C Dean

Publications (26)90.59 Total impact

• Article: Two erbB-4 transcripts are expressed in normal breast and in most breast cancers

  C. Sawyer, I. Hiles, M. Page, M. Crompton, C. Dean
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  ABSTRACT: ErbB-4 is a recently described member of the epidermal growth factor receptor (EGFR) family which together with erbB-3 acts as a receptor for a group of ligands known as the neuregulins (NRGs) or heregulins (HRGs). Unlike the EGFR and erbB-2 relatively little is known about the expression of erbB-4 in human tumours. Using RT-PCR and Southern blotting analysis we have investigated the expression of erbB-4 mRNA in a range of human tumour cell lines and in normal and malignant breast tissue. Using primers which amplified a 658 base pair (bp) region corresponding to part of the cytoplasmic domain of c-erbB-4 we found the receptor was expressed in some but not all breast and ovarian tumour cell lines and also in a glioma cell line. The highest level of erbB-4 expression was found in the ovarian carcinoma OVCAR-3 and the breast carcinoma T-47D. In all cell lines where the 'full-length' erbB-4 was detected, a second previously undescribed c-erbB-4 sequence was also found as a 610 bp PCR product. The alternative PCR product was identical in sequence to c-erbB-4 except for a deletion of 48 bp which encodes a consensus phosphatidylinositol 3-kinase (PI3K) binding site. This suggested that the two forms of erbB-4 might interact with different intracellular signalling pathways and therefore influence a wider variety of cellular responses to heregulin than previously thought. Expression of both erbB-4 variants was found in 7/7 normal breast tissues but only in 9/12 breast tumours analysed. In line with the terminology of Elenius et al. (1997b) we have designated the two isoforms of the C-terminal transcripts as CT-a (full-length) and CT-b which lacks the P13K binding motif. These results identify suitable cell lines for the further investigation of erbB-4 expression and function and suggest that the role of erbB-4 in breast cancer warrants further investigation with larger numbers of normal and malignant breast tissues.
  Oncogene 09/1998; 17(7):919-24. · 6.37 Impact Factor
• Article: EGFR blockade by tyrosine kinase inhibitor or monoclonal antibody inhibits growth, directs terminal differentiation and induces apoptosis in the human squamous cell carcinoma HN5.

  H Modjtahedi, K Affleck, C Stubberfield, C Dean
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  ABSTRACT: Human squamous cell carcinomas frequently overexpress the epidermal growth factor receptor (EGFR) and this is often associated with poor prognosis in patients with these cancers. The high level of expression of the EGFR provides an important target for therapy and we and others have shown that monoclonal antibodies (mAbs) which block the activation of the receptor by the EGF family of ligands inhibit the growth of EGFR overexpressing tumours in vitro and induce the regression of established tumours grown as xenografts in athymic mice. Inhibitors of the tyrosine kinase associated with the EGFR have also been shown to block receptor activation and prevent tumour cell proliferation. Using the EGFR-overexpressing head and neck carcinoma cell line HN5, we have compared the biological consequences of treatment with an inhibitor of EGFR tyrosine kinase (PD153035) with anti-EGFR monoclonal antibodies (mAbs) ICR63 or ICR80. We found that both the anti-EGFR mAbs and the TK inhibitor produce similar biological changes namely, they inhibit the EGF and TGFá-induced tyrosine phosphorylation of the receptor and the growth in culture of HN5 cells. At concentrations above 100 nM, the TK inhibitor prevented the growth in culture of HN5 cells completely with an IC50 of 40 nM. With the anti-EGFR mAbs, growth of HN5 cells was inhibited completely at concentrations above 4 nM with an IC50 of 1 nM. More importantly we found that, like the anti-EGFR mAbs, treatment with the TK inhibitor directs HN5 cells to undergo terminal differentiation as monitored by the expression of cytokeratin 10. In addition, our results indicate that the growth inhibitory effects of the anti-EGFR agents also lead to induction of apoptosis as determined by 7-amino actinomycin D staining (7-AAD). We conclude that EGFR blockade by anti-EGFR mAbs or TK inhibitor influences the growth in culture of EGFR overexpressing tumours by directing terminal differentiation and inducing apoptosis.
  International Journal of Oncology 09/1998; 13(2):335-42. · 2.40 Impact Factor
• Article: Anti-EGFR monoclonal antibodies which act as EGF, TGF alpha, HB-EGF and BTC antagonists block the binding of epiregulin to EGFR-expressing tumours.

