Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-01-24
2001-09-25
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S006120, C435S069100, C435S252300, C435S254110, C435S325000, C435S320100, C536S023100, C536S023500
Reexamination Certificate
active
06294335
ABSTRACT:
The present invention relates generally to a method of diagnosing abnormal cell growth or a predisposition to abnormal cell growth. More particularly, the present invention contemplates a method of diagnosing abnormal prostatic cell growth or a predisposition to abnormal prostatic cell growth and even more particularly prostate cancer or a predisposition to developing prostate cancer.
The bibliographic details of the publications referred to by author in the specification are collected at the end of the description.
Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or groups of elements or integers.
Disorders of the prostate gland are of particular concern in ageing men. Figures suggest that approximately one in four males above the age of 55 will suffer from a prostate disease in some form. The incidence in Australia of prostatic cancer is high and similarly prevalent rates occur in most communities. This represents a significant cost to health care systems and decreases the quality of life of men suffering from this disorder.
Inhibins are glycoprotein hormones produced by the gonads which have a negative feedback action on the release of FSH from the pituitary gland. They consist of two disulphide linked subunits, &agr; and either &bgr;
A
or &bgr;
B
, which give rise to inhibin A or B respectively. Activins are formed by the dimerisation of two &bgr; subunits. Three dimeric forms of activin have been published: activin A [&bgr;
A
&bgr;
A
], activin B [&bgr;
B
&bgr;
B
] and activin AB [&bgr;
A
&bgr;
B
]. In contrast to inhibins, activins stimulate pituitary FSH (Ling et al., 1986).
Activins have been shown to have either proliferative or anti-proliferative actions in reproductive, neuroendocrine and erythroid tissues (Hedger et al.,1989, Mather et al., 1990, Nakao et al., 1991). The effects of activins on cultured cells include induction of cell cycle arrest (Kojima et al.,1993) and apoptosis (Nishihara et al., 1993). A further three activin &bgr; subunits termed &bgr;
C
-&bgr;
E
(Hotten et al., 1995, Oda et al., 1995, Fang et al., 1996) have been cloned, but the putative activin homo- and hetero-dimers from these subunits have yet to be isolated, purified, and their biological roles established.
Follistatins are structurally unrelated proteins (which also stimulate FSH secretion) (Robertson et al., 1987), but importantly follistatins bind activins and result in the neutralisation of activin bioactivity (Mather et al., 1993, Nishihara et al., 1993). Follistatins are glycosylated monomeric proteins that arise from two alternatively spliced mRNA (FS315 and FS288), resulting in three protein cores; nine molecular weight forms are postulated, based on alternative splicing, proteolytic cleavage, variable glycosylation, and six have been identified and characterised (Sugino et al., 1993).
It has been shown that inhibins, activins and follistatins are synthesised by the human prostate gland (Thomas et al., 1997a; 1997b).
Understanding the cellular localisation and expression of follistatin is required to determine the role of follistatin in prostate cancer. In work leading up to the present invention, the inventors discovered that whereas follistatin mRNA is detectable in both stromal and basal epithelial cells of the non-malignant prostate, in malignant prostate cells follistatin mRNA is expressed throughout the disordered epithelium. In contrast to follistatin mRNA expression, the follistatin proteins that are expressed are of different form in the stroma and basal epithelial prostate cells. Further, expression of said follistatin proteins is modulated in the transition from non-malignancy to malignancy resulting in the co-expression of at least 2 different forms of the follistatin proteins in the malignant cells and is therefore indicative that an individual has or will develop prostate cancer.
Accordingly, one aspect of the present invention relates to a method of diagnosing a mammal having abnormal prostatic cell growth or a predisposition to developing abnormal prostatic cell growth, said method comprising screening for the modulation of the expression of follistatin protein in said mammal.
The term “mammal” includes humans, primates, livestock animals (e.g. horses, cattle, sheep, pigs, donkeys), laboratory test animals (e.g. mice, rats, rabbits, guinea pigs), companion animals (e.g. dogs, cats) and captive wild animals (e.g. kangaroos, deer, foxes). Preferably, the mammal is a human or a laboratory test animal. Even more preferably, the mammal is a human.
The term “expression” refers to the synthesis of a peptide, polypeptide or protein utilising the mechanisms of transcription and translation of a nucleic acid molecule.
Reference hereinafter to “follistatin” should be read as including reference to all forms of follistatin and to all proteins belonging to the follistatin family of proteins and derivatives, homologs, analogs, mutants, variants and fragments thereof including, by way of example, the three protein cores and six molecular weight forms of follistatin which have been identified as arising from the alternatively spliced mRNAs FS315 and FS288 and including but not limited to fragments, derivatives, homologs, analogs, mutants and variants thereof. “Follistatin” should also be understood to include, for example, reference to any peptide, polypeptide or protein which exhibits homology to follistatin for example the proteins described by Patthy et al (1993) and Hohenester et al (1997) or any protein which comprises any one or more of the epitopes of follistatin. Preferably, said follistatin proteins are one or both of the forms of follistatin protein detected by, but not limited to, the OxB288 antibody (Madjic et al., 1997)and the AS#202 antibody (Klein et al., 1991).
More particularly, the present invention relates to a method of diagnosing a mammal having abnormal prostatic cell growth or a predisposition to developing abnormal prostatic cell growth, said method comprising screening for the modulation of the expression of one or both of the forms of follistatin protein detected by the OxB288 antibody and the AS#202 antibody.
The term “modulation” refers to changes in the expression of the follistatin proteins. This includes but is not limited to, up-regulation of the expression in a cell of one or more follistatin proteins which were not previously expressed by said cell, co-expression of two or more forms of follistatin proteins or up-regulation of the level of expression of one or more follistatin proteins in a cell. For example, in non-malignant prostatic basal cells which are located adjacent to high grade malignant prostatic cells, the form of follistatin protein detected by the OxB288 antibody is expressed while the form of follistatin detected by the AS#202 antibody is not. In said adjacent high grade malignant prostatic cells, both of the forms of follistatin proteins detected by the OxB288 antibody and the AS#202 antibody are expressed. Accordingly, a preferred method is to detect the co-expression of the forms of follistatin proteins detected by the OxB288 antibody and the AS#202 antibody. Changes in expression of follistatin proteins may be due, for example, to alternative splicing of follistatin mRNA.
According to this preferred embodiment, the present invention relates to a method of diagnosing a mammal having abnormal prostatic cell growth or a predisposition to developing abnormal prostatic cell growth, said method comprising screening for the co-expression of the forms of follistatin protein detected by the OxB288 antibody and the AS#202 antibody.
The phrase “abnormal cell growth” includes but is not limited to cell growth which, relative to normal cell growth, exhibits an increase or a decrease in the rate of cell division, an increase or a decr
De Kretser David Morritz
Risbridger Gail Petuna
Jones W. Gary
Monash University
Morrison & Foerster / LLP
Taylor Janell E.
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