Insulin-like growth factor II as antitumour agent

Details Insulin-like growth factor II as antitumour agent Insulin-like growth factor II as antitumour agent

1996-05-15

1999-05-11

Caputa, Anthony C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 12, 514 2, 514 44, A61K38/30

Patent

active

059027886

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the use of IGF-II for the manufacture of a medicament for the treatment of tumours and especially for the treatment of cutaneous melanomas.
The incidence of cutaneous melanomas in the United Kingdom is approximately 8000 per annum and is increasing; treatment of the disease is usually ineffective. Primary melanomas can be removed surgically and be subjected to biochemotherapy, but this is only marginally successful. Recent studies have shown that interleukin-2 based treatment regimes can result in an approximately 20 percent partial/complete response rate but there is a need to develop new therapies for treating disseminated tumours.
Melanomas of the ciliary body and choroid are the most common primary intraocular malignancy in adults and are fatal in approximately half of the patients. The incidence in the U.K. is seven per million per year. Death occurs within a 15 year period following initial treatment, and metastases, almost exclusively in the liver, are responsible for virtually all tumour related deaths. Median survival is less than six months. Despite the development of techniques which may preserve vision by obviating the need for enucleation or local removal, overall patient survival has remained unaltered. In most fatal cases, tumour dissemination has probably occurred before the patient presents for treatment. Recognition of early tumour spread, or identification of patients at most risk of developing metastases, coupled with, as yet, undefined forms of treatment aimed at the destruction of occult metastatic diseases remains our best hope for the future management of these tumours.
Insulin-like growth factor II (IGF-II) is a peptide present in plasma and other body fluids. It comprises 67 amino acids, including 3 disulphide bonds and its primary sequence shows 64% homology to IGF-1. It can stimulate growth of a wide range of cell types. IGF-II has been purified from human plasma and the complete amino acid sequence is known. Sequences with extensive homology to human IGF-II are present in IGF-II purified from plasma of other species. IGF-II has both systemic and local effects and appear to be mostly associated with different specific binding proteins, six of which are sequenced and are termed IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5 and IGFBP6. These appear to modulate the biological functions and availability of IGF-II in both a positive and negative manner. IGF-II appears to act mainly by interactions with the IGF-type 1 receptor exposed on the outer surface of plasma membranes in many different cell types--however relative specificity of action may be found because of the influence of binding proteins. IGF-II may also have distinct actions as it binds to a distinct and unrelated type 2 receptor also found on cell membranes.
IGF-II has been shown to experimentally reduce the catabolic state in starved animals and to antagonise some metabolic actions of IGF-1 (Koea et al. Endocrinology 1992, 130, 2423-2425).
The insulin-like growth factors IGF-I and IGF-II have been shown to be mitogenic polypeptides with structural and functional homology to insulin. They are capable of supporting differentiation in many foetal and embryonic cell types, and for certain cancers the growth pattern may reflect IGF-I and IGF-II gene expression.
Heinze-Erian et al, Endocrinology, (1991) Vol 129, No 4, 1769, reports that there is an essential role for both IGF receptors in the regulation of cell mitogenesis and growth.
Commercial large scale production of IGF-II can nowadays readily be achieved by using recombinant DNA techniques.
A review is given by Schofield and Engstrom in The Insulin like growth factors Structure and biological functions , pages 240-57 (1992, OUP) regarding the expression of IGF-II by a wide range of human tumours.
The reason for the high degree of interest in IGF-II tumour expression is of IGF-II and proliferation which may or may not initiate or promote tumour growth. However data differ from system to system, and although it is possible to demonstrate either p

REFERENCES:
Schofield et al., Tumour suppression associated with expression of human insulin-like growth factor II, Br. J. Cancer (1991), vol. 63, pp. 687-692.
Schofield, P.N. et al., Cancer Letters, 94: 71-77, 1995.
Zumkeller, W. et al., J. Clin. Pathol.: Molec. Pathol, 48:M333-M341, 1995.
Kohn, E.C. et al., Int. J. Cancer, 46: 287-92, 1990.
Granerus, M. et al., J. Clin. Pathol.: Molec. Pathol., 48: M153-157, 1995.

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