Related Experiment Videos
Growth factors as novel therapeutic targets in neoplastic disease
R Greig1, D Dunnington, U Murthy
1Department of Cell Biology, Smith Kline & French Laboratories, King of Prussia PA 19406-0939.
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.
Insights
Discovering novel antineoplastic drugs targeting cancer cell proliferation is crucial. This research explores using potent, low molecular weight growth factor antagonists to block autocrine/paracrine signaling in tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Autocrine/paracrine signaling pathways involving growth factors are implicated in tumor cell proliferation.
- Growth factors and their receptors are found in various human tumors, potentially driving unregulated cell growth.
- Targeting these mediators offers therapeutic opportunities, especially for metastatic cancers.
Purpose of the Study:
- To explore the potential of novel antineoplastic drugs targeting tumor cell proliferation.
- To investigate the therapeutic utility of selective antagonists for growth factors.
- To address the pharmacological challenge of developing potent antagonists for large polypeptide growth factors.
Main Methods:
- Investigating the role of polypeptide mitogens in tumor growth.
- Identifying growth factors and receptors in human tumors.
- Exploring strategies for generating growth factor antagonists, including site-directed mutagenesis and peptide synthesis.
- Studying the synthesis, processing, release, and mitogenic effects of growth factors.
Main Results:
- Growth factors and their receptors are present in human tumors, contributing to proliferation.
- Selective antagonists could be therapeutically valuable, particularly in metastatic disease.
- Developing potent, low molecular weight antagonists is a significant pharmacological challenge.
- Understanding structure-function relationships and growth factor mechanisms is key to antagonist development.
Conclusions:
- Potent, low molecular weight growth factor antagonists are essential for testing the autocrine/paracrine hypothesis in cancer.
- Developing such antagonists will illuminate the in vivo functions of growth regulatory molecules.
- This approach holds promise for novel cancer therapies, especially for metastatic conditions.