  H Modjtahedi, T Komurasaki, H Toyoda, C Dean
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  ABSTRACT: Epiregulin is the newest member of the epidermal growth factor (EGF) family of ligands that was isolated from conditioned medium of the murine fibroblast-derived tumour cell line NIH3T3/T7. Here, using a panel of anti-EGFR receptor (EGFR) monoclonal antibodies (MAbs) directed against 4 distinct epitopes on the external domain of the receptor, we have investigated the importance of the EGFR in transmitting the biological action of epiregulin. We found that MAb ICR9, which enhances the binding of EGF, TGF alpha, HB-EGF and betacellulin to the EGFR, also increases the binding of 125I-epiregulin to a number of EGFR-expressing tumour cell lines, including EJ, SKBR3, SKOV3, MDA-MB468 and HN5. In addition, anti-EGFR MAbs ICR15, ICR16, ICR61, ICR62 and ICR80, which block the binding of 125I-EGF to the EGFR, inhibit the binding of 125I-epiregulin to these tumour cell lines. Like EGF, we found that both the epiregulin-induced growth inhibition of HN5 and MDA-MB468 cells and tyrosine phosphorylation of the 170 kDa EGFR on HN5 cells are reversed in the presence of anti-EGFR MAbs ICR62 and ICR80. Surprisingly and unlike 125I-EGF, radiolabelled epiregulin bound very poorly to human bladder carcinoma EJ cells and its binding to SKOV3 cells was not inhibited efficiently in the presence of blocking antibodies. We conclude that the EGFR plays an important role in transmitting the biological action of epiregulin and that these effects could be blocked in the presence of anti-EGFR MAbs. The low level of binding of epiregulin compared with EGF to EJ cells suggests that the EGFR may not be the primary receptor for epiregulin.
  International Journal of Cancer 02/1998; 75(2):310-6. · 5.44 Impact Factor
• Article: Monoclonal antibodies directed against the EGF receptor show differential bindings of amphiregulin and EGF to the EGF receptor.

  H Modjtahedi, B Cohen, C Dean
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  ABSTRACT: Amphiregulin (AR), a new member of the EGF family of ligand, is a glycoprotein containing a 78 or 84 amino acid core polypeptide that was originally purified from the conditioned medium of the breast carcinoma cell line MCF-7 after treatment with phorbol 12-myristate 13-acetate. The aim of the present study was to determine whether, like EGF, TGF alpha, heparin binding EGF-related growth factor (HB-EGF) and betacellulin (ETC), the recombinant 78 amino acid form of mature human AR transmits its biological effects following binding to the EGF receptor (EGFR). We show that unlike EGF, TGF alpha, HB-EGF and BTC, the mature AR is not effective in blocking the binding of I-125-EGF or the iodinated anti-EGFR antibodies (mAbs) I-125-ICR62 and I-125-ICR80 to the external domain of the EGF receptor on EJ cells. Again, in contrast to other EGF ligands, AR is not effective in enhancing the binding of another anti-EGFR mAb ICR9 to the EGFR on EJ cells. Like EGF, TGF alpha and HB-EGF, AR could inhibit the growth in culture of EGFR overexpressing tumour cell lines, namely HN5, HSC-1 and MDA-MB468 cells, and again compared to other ligands AR was moderately effective at low concentration. Despite these differences, we show that like EGF, AR could induce the tyrosine phosphorylation of the 170 kDa EGF receptor on HN5 cells and that this effect could be blocked in the presence of anti-EGFR mAbs ICR62 and ICR80. Moreover, like EGF, the AR-induced growth inhibition of MDA-MB468 cells could also be reversed in the presence of anti-EGFR mAbs ICR62 and ICR80. On the basis of our results we conclude that, unlike the EGF, TGF alpha, HB-EGF and BTC, the AR-induced activation of the EGFR may involve another receptor.
  International Journal of Oncology 02/1997; 10(2):339-47. · 2.40 Impact Factor
• Article: Monoclonal antibodies to the EGF receptor act as betacellulin antagonists.

