors of mixed histopathologic type of ductal carcinoma in situ, variable staining was seen; the cells with small nuclei never stained, while the majority of cells with large nuclei reacted positively. The possible relevance of these findings to the biologic behavior of DCIS is discussed.

Breast Neoplasms↗