The EGF Receptor System as a Target for Antitumor Therapy

Abstract

Monoclonal anti-EGF receptor antibodies, EGF receptor antibodies coupled to toxins, TGF alpha-toxin conjugates and tyrosine kinase inhibitors show great potential as antitumor agents. These compounds are effective inhibitors of the EGF receptor system as it functions in the mitogenic stimulation of malignant cells. The effectiveness of cell growth inhibition mediated by anti-EGF receptor antibody and tyrosine kinase inhibitors may prove to be limited and selective. This is in view of the possibility that malignant cell proliferation may be controlled by various mechanisms instead of that which involves the EGF receptor system, despite the expression of both EGF receptor and TGF alpha in the same cell. Other growth control mechanisms could involve hormone receptor systems such as estradiol and the estrogen receptor, oncogene activation or other growth factor-receptor systems. In those malignancies in which growth control resides in the EGF-receptor system, antitumor therapy using monoclonal anti-EGF receptor antibodies and tyrosine kinase inhibitors is a possibility worth pursuing. The effectiveness of immunotoxins and TGF alpha-toxin conjugates may only require the presence of EGF receptor and not be limited to those cells whose growth is controlled exclusively by the EGF receptor system. Nonspecific toxicity may, however, limit the use of these compounds. Further studies assessing the extent of such a toxicity are in order. In the face of the preceding reservations, however, one must not overlook the potential for great achievement as this novel therapeutic avenue is traversed.

Epidermal growth factor receptor expression by human squamous cell carcinomas of the head and neck, cell lines and xenografts

“…Overexpression of EGFR by SCC cell lines might help them respond to low amounts of EGF or TGF-a, while inhibition of ligand binding to the EGFR by EGFR-specific monoclonal antibodies seems to block the growth of SCC cell lines in tissue culture and xenografts, which highlights the importance of the EGFR to the growth of SCC (Masui et al, 1984;Modjtahedi et al, 1993a, b). Owing to its reported overexpression, the EGFR has been suggested to be a potential target for diagnosis (Soo et al, 1987;Divgi et al, 1991) or directed therapy of SCC (Harris, 1990;Ennis et al, 1991). Although several studies have indicated that the EGFR is overexpressed on human SCC, quantitation of the overexpression relies heavily on the study of SCC-derived cell lines in which the frequency of significant overexpression is very high (Cowley et al, , 1986.…”

Prognostic value of cytosolic tyrosine kinase activity in 249 node-positive breast cancer patients

“…TPK activity therefore represents an excellent biological target for the development of new cancer drugs (Dvir et al, 1991;Ennis et al, 1991). New therapeutic strategies diected against growth factors might thus include tyrosine kinase inhibitors to interfere with signalling transduction cascades after growth factor is bound to its receptor (Harris et al, 1992).…”

Immunoconjugates made of an anti-EGF receptor monoclonal antibody and type 1 ribosome-inactivating proteins from Saponaria ocymoides or Vaccaria pyramidata

“…The EGFR overexpression in some tumour cells compared with normal tissues has been indicated previously as an operational marker for tumour therapy with anti-EGFR monoclonal antibodies (Ennis et al, 1991). Tosi et al (1995) show that MintS inhibits the proliferation of tumour cell lines to the same extent despite the difference in EGFR levels.…”

“…The potential value of EGFR as a target for the diagnosis and therapy of human tumours has been recognized for several years, and the use of anti-EGFR monoclonal antibodies may provide therapeutic tools in the treatment of tumours overexpressing the receptor (Ennis et al, 1991).…”