CYTOKINES AND THEIR USE IN TREATMENT AND/OR PROPHYLAXIS OF BREAST CANCER

Abstract: The present invention relates generally to a method for the treatment or prophylaxis of animals including humans suffering from or predisposed to breast cancer or other related cancers which comprises the use of cytokines and/or functionally active derivatives, hybrids and/or analogs thereof and to pharmaceutical compositions comprising same as therapeutic agents. In particular, but not exclusively, the present invention is directed to the use of cytokines which are ligands of members of the haemopoietin receptor super family or their derivatives, hybrids or analogs as therapeutic agents. The present application also contemplates breast cancer therapies and methods of suppressing growth of normal breast cells or breast cancer cells by the use of one or more cytokines optionally in combination with other therapeutic agents as well as the use of agonists or antagonists of cytokine activity. Particularly preferred are oncostatin M (OSM) and leukaemia inhibitory factor (LIF).

Description: CYTOKINES AND THEIR USE IN TREATMENT AND/OR PROPHYLAXIS OF BREAST CANCER The present invention relates generally to a method for the treatment or prophylaxis of animals including humans suffering from or predisposed to breast cancer or other related cancers which comprises the use of cytokines and/or functionally active derivatives, hybrids and/or analogs thereof and to pharmaceutical compositions comprismg same as therapeutic agents. In particular, but not exclusively, the present invention is directed to the use of cytokines which are ligands of members of the haemopoietin receptor super family or their derivatives, hybrids or analogues as therapeutic agents. The present invention also contemplates breast cancer therapies and methods of suppressing growth of normal breast cells or breast cancer cells by the use of one or more cytokines optionally in combmation with other therapeutic agents as well as the use of agonists or antagonists of cytokine activity. Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide and amino acid sequences referred to in the specification are defmed following the bibliography. Throughout this specification and the claims which follow, 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 integer or group of integers but not the exclusion of any other integer or group of integers. Breast cancer is the most common malignancy of females in Western cultures and affects 1 in 13 women in Australia. The risk of death is related to a number of prognostic factors, the most powerful being whether the axillary lymph nodes are involved. The relapse rate at 10 years has been found to be as high as 85% for women with Stage II disease who display involvement of four or more axillary lymph nodes (Antman, 1992). In premenopausal patients with more than 10 involved nodes given standard dose adjuvant chemotherapy cyclcphosphamide ( methotrexate (M) 5 fluroviracil (F) prednisolone (P), greater than 70% have disease recurrence within 5 years of diagnosis. When estrogen receptor (ER) status is included as a prognostic indicator, those patients who have an ER negative tumor with 4 or more nodes involved have risk of recurrence and death which approaches that for patients 5 with 10 or more positive lymph nodes. In patients with a large primary tumor (eg > 5 cm) and positive nodes (Stage III disease) the 5-year relapse rate is between 65% and 79% (Nemoto et al., 1980; Valagussa et al., 1978; Fisher et al., 1969). In Halsteds original series only 2 of 44 (5%) women with 0 supraclavicular node involvement were free of cancer at 5 years (Halsted, 1907). In women with either fixed axillary nodes, axillary nodes more than 2.5 cm in diameter, tumor fixed to the chest wall or skin ulceration, 5-year disease free survival ranges from only 5 % to 38 % (Haagensen, 1986). The addition of either CMF chemotherapy or anthracycline-containing chemotherapy to local therapy (surgery +/- radiation to the breast) of stage III breast cancer 5 appears to improve 5-year relapse free survival from 26% to 40% (Balawadjer, 1983). Stage IV breast cancer (metastatic disease) is invariably fatal. Thus, this is a disease with a poor outlook and for which new therapeutic strategies are required. Chemotherapy is currently the mainstay of systemic therapy for breast cancer. Both 0 retrospective (Bonadonna et al., 1981; Hryniuk and Levine, 