Download (direct link):
Calcitonin produced by virtually all species is a single-chain, 32 amino acid residue polypeptide, displaying a molecular mass in the region of 3500 Da. Salmon calcitonin differs in sequence from the human hormone by nine amino acid residues. It is noteworthy, however, as it is approximately 100-fold more potent than the native hormone in humans. The higher potency appears due to both a greater affinity for the receptor and greater resistance to degradation in vivo. As such, salmon, as opposed to human calcitonin, is used clinically. Traditional clinical preparations were manufactured by direct chemical synthesis, although a recombinant form of the molecule has now gained marketing approval. The recombinant calcitonin is produced in an engineered E. coli strain. Structurally, salmon calcitonin displays C-terminal amidation. A C-terminal amide group (— CONH2) replacing the usual carboxyl group is a characteristic feature of many polypeptide hormones. If present, it is usually required for full biological activity/ stability. As E. coli cannot carry out post-translational modifications, the amidation of the recombinant calcitonin is carried out in vitro using an a-amidating enzyme which is itself produced by recombinant means in an engineered CHO cell line. The purified, amidated finished
product is formulated in an acetate buffer and filled into glass ampoules. The (liquid) product exhibits a shelf-life of 2 years when stored at 2-8°C.
Several hormone preparations have a long history of use as therapeutic agents. In virtually all instances they are administered simply to compensate for lower than normal endogenous production of the hormone in question. Since it first became medically available, insulin has saved or prolonged the lives of millions of diabetics. Gonadotrophins have allowed tens, if not hundreds, of thousands of sub-fertile individuals to conceive. Growth hormone has improved the quality of life of thousands of people of short stature. Most such hormones were in medical use prior to the advent of genetic engineering. Recombinant hormonal preparations are now however gaining greater favour, mainly on safety grounds. Hormone therapy will remain a central therapeutic tool for clinicians for many years to come.
Bercu, B. (1998). Growth Hormone Secretagogues in Clinical Practice. Marcel Dekker, New York.
Fauser, B. (1997). FSH Action and Intraovarian Regulation. Parthenon, Carnforth, UK.
Hakin, N. (2002). Pancreas and Islet Transplantation. Oxford University Press, Oxford.
Juul, A. (2000). Growth Hormone in Adults. Cambridge University Press, Cambridge.
Mac Hadley, E. (1999). Endocrinology. Prentice-Hall, Hemel Hempstead, UK.
Norman, A. (1997). Hormones. Academic Press, London.
O’Malley, B. (1997). Hormones and Signalling. Academic Press, London.
Walsh, G. & Headon, D. (1994). Protein Biotechnology. Wiley, Chichester.
Insulin and diabetes
Atkinson, M. & McClaren, N. (1990). What causes diabetes? Sci. Am. July, 42-46.
Blundell, T. et al. (1972). Insulin: the structure in the crystal and its reflection in chemistry and biology. Adv. Protein Chem. 26, 279-402.
Bristow, A. (1993). Recombinant DNA derived insulin analogues as potentially useful therapeutic agents. Trends Biotechnol. 11, 301-305.
Brunetti, P. & Bolli, G. (1997). Pharmacokinetics and pharmacodynamics of insulin relevance to the therapy of diabetes mellitus. Diabet. Nutrit. Metab. 10(1), 24-34.
Cao, Y. & Lam, L. (2002). Projections for insulin treatment for diabetics. Drugs Today 38(6), 419-427.
Ciszak, E., Beals, J. M., Frank, H. et al. (1995). Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric LysB28 ProB29-human insulin. Structure 3, 615.
Combettes-Souverain, M. & Issad, T. (1998). Molecular basis of insulin action. Diabet. Metab. 24, 477-489.
Conrad, B. et al. (1994). Evidence for superantigen involvement in insulin-dependent diabetes mellitus aetiology. Nature 371, 351-354.
Docherty, K. (1997). Gene therapy for diabetes mellitus. Clin. Sci. 92(4), 321-330.
Drucker, D. (2002). Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 122(2), 531-544.
Goa, L. et al. (1997). Lisinopril — a review of its pharmacology and use in the management of the complications of diabetes mellitus. Drugs 53(6), 1081-1105.
Greenbaum, C. (2002). Insulin resistance in type 1 diabetes. Diabet. Metab. Res. Rev. 18(3), 192-200.
Hinds, K. & Kim, S. (2002). Effects of PEG conjugation on insulin properties. Adv. Drug Delivery Rev. 54(4), 505-530.
Ikegami, H. & Ogihara, T. (1996). Genetics of insulin-dependent diabetes mellitus. Endocr. J. 43(6), 605-613.
Johnson, I. (1983). Human insulin from recombinant DNA technology. Science 219, 632-637.
Kroeff, E. et al. (1989). Production scale purification of biosynthetic human insulin by reverse phase high performance liquid chromatography. J. Chromatogr. 461, 45-61.