  H Modjtahedi, C Dean
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  ABSTRACT: Betacellulin (BTC), a recently discovered member of the EGF family that is produced by certain tumour cells, is thought to be involved in autocrine growth by activating the EGF receptor (EGFR). We have investigated whether monoclonal antibodies (mAbs) to the EGFR which act as EGF, TGF alpha and HB-EGF antagonists could also be effective as BTC antagonists by blocking its binding to the EGFR. We report that the binding of 125I-BTC to a range of tumour cells expressing the EGFR was inhibited by rat mAbs that bound to three distinct epitopes on the extracellular domain of the EGFR. We show that one of these mAbs (ICR62) also prevents activation of the EGFR by betacellulin as evidenced by reversal of the effects on the growth of human fibroblasts and the head and neck carcinoma cell line HN5 and by inhibition of receptor phosphorylation in HN5 cells. We conclude that mAbs such as ICR62 have potential for use as therapeutic agents by blocking betacellulin-induced growth of tumours which over-express the EGFR.
  Biochemical and Biophysical Research Communications 05/1996; 221(3):625-30. · 2.48 Impact Factor
• Source

  Available from: nih.gov

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

  H Modjtahedi, T Hickish, M Nicolson, J Moore, J Styles, S Eccles, E Jackson, J Salter, J Sloane, L Spencer, K Priest, I Smith, C Dean, M Gore
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  ABSTRACT: 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.
  British Journal of Cancer 02/1996; 73(2):228-35. · 5.04 Impact Factor
• Article: Antibody-induced inhibition of growth of egfr overexpressing tumors occurs in the absence of receptor down-regulation.

  H Modjtahedi, C Dean
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  ABSTRACT: Using two antibodies which bind to distinct epitopes on the extracellular domain of the EGF receptor (EGFR) we have developed a novel method for monitoring EGFR expression and the behaviour of monoclonal antibody (mAb) bound to the receptor. We have used this method to investigate the fate of the rat mAb ICR80 following binding to the EGF receptor on tumour cells. Antibody ICR80, which was raised against the external domain of the EGF receptor on a human brain tumour (A172) cell line and was employed in this study, has the following properties. It (a) blocks the binding of EGF, TGF alpha and HB-EGF to the EGFR, (b) prevents the EGF, TGF alpha and HB-EGF induced tyrosine phosphorylation of the EGFR, and (c) inhibits the growth in vitro of the head and neck tumour (HN5) cell line overexpressing the EGF receptor. Our results presented herein also show that EGF receptor blockade by antibody ICR80 is not accompanied by detectable loss of antibody from the cell surface or down-regulation of the receptor. On the basis of these results we conclude that the long-lasting blockade of the EGF receptor on tumour cells by antibody may be an important factor in preventing the binding of growth factors which are essential for their continued proliferation.
  International Journal of Oncology 10/1995; 7(4):783-8. · 2.40 Impact Factor
• Article: Primary structure of the variable regions encoding antibody to NG2, a tumour-specific antigen on the rat chondrosarcoma HSN. Correlation of idiotypic specificities with amino acid sequences.