1986; Hryniuk and Bush, 1984) and prospective (Jones et al., 1987; Focan et al., 1993; Carmo-Pereira et al., 1987; Tannock et al., 1988; Neri et al., 1993; Wood et al., 1994) data demonstrate a dose-response relationship for cytotoxic drugs in breast cancer. On the whole, these clinical studies show that any significant reduction of chemotherapy below a certain critical dose results in a 25 compromise of response rate or shortening of survival. What is not clear is whether the in vivo dose-response curve in breast cancer is linear, so that ever increasing doses of cytotoxic agents result in a greater chance of response, or whether a plateau is reached, above which only greater toxicity is observed. A hint is given that the former might apply by the activity reported in studies of growth factor supported, dose-intensive regimens (Bronchud et al., 30 1989; Ardizzoni et al., 1994; Lalisang et al., 1994; Hoekman et al., 1991; Ferguson et al., 1993; Scinto et al., 1995; Piccart et al., 1995) and high-dose chemotherapy with autologous progenitor cell rescue in patients with metastatic breast cancer (Eddy, 1992). These single arm studies produced response rates of 60% to 100% which compares favourably to the 25% to 50% response rates obtained using conventional dose chemotherapy (Jain et al., 1985; Rozencweig et al. , 1984; Van Oosterrom, 1987; Marchner, 1994). While high-dose chemotherapy in metastatic breast cancer produces impressive response rates, it does not appear to have impacted on survival (Eddy, 1992). However, it might be expected to be more affective if given to patients with early stage breast cancer and features that suggest a likelihood of recurrence. The use of this approach in high-risk stage II and III breast cancer has produced promising initial results. Peters et al. (1993) delivered 4 cycles of standard-dose chemotherapy followed by high-dose cyclophosphamide, l,3-bis(2- chloroethyl)-l-nitrosourea (BCNU) and cisplatin to 85 patients with high-risk (> 10 involved axillary lymph nodes) stage II and III breast cancer. At a median follow-up of 2.5 years, the relapse-free survival was 72% and overall survival 82% (Peters et al., 1993). However, this regimen was associated with a 12% treatment-related mortality rate and a high incidence of chronic pulmonary drug toxicity (Todd et al., 1993). Gianni et al. (1992) gave 48 patients with > 10 involved axillary nodes growth factor supported high-dose sequential chemotherapy. This regimen included cyclophosphamide, vincristine and methotrexate, cisplatin then melphalan. At a median follow-up of 21 months, relapse-free and overall survival was 93% (Gianni et al., 1992). The present inventors recently conducted a feasibility study of three cycles of high-dose epi ubicin (200mg/m 2 ) and cyclophosphamide (4 gm/11- 4 ) with peripheral blood progenitor support in women with high risk breast cancer (Basser et al., 1995). Myelosuppression and acute-non-haematological toxicities were marked, but reversible. Given that repeated use of anthracylines is limited by a dose-dependent, irreversible cardiomyopathy, cardiac function of patients was monitored closely. The left ventricular ejection fraction fell by 15 % from baseline in only 4 of 30 patients (13 %) when measured at me completion of the third cycle of chemotherapy. No patients at any stage developed symptoms or signs of congestive heart failure. Therefore, although chemotherapy is efficious in the treatment of breast cancer, it is associated with significant toxicities. These toxicities justify the development of new approaches in this disease and have provided the impetus for further research into such new approaches. Breast cancer has been recognised as a hormone-responsive tumor for nearly a century. The recognition that growth stimulation occurs following the interaction of estrogen with its receptor led to the development of competitively binding anti-estrogens capable of inhibiting breast cancer growth (Li et al., 1992). In addition the presence of estrogen receptors in breast tumors predicts both patient prognosis, and response to hormonal therapy. Moreover treatment with anti-estrogens improves survival of these patients (Osborne et al., 1991; Early Breast Trial Collaborative Group, 1992). More recently, the focus has moved to the possible role of additional growth factors and their cell surface receptors in development and progression of breast cancer and the possibility these