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biopharmaceuticals biochemistry and biotecnology - Walsh G.

Walsh G. biopharmaceuticals biochemistry and biotecnology - John Wiley & Sons, 2003. - 572 p.
ISBN 0-470-84327-6
Download (direct link): biochemistryandbiotechnology2003.pdf
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• Inositol triphosphate (IP3), which raises intracellular Ca2+ concentrations by inducing its release from intracellular stores. This Ca2+, in turn, activates a cytoplasmic serine/ threonine protein kinase.
• Diacylglycerol (DG), which subsequently activates protein kinase C.
(b) Activation of the Ras pathway (Ras proteins are G proteins). Their activation, upon binding of GTP, results in triggering intracellular mitogenic events.
(c) The EGF-receptor complex also appears to be capable of translocating to the nucleus. The significance of this remains to be determined.
GROWTH FACTORS 287
Figure 7.3. Structure of PD 153035, a tyrosine kinase inhibitor that may be of therapeutic use in the treatment of cancers caused by inappropriate overexpression of EGF-associated tyrosine kinase activity
Several cancer cell types are characterized by expressing a truncated EGF receptor. The related viral oncogene, V-erbB, also encodes a truncated receptor which lacks most of the extracellular domain (the EGF receptor is also known as C-erbB). Mutant receptors that display inappropriate constitutive activity can lead to cellular transformation, due to the continuous generation of mitogenic signal.
Overexpression of the EGF receptor (or any of its ligands), can also induce cancer in both cell lines and transgenic animal models. Monoclonal antibodies capable of blocking receptor activity can promote tumour regression in mice suffering from various carcinomas. A direct correlation also exists between elevated EGF receptor numbers and a shorter patient survival span in the case of several forms of breast, oesophageal, bladder and squamous cell carcinomas.
Tyrosine kinase inhibitors may represent effective chemotherapeutic agents for such cancers. Potentially attractive candidates include the inhibitor known as PD 153035 (Figure 7.3) which, even at picomolar (pM) concentrations, inhibits EGF-associated tyrosine kinase activity. While PD 153035 also inhibits additional cellular tyrosine kinases, it does so only at concentrations in the micromolar (mM) range.
EGF may also find a novel agricultural application in the defleecing of sheep. Administration of EGF to sheep has a transient effect on the wool follicle bulb cell, which results in a weakening of the root that holds the wool in place. While novel, this approach to defleecing is unlikely to be economically attractive.
PLATELET-DERIVED GROWTH FACTOR (PDGF)
Platelet-derived growth factor (PDGF) is a polypeptide growth factor which is sometimes termed ‘osteosarcoma-derived growth factor’ (ODGF) or ‘glioma-derived growth factor’ (GDGF). It was first identified over 20 years ago as being the major growth factor synthesized by platelets. It is also produced by a variety of cell types. PDGF exhibits a mitogenic effect on fibroblasts, smooth muscle cells and glial cells, and exerts various additional biological activities (Table 7.7).
PDGF plays an important role in the wound healing process. It is released at the site of damage by activated platelets, and acts as a mitogen/chemoattractant for many of the cells
288 BIOPHARMACEUTICALS
Table 7.7. Range of cells producing PDGF and its major biological activities
Synthesized by Platelets Macrophages
Fibroblasts Endothelial cells
Astrocytes Megakaryocytes
Myoblasts Kidney epithelial cells
Biological activities Vascular smooth muscle cells Many transformed cell types
Mitogen for Fibroblasts Variety of transformed cells
Smooth muscle cells Glial cells
Chemoattractant for Fibroblasts Monocytes
Neutrophils Smooth muscle cells
responsible for initiation of tissue repair. It thus tends to act primarily in a paracrine manner. It also represents an autocrine/paracrine growth factor for a variety of malignant cells.
Active PDGF is a dimer. Two constituent polypeptides, A and B, have been identified and three active PDGF isoforms are possible: AA, BB and AB. Two slightly different isoforms of the human PDGF A polypeptide (generated by differential mRNA splicing) have been identified. The short A form contains 110 amino acids, while the long form contains 125 amino acids. Both exhibit one potential glycosylation site and 3 intra-chain disulphide bonds. The B-chain closely resembles the p28sic protein, the transforming protein of the simian sarcoma virus. It is a 16 kDa, 109 amino acid polypeptide, which also exhibits three intra-chain disulphide linkages. Mature dimeric PDGF contains two additional inter-chain disulphide linkages. PDGF A- and B-chains are products of distinct genes, although they do display a high degree of homology. Transcription of the two genes are subject to different regulatory mechanisms, resulting in the production of the A- and B-chains in different ratios in different cells. Dimerization thus yields a range of different isomers (PDGF of platelets consist approximately of 70% AB, 20% BB and 10% AA species). Unlike AA/AB, which is generally secreted, a large proportion of the BB homodimer remains attached to the plasma membrane, mainly via electrostatic interactions.
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