  O Léger, E Jackson, C Dean
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  ABSTRACT: Eight syngeneic rat monoclonal antibodies that recognize structurally overlapping epitopes on the chondroitin proteoglycan NG2, a tumour-specific antigen on the chemically induced rat chondrosarcoma HSN, have been analysed for the sequence of their immunoglobulin heavy (H) and light (L) chain variable (V) regions. This analysis defined five groups of antibodies which are very similar for both the H and L chains and revealed that a wide range of different V regions are capable of binding to the same antigenic determinant. However, three mAbs, 11/160, ALN/12/17 and ALN/9/94, which recognize a sequential epitope, were found to use almost identical heavy (V-D-J) and light (V-J) chains in regions demonstrating an exclusivity in specific protein-protein interaction for this particular epitope. Two other mAbs, ALN/11/53 and AL/3/12, used similar V and J segments but totally different D regions. With the exception of the pair ALN/11/53 and AL/3/12, this grouping of antibodies matches that derived from the idiotypic specificity study we have reported previously. The reactivity pattern of Ab1 11/160, ALN/12/17 and ALN/9/94 with six anti-idiotopic mAbs raised against 11/160 demonstrated that the idiotope recognized by Ab2 HIM/3/41 was defined by a single amino acid, Asn, at position 52 within the CDR2 loop of the VH region; whereas the D region of Ab1 ALN/11/53 was implicated as the structural correlate of idiotypy. The substitution of AsnH52 influenced the Id recognition but Ag binding was not affected suggesting that Ab2 HIM/3/41 did not mimic the NG2 Ag.
  Molecular Immunology 08/1995; 32(10):697-709. · 2.90 Impact Factor
• Article: The binding of HB-EGF to tumour cells is blocked by mAbs which act as EGF and TGF alpha antagonists.

  H Modjtahedi, C Dean
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  ABSTRACT: Heparin binding EGF (HB-EGF), a newly discovered member of the EGF family of mitogens, binds to the EGF receptor (EGFR) and to heparan sulfate proteoglycans on the cell surface. Here, we show that the binding of HB-EGF to the EGFR is inhibited by mAbs which prevent the interaction of EGF and TGF alpha with the receptor. Also, we show that, like EGF and TGF alpha, treatment with HB-EGF inhibits the growth in vitro of tumours (HN5, HSC-4) that overexpress the EGFR. We conclude that mAbs which act as EGF and TGF alpha antagonists should also be effective therapeutic agents for blocking the growth of EGFR overexpressing tumours induced by HB-EGF.
  Biochemical and Biophysical Research Communications 03/1995; 207(1):389-97. · 2.48 Impact Factor
• Article: A model for Lorentz microscopy and magnetic behaviour of longitudinal thin film with an irregular lattice

  N.S. Walmsley, C. Dean, A. Hart, D.A. Parker, R.W. Chantrell
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  ABSTRACT: Lorentz microscopy is an important experimental technique currently being used to investigate magnetic microstructures found in longitudinal thin films. Micromagnetic models of thin films have previously been based on regular hexagonal lattices; a Monte-Carlo algorithm has been developed which produces an irregular structure with a grain size distribution. We model Lorentz microscopy by integrating the in-plane components of the stray field along a straight line trajectory. The effects of packing fraction and structure regularity on the remanence and coercivity values are discussed; we show that regularity has a qualitative effect on the simulated Lorentz images of coercive states
  IEEE Transactions on Magnetics 12/1994; · 1.36 Impact Factor
• Article: The chondroitin sulfate proteoglycan NG2 is a tumour-specific antigen on the chemically induced rat chondrosarcoma HSN.