pathways might serve as potential targets for therapy. The in-vitro growth of breast cells requires exogenous serum-derived factors for optimal growth. Isolation of protein fractions responsible for this activity resulted in the recognition of several families of growth factors, including epidermal growth factor (EGF), transforming growth factor (TGF), fibroblast growth factor (FGF), insulin and insulin-like growth factors (IGF's), that are important in the growth of these cells. Likewise surface receptors for these growth factors have been identified on breast cells and are found with variable frequency in primary human breast tumor samples (Dickson and Lippmann, 1992; Kacinski et al., 1991; Harris, 1994; Chrysagekos and Dickson, 1994). A number of "haemopoietic" growm-factors have been characterized that display diverse functions on many different tissues. In some cases, these growth-factors can even display conflicting actions on different tissues. Thus, for example, Leukemia Inhibitory Factor (LIF) was named because of its ability to induce terminal differentiation in murine Ml leukemia cells. Paradoxically, however, LIF acts to inhibit differentiation on embryonic stem (ES) cells. Moreover, LIF is also active on many cell types including neurones, hepatocytes, osteoblasts, adipocytes and megakaryocytes. These activities of LIF are mediated via specific cell-surface receptors that are present on all these tissues (Hilton et al., 1991). A number of other molecules also display a broad-range of activities. These pleiotropic molecules include cytokines such as interleukin-6 (IL-6), oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and interleukin- 11 (IL-11). In accordance with the present invention, it is proposed diat certain cytokines are effective in treating breast cancer. Accordingly, one embodiment of the present invention contemplates a method for the treatment or prophylaxis of breast cancer in an animal, which method comprises administering to said animal an effective amount of one or more cytokines or functional derivatives or agonists of said one or more cytokines for a time and under conditions sufficient to ameliorate the effects of or to delay onset of said cancer. Another embodiment of me present invention provides a method for suppressing grow , proliferation or enhancing differentiation of normal breast cells or breast cell carcinomas from animals or immortalised animal breast cell lines by contacting said cells with an effective amount of one or more cytokines or functional derivatives or agonists of one or more cytokines for a time and under conditions sufficient to suppress growth, proliferation or enhancing differentiation of said cells. In a particularly preferred embodiment the present invention contemplates a method of treating or prophylaxis of breast cancer in an animal including a human which method comprises administering to said animal an effective amount of a cytokine selected from OSM, LIF, IL-6, IL-11 and EGF and other members of the EGF family, or functional derivatives or agonists thereof optionally in association with one or more other cytokines or other therapeutic agents. Another embodiment ofthe present invention contemplates a therapeutic composition for the treatment of animals including humans suffering from breast cancer or having a predisposition to develop breast cancer which comprises one or more cytokines or functional derivatives or agonists thereof optionally in association with other therapeutic agents and also in association with one or more pLtar aceuticaiiy acceptable carriers and/or diluents. Administration of the active components of the present invention is for a time and under conditions sufficient for said components to exhibit the requisite effect. The term "breast cancer" is used in its broadest sense and includes all forms of breast cancer including but not limited to metastic breast cancer and early breast cancer. It also includes oilier cancers epidemiologically related to breast cancer. By the term "animal" it is to be understood that the methods of treatment of the present invention are applicable to the treatment of breast cancer in all mammals and in particular humans as well as in livestock animals (e.g. sheep, cows, pigs, goats, horses, donkeys), laboratory test animals (e.g. mice, rats, guinea pigs, hamsters, rabbits), domestic companion animals (e.g. dogs, cats) and captive wild or tamed animals (e.g. monkeys, foxes, kangaroos, dingoes). Preferably, the cytokine is a recombinant cytokine of human, murine, livestock animal, companion animal, laboratory test animal or captive wild animal origin. More preferably however, the cytokine is of human origin. The present invention extends to all cytokines which bind to surface receptors of breast cells whether they be normal breast cells, breast cell carcinomas or immortalised breast cell lines of human or animal origins, and which exhibit an activity on cell growth, proliferation or differentiation. In particular, the cytokines of the present invention include oncostatin M (OSM), interleukin-6 (IL-6), mterleukin-11 (IL-11), leukemia inhibitory factor (LIF) and EGF and other members of the EGF family. Most preferably, the cytokine of the present invention is OSM of either human or murine origin, but preferably of human origin. In this regard, homologous or heterologous treatments are contemplated by the present invention. A homologous treatment employs a cytokine from one animal species in the treatment of an animal from the same species (e.g. human OSM in humans). Heterologous treatment employs a cytokine from one animal species in the treatment of an animal of a different species (e.g. murine OSM in humans). The term "derivatives" extends to functionally active parts, mutants, fragments and analogues of cytokines which exhibit the desired activity herein described. The terms "agonists" and "antagonists" are envisaged compounds wliich may or may not be cytokines but which facilitate cytokine interaction with its receptors on breast cells or breast cancer cells to ellicit an activity, preferably an enhanced or diminished activity depending on whether it is an agonist or antagonist, respectively. One example of an antagonist of a cytokine is use of antisense oligonucleotide sequences. Useful oligonucleotides are those which have a nucleotide sequence complementary to at least a portion of the protein coding or "sense" sequence which encodes the particular cytokine concerned can be utilised. These anti-sense nucleotides can be used to effect the specific inhibition of gene expression (Markus- Sekura, 1988). The antisense approach can cause inhibition of gene expression apparently by forming an anti parallel duplex by complementary base pairing between the antisense construct and the targeted mRNA, presumably resulting in hybridisation arrest of translation. There have been several reports of antisense effects on cytokine-responsive cells, such as IL- β-responsive lymphokine-activated cells (Fujiwara and Grimm, 1992), TNF-o-responsive differentiating macrophages (Witsell and Schook, 1992), M-CSF-responsive HL-60 cells (Wu et al, 1990) and IL-6-responsive cells (Levy et al, 1991). These studies have demonstrated the critical role of these genes in the growth of different cell types. The present invention extends to analogues of cytokines and their use in the treatment or prophylaxis of breast cancer. Analogues of cytokines contemplated herein include, but are not limited to, modification to side chains, incorporating of unnatural amino acids and or their derivatives during peptide, polypeptide or protein synthesis and the use of crosslinkers and other methods which impose conformational constraints on the proteinaceous molecule or their analogues. Examples of side chain modifications contemplated by the present invention include modifications of amino groups such as by reductive alkyiation by reaction with an aldehyde followed by reduction with NaBH- , amidination with methylacetimidate; aeylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2, 4, 6-trinitrobenzene sulphonic acid (TNBS); aeylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation of lysine with pyridoxal-5- phosphate followed by reduction with NaBH The guanidine group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal. The carboxyl group may be modified by carbodiimide activation via O-acylisourea formation followed by subsequent derivitisation, for example, to a corresponding amide. Sulphydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of a mixed disulphides with other thiol compounds; reaction with maleimide, maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4-chloromercuribenzoate, 4- chloromercuriphenylsulphonic acid, phenylmercury chloride, 2-chloromercuri-4-nitrophenol and other mercurials; carbamoylation with cyanate at alkaline pH. Tryptophan residues