Growth factors as novel therapeutic targets in neoplastic disease

Abstract

The emerging concept of autocrine/paracrine control of tumour cell proliferation coupled with the identification of several polypeptide mitogens has created new opportunities for the discovery of novel classes of antineoplastic drugs. Growth factors (for example, transforming growth factor alpha, fibroblast growth factor and platelet-derived growth factor) and, in certain cases, their receptors have been identified in a number of human tumours and their expression may contribute to unregulated cell proliferation. Selective antagonists that block the activity of these mediators may have important therapeutic utility in the management of cancer patients, particularly in metastatic disease where patterns of tumour cell dissemination may be strongly influenced by paracrine mediators. However, since many, if not all, of these growth factors are polypeptides with molecular weights over 5 kDa, the discovery of potent antagonists represents an important pharmacological challenge. Advances in understanding protein structure-function relationships will be essential in guiding rational attempts at generating growth factor antagonists through site-directed mutagenesis and peptide synthesis, while better insights into the mechanisms by which growth factors are synthesized, processed, released and exert their mitogenic effects may also reveal new sites for pharmacological assault. The availability of (low molecular weight) potent growth factor antagonists will allow the autocrine/paracrine hypothesis to be clinically tested and in the process will throw considerable light on the function of these growth regulatory molecules in vivo.