  O Léger, C Johnson-Léger, E Jackson, B Coles, C Dean
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  ABSTRACT: N-terminal sequences of 19 and 11 amino acids obtained from 2 different tryptic fragments of the tumour-specific antigen on the chemically induced rat chondrosarcoma HSN show a 100% homology with the rat chondroitin sulfate proteoglycan NG2. Using a scheme of overlapping oligonucleotide primers we have cloned by PCR amplification the cDNA for the specific antigen of the HSN tumour that is immunogenic in immunocompetent CBH/Cbi rats and now report that its cDNA sequence is identical to that of NG2. The cDNA codes for a transmembrane protein of 2,325 amino acids with a large extracellular domain of 2,224 amino acids containing 2 cysteine-rich regions, a transmembrane domain (25 amino acids) and a short cytoplasmic tail (76 amino acids). The tumour-specific determinant was found to lie between amino acid residues 556 and 992 on the core glycoprotein.
  International Journal of Cancer 10/1994; 58(5):700-5. · 5.44 Impact Factor
• Source

  Available from: Gary Box

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

  H Modjtahedi, S Eccles, J Sandle, G Box, J Titley, C Dean
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  ABSTRACT: 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.
  Cancer Research 05/1994; 54(7):1695-701. · 7.86 Impact Factor
• Article: Immunotherapy with antibodies to the EGF receptor.

  C Dean, H Modjtahedi, S Eccles, G Box, J Styles
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  ABSTRACT: 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.
  International journal of cancer. Supplement = Journal international du cancer. Supplement 02/1994; 8:103-7.
• Article: The receptor for EGF and its ligands - expression, prognostic value and target for therapy in cancer (review).

  H Modjtahedi, C Dean
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  ABSTRACT: The results of recent studies suggest that overexpression of the EGF receptor accompanied by production of its ligands is an important characteristic of human squamous cell carcinomas. The EGF receptor which transmits the growth promoting or inhibitory effects of epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha) and amphiregulin is a member of the type I family of growth factor receptors which possess tyrosine kinase activity. In this review we a) discuss the role played by this receptor and its ligands in the transformation of normal cells, b) analyze the evidence for expression of the receptor and its ligands as prognostic markers in cancer patients and c) indicate ways that the overexpressed EGF-receptor system on human malignant cells can be targeted for therapeutic application.
  International Journal of Oncology 02/1994; 4(2):277-96. · 2.40 Impact Factor
• Article: Simulations of the remanent behaviour of longitudinal thin films

  C. Dean, R.W. Chantrell, A. Hart, D.A. Parker, K. O'Grady
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  ABSTRACT: A computer model of a longitudinal thin film has been developed and applied to a study of the remanent behavior of the films. The exchange coupling between grains is shown to give rise to a difficulty of obtaining an AC erased state, this being interpreted in terms of the resultant cooperative magnetization reversal involving large areas of the film. Exchange coupling is also responsible for the positive δ I parameter determined by comparison of remanence curves. However, the δ I plot is shown to be dependent on the detailed behavior of exchange and magnetostatic coupling between grains
  IEEE Transactions on Magnetics 12/1993; · 1.36 Impact Factor
• Article: The growth-response of human tumor-cell lines expressing the EGF receptor to treatment with EGF and or mabs that block ligand-binding.