may be modified by, for example, oxidation with N-bromosuccinimide or alkyiation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphenyl halides. Tyrosine residues on the other hand, may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative. Modification of the imidazole ring of a histidine residue may be accomplished by alkyiation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate. Examples of incorporating unnatural amino acids and derivatives during peptide synthesis include, but are not limited to, use of norleucine, 4-amino butyric acid, 4-amino-3-hydroxy-5- phenylpentanoic acid, 6-aminohexanoic acid, t-butylglycine, norvaline, phenylglycine, ornithine, sarcosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thιenyl alanine and/or D- isomers of amino acids. A list of unnatural amino acid, contemplated herein is shown in Table 1. Crosslinkers can be used, for example, to stabilise 3D conformations, using homo-b .functional crosslinkers such as the bifunctional imido esters having (CH2) n spacer groups with n=l to n=6, glutaraldehyde, N-hydroxysuccinimide esters and hetero-bifunctional reagents which usually contain an amino-reactive moiety such as N-hydroxysuccinimide and another group specific-reactive moiety such as maleimido or dithio moiety (SH) or carbodiimide (COOH). In addition, peptides can be conformationally constrained by, for example, incorporation of C. and N B -methylamino acids, introduction of double bonds between C. and C p atoms of amino acids and the formation of cyclic peptides or analogues by introducing covalent bonds such as forming an amide bond between the N and C termini, between two side chains or between a side chain and the N or C terminus. These types of modifications may be important to stabilise the cytokines if administered to an individual or for use as a diagnostic reagent. TABLE 1 Non-conventional Code Non-conventional Code amino acid amino acid α-aminobutyric acid Abu L-N-methylalanine Nmala α-amino-α-methylbutyrate Mgabu L-N-methylarginine Nmarg aminocyclopropane- Cpro L-N-methylasparagine Nmasn carboxylate L-N-methylaspartic acid Nmasp aminoisobutyric acid Aib L-N-methylcysteine Nmcys aminonorbornyl- Norb L-N-methylglutamine Nmgln carboxylate L-N-methylglutamic acid Nmglu cyclohexylalanine Chexa L-N-methylhistidine Nmhis cyclopentylalanine Cpen L-N-methylisolleucine Nmile D-alanine Dal L-N-methylleucine Nmleu D-arginine Darg L-N-methyllysine Nmlys D-aspartic acid Dasp L-N-me ylmethionine Nmmet D-cysteine Dcys L-N-methylnorleucine Nmnle D-glutamine Dgln L-N-methylnorvaline Nmnva D-glutamic acid Dglu L-N-me ylornithine Nmorn D-histidine Dhis L-N-methylphenylalanine Nmphe D-isoleucine Dile L-N-methylproline Nmpro D-leucine Dleu L-N-methylserine Nmser D-lysine Dlys L-N-methylthreonine Nmthr D-methionine Dmet L-N-methyltryptophan Nmtrp D-ornithine Dorn L-N-methyltyrosine Nmtyr D-phenylalanine Dphe L-N-methylvaline Nmval D-proline Dpro L-N-me ylethylglycine Nmetg D-serine Dser L-N-me yl-t-butylglycine Nmtbug D-threonine Dthr L-norleucine Nle D-tryptophan Dtrp L-norvaline Nva D-tyrosine Dtyr α-methyl-aminoisobutyrate Maib D-valine Dval α-methyl-γ-amύiobutyrate Mgabu D-α-methylalanine Dmala α-methylcyclohexylalanine Mchexa D-α-methylarginine Dmarg α-methylcylcopentylalanine Mcpen D-α-methylasparagine Dmasn α-methyl-o-napthylalanine Manap D-α-methylaspartate Dmasp α-methylpenicillamine Mpen D-α-methylcysteine Dmcys N-(4-aminobutyl)glycine Nglu D-α-methylglutamine Dmgln N-(2-aminoethyl)glycine Naeg D-α-methylhistidine Dmhis N-(3-aminopropyl)glycine Norn D-α-methylisoleucine Dmile N-amino-α-methylbutyrate Nmaabu D-α-memylleucine Dmleu α-napmylalanine Anap D-α-methyllysine Dmlys N-benzylglycine Nphe D-α-methylmethionine Dmmet N-(2-carbamylethyl)glycine Ngln D-α-methylornidiine Dmorn N-(carbamylme yl)glycine Nasn D-α-methylphenylalanine Dmphe N-(2-carboxyethyl)glycine Nglu D-α-methylproline Dmpro N-(carboxymethyl)glycine Nasp D-α-methylserine Dmser N-cyclobutylglycine Ncbut D-α-methylthreonine Dmthr N-cycloheptylglycine Nchep D-α-methyltryptophan Dmtrp N-cyclohexylglycine Nchex D-α-memyltyrosine Dmty N-cyclodecylglycine Ncdec D-α-methylvaline Dmval N-cylcododecylglycine Ncdod D-N-methylalanine Dnmala N-cyclooctylglycine Ncoct D-N-memylarginine Dnmarg N-cyclopropylglycine Ncpro D-N-methylasparagine Dnmasn N-cycloundecylglycine Ncund D-N-methylaspartate Dnmasp N-(2,2-diphenylethyl)glycine Nbhm D-N-methylcysteine Dnmcys N-(3,3-diphenylpropyl)glycine