Growth factors, haemopoietic

The details of haemopoiesis presented thus far prompt two very important questions. How is the correct balance between stem cell self-renewal and differentiation maintained And what forces exist that regulate the process of differentiation The answer to both questions, in particular the latter, is beginning to emerge in the form of a group of cytokines termed haemopoietic growth factors (Table 6.2). This group includes  

Biopharmaceuticals Biochemistry and Biotechnology, Second Edition. Gary Walsh John Wiley Sons Ltd ISBN 0 470 84326 8 (ppc), ISBN 0 470 84327 6 (pbk) 

Most of these haemopoietic growth factors are glycoproteins, displaying a molecular mass in the region of 14-24 kDa. Most are produced by more than one cell type and several display redundancy in their actions. In general several such regulators can stimulate proliferation of any 

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Most of these haemopoietic growth factors are glycoproteins, displaying a molecular mass in the region of 14-24 kDa. Most are produced by more than one cell type, and several such regulators can stimulate proliferation of any one haemopoietic cell lineage. This is due to the presence of receptors for several such factors on their surface. Receptor numbers for any one growth factor are low (less than 500 per cell), and proliferation can be stimulated even when only a small proportion of these are occupied. 

EPO is an additional haemopoietic growth factor. It is primarily responsible for stimulating and regulating erythropoiesis (i.e. erythrogenesis, the production of red blood cells) in mammals. 

TPO is the haemopoietic growth factor now shown to be the primary physiological regulator of platelet production. This molecule may, therefore, represent an important future therapeutic agent in combating thrombocytopenia, a condition characterized by reduced blood platelet levels. The most likely initial TPO therapeutic target is thrombocytopenia induced by cancer chemo- or... 

HAEMOPOIETIC GROWTH FACTORS 257 Table 6.2. Major haemopoietic growth factors described to date... 

As haemopoietic growth factors serve to stimulate the production of mature blood cells, their clinical application in diseases characterized by sub-optimal production of specific blood cell types was obvious. Several CSF preparations have gained regulatory approval, or are currently being assessed in clinical trials (Table 6.4). G-CSF and GM-CSF have proved useful in the treatment of neutropenia. All three CSF types are (or are likely to be) useful in the treatment of infectious diseases, some forms of cancer and the management of bone marrow transplants (Table 6.4), as they stimulate the differentiation/activation of white blood cell types most affected by such conditions. 

Circular dichroism studies show that up to 50% of EPO s secondary structure is a-helical. The predicted tertiary structure is that of four anti-parallel helices formed by variable-sized loops, similar to many other haemopoietic growth factors. 

A number of clinical circumstances have been identified which are characterized by an often profoundly depressed rate of erythropoiesis (Table 6.7). Many, if not all, such conditions could be/are responsive to administration of exogenous EPO. The prevalence of anaemia, and the medical complications which ensue, prompts tremendous therapeutic interest in this haemopoietic growth factor. EPO has been approved for use to treat various forms of anaemia (Table 6.8). It was the first therapeutic protein produced by genetic engineering, whose annual sales value topped 1 billion. Its current annual sales value is now close to 2 billion. EPO used therapeutically is produced by recombinant means in CHO cells. 

Vial T, Descotes J. Clinical toxicity of cytokines used as haemopoietic growth factors. Drug Saf 1995 13(6) 371 t06. 

Rational use of haematinic drugs is essential to the correction of anaemia in its various forms. The emergence of haemopoietic growth factors as drugs that stimulate eryihroid or m> eloid cell lines has opened the way to successful management of other forms of haematological disease. 

Goldstone AH, Khwaja A. The role of haemopoietic growth factors in bone marrow transplantation. Leuk Res 1990 14(8) 721-9. 

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