Discovery Of Hematopoietic Growth Factors

The study of hematopoiesis was greatly facilitated in the mid-1960s when techniques for studying hematopoietic stem cells and progenitor cells in vivo (27) and in clonal culture (28,29) were developed. It was clear that the proliferation and development of these cells was dependent on growth factors. In cultures, these growth factors were provided by serum, conditioned medium, or cell underlayers. The growth factors present in these sources were called colony-stimulating factors (CSFs) (30).

In the 1970s and early 1980s, many of the growth factors were purified. It was recognized that several growth factors acted on the granulocyte lineage, including G-CSF, GM-CSF, and IL-3. At the time, it was a great challenge to achieve purity because these factors were present at very low concentrations. By the mid-1980s, it was apparent that the criterion for purity was when a single protein sequence could be obtained from the pure preparation and the gene encoding this sequence could be cloned and expressed to produce the same protein.

Once recombinant human forms of HGF were produced by recombinant DNA technology in large amounts, the focus shifted to studying the pharmacology and clinical effects. The focus of laboratory research changed from identifying additional growth factors to studying their mode of action. Site-directed mutagenesis and other techniques allowed the structure of the growth factors, their binding to receptors, and their intracellular signaling to be defined in detail. The study of HGFs in vivo was greatly facilitated by gene knockout as well as by gene overexpression studies. These areas are reviewed in later chapters of this book.

When the clinical development of recombinant human forms of HGF was initiated, a common belief was that since they were natural regulators of hematopoiesis, they would be well tolerated. Laboratory studies indicated redundancy in the effects of these HGF and also showed that their maximal effects were produced when they were used in combination with each other. Clinical studies appeared to indicate that the factors most selective on one cell lineage (such as recombinant forms of G-CSF, EPO, and TPO) were better tolerated than broadly acting factors. Combinations of recombinant growth factors in the clinic were not extensively tested, but combinations of rHuG-CSF and rHuEPO, rHuG-CSF and rHuGM-CSF, and rHuSCF and rHuG-CSF have been studied, with beneficial effects reported in some cases, for example, rHuG-CSF and rHuSCF for progenitor cell mobilization (31).

Other chapters in this volume review the pharmacology of HGF in normal and special populations, as well as in relation to some of the most common cancers. The use of HGF in the oncology sector revolutionized the treatment of patients. Further work should offer more innovative methods for the treatment of patients with cancer.

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