  H Modjtahedi, J Styles, C Dean
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  ABSTRACT: We have investigated the effect of treatment with epidermal growth factor (EGF) and/or monoclonal antibodies (Mabs) to the epidermal growth factor receptor (EGFR) on the growth in vitro of a number of human tumour cell lines. Mabs ICR10, ICR11, and ICR16 that prevent the binding of both I-125-EGF and I-125-TGFalpha to the EGF receptor were found to inhibit the growth of human tumour cell lines overexpressing the EGF receptor. At high concentrations (5 nM), EGF was also found. to inhibit the growth of HN5, A431 and MDA MB-468 cells whereas the proliferation of SKBR3 and HN6 cells was stimulated. While some of the cell lines (e.g. HN5 and HN6) were very susceptible to growth inhibition by antibodies to the EGFR others, known to secrete autocrine growth factors (e.g. A431 and MDA MB-468), were less affected by these antibodies. Indeed, growth of the latter cell lines was inhibited more effectively by the addition of 5 nM of exogenous EGF than by treatment with 156 nM of the anti-EGFR Mabs ICR16, ICR11, and ICR10. In addition, we show that the growth of HN5 cells, which express very large numbers of EGF receptors (1.4x10(7)/cell), was stimulated at picomolar concentrations of EGF but inhibited at concentrations of EGF in the nanomolar range. Maximal stimulation (25% above control) was observed with the addition of 78 pM EGF to the cultures. The mitogenic effect of low concentrations of EGF and the growth inhibitory effect of nanomolar concentrations of EGF on HN5 cells could be reversed by the addition of 156 nM of the anti-EGFR antibodies. We conclude that growth inhibition can follow from either inhibition of signal transduction by blocking ligand binding to the EGFR or from excess binding of ligand. With tumours that produce significant quantities of autocrine growth factors the latter will compete with the Mabs for binding to the receptor and reduce their effectiveness.
  International Journal of Oncology 08/1993; 3(2):237-43. · 2.40 Impact Factor
• Source

  Available from: nih.gov

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

  S M Allan, C Dean, I Fernando, S Eccles, J Styles, V R McCready, M Baum, N Sacks
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  ABSTRACT: 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.
  British Journal of Cancer 05/1993; 67(4):706-12. · 5.04 Impact Factor
• Source

  Available from: Gary Box

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

  H Modjtahedi, S Eccles, G Box, J Styles, C Dean
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  ABSTRACT: 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.
  British Journal of Cancer 03/1993; 67(2):254-61. · 5.04 Impact Factor
• Article: Immunocytochemical staining for the c-erbB-2 gene product in breast aspirates: a preliminary report.

  I N Fernando, S M Allan, J Sandle, C Dean, N Sacks, P A Trott
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  ABSTRACT: The results of the determination of c-erbB-2 gene expression by immunocytochemical staining of cytological aspirates, prepared by cytocentrifugation, have been compared with paraffin-embedded tissue sections from the same tumour. Our results show equivalent staining in 20/22 cases, with six cases being both scored positive and fourteen cases being both negative. Two samples gave conflicting results. One case was scored as being positive on the cytological aspirate, whereas in the tissue sections taken from the same tumour positive staining was only seen in areas of non-invasive intraduct carcinoma. This sample was scored as being negative. In another case, cytoplasmic staining with less than 50% of the cells showing any positivity was observed in the cytospin sample, with negative staining in the corresponding tissue section. We conclude that expression of c-erbB-2 immunostaining is detectable on cytological preparations prepared by cytocentrifugation but must be interpreted with caution in tumours which may have a large intraduct component or which give predominant cytoplasmic staining.
  Cytopathology 02/1993; 4(4):219-24. · 1.59 Impact Factor
• Article: Circulating levels of epithelial membrane antigen in patients with breast or colorectal-cancer.

  B Davidson, J Babich, P Okeefe, J Styles, C Dean
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  ABSTRACT: Epithelial membrane antigen (EMA) is expressed by adenocarcinomas of the breast, ovary and colon and has been suggested as a circulating tumour marker. Serum EMA levels were measured in 126 patients, 31 with colorectal cancer, 52 with breast cancer and 43 age matched controls using a competitive binding radioimmunoassay and the rat anti-EMA monoclonal antibody (MAb) ICR2. The EMA levels in the control group varied widely from 90-3240ng/ml with a median value of 570ng/ml. This was not significantly different from the levels in patients with colorectal cancer (60-8530, median 580ng/ml) or those with breast cancer (210-13300, median 655ng/ml). However, the highest EMA levels (>5000ng/ml) were found in patients with cancer. The wide range of EMA levels in the control group prohibit its use for screening.
  International Journal of Oncology 10/1992; 1(5):611-4. · 2.40 Impact Factor