Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 8 to 10 amino acid residues in defined sequence
Reexamination Certificate
2000-07-27
2003-12-16
Low, Christopher S. F. (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
8 to 10 amino acid residues in defined sequence
C514S015800
Reexamination Certificate
active
06664369
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the fields of biochemical endocrinology and anti-neoplastic pharmacology. More specifically, the present invention relates to novel GnRH analogues having antitumour effects and pharmaceutical compositions thereof.
2. Description of the Related Art
It is known that this factor of hypothalamic origin (a peptide hormone built up of 10 amino acids) is responsible for the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). A number of agonistic and antagonistic analogues of GnRHs proved to be not only useful for the successful influencing of processes of the reproduction biology but also suitable as antitumour drugs.
GnRH analogues can exert their antitumour effect not only through chemical castration but also in a selective way by directly acting on the tumour cells. The presence of receptor(s) specifically binding GnRH or GnRH analogues, respectively, as well as that of GnRH-mRNA were shown in cell cultures of cancers of human mammary, prostate, ovary and pancreas. Furthermore, the in vitro proliferation-inhibiting action of GnRH analogues was proven on the same cell lines. The specific binding of tritium-labelled D-Phe
6
-GnRH(1-9)-ethylamide (OVURELIN), a human GnRH superagonist, to cells of MCF-7 and MDA-MB-231 human mammary carcinoma cell lines was demonstrated in experiments. These results confirm the presence of receptor(s) specifically binding GnRH analogues, which is a fundamental condition for development of a direct effect. Similarly, D-Trp
6
-hGnRH (DECAPEPTYL), an agonistic analogue brought into the therapeutical practice, proved to possess a receptor on the MDA-MB-231 tumour cell line and a direct growth-inhibiting effect on the human mammary tumour cell line mentioned above.
Based on the effective concentration it can be supposed that low-affinity binding site or sites may play an important role in the development of direct antitumour effect. According to the literature the direct antitumour action of GnRH analogues occurs only at relatively high peptide concentrations (10
−6
-10
−5
M). This pharmacological effect can be achieved only in the case when the active molecule is present in the body not only in a high concentration but also for a long time. For a long time, GnRH was not believed to be a species-specific hormone; it has become known as late as in the early 80's that the structure of gonadoliberin of some fish and bird species, respectively, is different from that of the mammals. In comparison to the mammalian GnRH, the structure of fish- and bird-specific GnRH, respectively, differs in the amino acid position(s) 7 and/or 8. In relation to the release of LH and FSH, respectively, of mammals, the analogues of chicken GnRH or salmon GnRH are not hyperactive and therefore, they do not desensitize the gonadotropic cells of hypophysis in the corresponding dose range. The composition of mammalian, e.g. human, GnRH is as follows: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH
2
(SEQ ID NO:1).
In 1993, researchers isolated and synthesized the Lamprey-III-GnRH decapeptide from lamprey (Petromyzon marinus) (pGlu-His-Trp-Ser-His-Asp-Trp-Lys-Pro-Gly-NH
2
(SEQ ID NO:2)). This Lamprey-III-GnRH (herein below GnRH-III) exerts a significant tumour growth-inhibiting effect on human mammary tumour cell lines. Simultaneously, on investigating the endocrinological effect of GnRH-III on rat hypophysis by using the superfusion method it has been found that the LH-releasing effect of this hormone is about thousand times weaker than that of the human GnRH. In the course of in vivo investigations it has been found that, during a prolonged treatment for three cycles, it did not inhibit the ovulation of female rats even in high doses; therefore, it did not induce desensitisation and chemical castration. In relation thereto, a “flair up” tumour growth occurring at the beginning of treatment did not appear on the tumour-bearing animals in contrast to other known human hormone analogues acting through the same mechanism of action. Thus, GnRH-III is a selective, highly active antitumour compound.
During the therapeutical use of peptide hormones and their synthetic analogues, a frequent demand is to retain the amount of the pharmacologically active molecule at a high and steady level. Thus, e.g. several agonistic and antagonistic synthetic analogues of gonadoliberin (GnRH), a peptide hormone built up from ten amino acids stimulating the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the hypophysis, proved to be useful not only for successfully influencing processes of reproduction biology but also to provide the possibility of use as antitumour drugs. Depending on the way of use, GnRH and its analogues are able to stimulate or inhibit the secretion of gonadotropin. On carrying out a treatment repeatedly or continuously for a prolonged time with GnRH analogues, a so-called pharmacological gonadectomy is induced as a result of a desensitizing effect exerted on the hypophysis by a pronounced reduction of release of gonadotropin and steroids. Gonadectomy is a required therapeutical intervention in the treatment of steroid-dependent gonadal disease-entities. Simultaneously, gonadectomy is reversible and does not psychically disturb the patient. These analogues proved to be effective in the therapy of prostate, mamma and endometrium carcinomas and even cancers of pancreas and hypophysis on the basis of most recent data. Synthetic-GnRH antagonists are derivatives competitively inhibiting the native hormone. In the case of potent antagonists the amino acids in positions 1 to 3, 6 and 10 are usually exchanged for non-coded amino acids, e.g. of D-configuration. The anti-ovulatory effect of GnRH antagonists is well known. The GnRH analogues may exert their antitumour action not only through chemical castration but also through a direct effect on the tumour cells. Eidne et al. [J. Clin. Endocrinol. Metab. 64, 423-432 (1987)] demonstrated the presence of low-affinity binding sites in the cell cultures of MCF-7 and MDA-MB-231 human mammary tumours; based on the direct inhibitory effect of antagonistic analogues they concluded that GnRH behaves as an autocrine regulatory factor in mammary carcinoma cells. Results most recently published in the literature confirm the expression of GnRH gene in mammary carcinoma cells, which likely occurs during lactation and malignant transformation [Harris et al.: Cancer Res. 51, 2577-2581 (1991)]. The presence in the neoplastic tissue of GnRH-binding sites supports that GnRH has very probably an immediate palliative effect in the therapy of patients suffering from mammary carcinoma. Human mammary carcinoma cell lines or xenografts developed therefrom are useful in vitro and in vivo model systems for demonstrating the direct action of GnRH. GnRH agonists, when administered alone in substance form, are proteolytically decomposed and rapidly eliminated; thus, a steady and high GnRH analogue level, required for development of a direct or indirect antitumour effect, cannot be achieved. The retention of a high and steady level required for the inhibition of the tumour can be solved by a very frequent administration (daily several times) or by means of pharmaceutical compositions with prolonged effect. Up to the present, the microcapsule or microgranular form of GnRH analogues has been used for tumour inhibition in the clinical practice (Buserelin retard® and Decapeptyl retard® agonistic compositions).
According to another method to achieve a prolonged effect the pharmacologically active molecule is chemically coupled to molecules (e.g. polymers) slowly eliminating from the body. Conjugates thus obtained slowly diffuse in biological systems and alter the distribution in the body and absorption properties of the active agent. Thus, targeted transport of the pharmacologically active molecule and the reduction of undesired side effects can also be attained.
Preferred carriers are the water
Kalnay Adrienn
Lovas Sandor
Mezom Imre
Mora Melinda
Murphy Richard F.
Creighton University
Low Christopher S. F.
Lukton David
Mueting Raasch & Gebhardt, P.A.
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