Nbhe D-N-memylglutamine Dnmgln N-(3-guanidinopropyl)glycine Narg D-N-methylglutamate Dnmglu N-(l-hydroxyethyl)glycine Nthr D-N-methylhistidine Dnmhis N-(hydroxyethyl))glycine Nser D-N-methylisoleucine Dnmile N-(imidazolylethyl))glycine N is D-N-methylleucine Dnmleu N-(3-indolylyethyl)glycine Nhtrp D-N-methyllysine Dnmlys N-memyl-γ-aminobutyrate Nmgabu N-methylcyclohexylalanine Nmchexa D-N-methylmethionine Dnmmet D-N-memylor thine Dnmorn N-memylcyclopentylalanine Nmcpen N-methylglycine Nala D-N-methylphenylalanine Dmnphe N-methylaminoisobutyrate Nmaib D-N-methylproline Dnmpro N-(l-methylpropyl)glycine Nile D-N-methylserine Dnmser N-(2-methylpropyl)glycine Nleu D-N-methylthreonine Dnmthr D-N-methyltryptophan Dnmtrp N-(l-methylethyl)glycine Nval D-N-methyltyrosine Dnmtyr N-memyla-napthylalanine Nmanap D-N-methylvaline Dnmval N-methylpenicillamine Nmpen γ-aminobutyric acid Gabu N-(p-hydroxyphenyl)glycine Nhtyr L-t-butylglycine Tbug N-(thiomethyl)glycine Ncys L-ethylglycine Etg penicillamine Pen L-homophenylalanine Hphe L-α-methylalanine Mala L-α-memylargi-αine Marg L-α-methylasparagine Masn L-α-methylaspartate Masp L-α-methyl-/-butylglycine Mtbug L-α-methylcysteine Mcys L-methylethylglycine Metg L-α-methylglutamine Mgln L-α-methylglutamate Mglu L-α-me ylhistidine Mhis L-α-methylhomophenylalanine Mhphe L-α-methylisoleucine Mile N-(2-methylthioethyl)glycine Nmet L-α-methylleucine Mleu L-α-methyllysine Mlys L-α-memylmethionine Mmet L-α-methylnorleucine Mnle L-α-methylnorvaline Mnva L-α-memylornithine Morn L-α-methylphenylalanine Mphe L-α-methylproline Mpro L-α-methylserine Mser L-α-methylthreonine Mthr L-α-methyltryptophan Mtrp L-α-methyltyrosine Mtyr L-α-methylvaline Mval L-N-methylhomophenylalanine Nmhphe N-(N-(2,2-diphenylethyl) Nnbhm N-(N-(3 , 3 -diphenylpropyl) Nnbhe carbamylmethyl)glycine carbamylmethyl)glycine 1 -carboxy- l-(2,2-diphenyl- Nmbc ethylamino)cyclopropane Ihe cytokines may optionally be administered together with one or more other therapeutic agents. These other agents contemplated by the present invention are agents such as chemotherapeutic and hormonal agents which are well known in the art. Examples of some chemotherapeutic agents are cyclophosphamide, vincristine and methotrexate, cisplatin, melphalan and an example of a common hormonal type agent is tamoxifen. This list of other therapeutic agents is by no means exhaustive. Other useful molecules contemplated herein include taxol (and related molecules such as taxitere) and adriamycin. Such combination therapy may prove effective in treating metastatic breast cancer or in treatment of early breast cancer in particular. It is contemplated by the invention that when one or more cytokines are administered in combination with other agents that the administration is done simultaneously or sequentially. Simultaneous administration occurs when the cytokine is cc-aα^inistered with the other therapeutic agent. Sequential therapy includes a time difference between administration of the various molecules which may be in the order of seconds, minutes, hours, days, weeks or months depending upon the severity of the patient's condition, the type of mammal being treated and the effectiveness of the overall treatment. It is also within the scope of me invention to administer a combination of different cytokines. Preferably, the combination comprises a haemopoetin receptor cytokine with another cytokine of the same family or comprises a haemopoietic receptor cytokine and a cytokine from another family. Preferably, the combination comprises OSM and at least one other cytokine. Even more preferably, the combmation comprises OSM together with one or more of IL-6, IL-11, LIF and/or EGF or another member of the EGF family. For example, administration of OSM and IL-11 or OSM and LIF or OSM and IL-6 or OSM and EGF or OSM together with LIF, two or more of IL-6, IL-11 and EGF is clearly contemplated by the present invention. The amount of cytokine administered is to be determined on a case by case basis taking into account the condition of the patient, species, weight, age, other concurrent treatments and other factors which would be apparent to a physician. As an example it is envisaged that an amount of from about 0.5 micrograms to about 2 milligrams of cytokine per kilogram of body weight per day may be administered. Naturally, dosage regimes may be adjusted to provide the optimum prophylactic or therapeutic response. For example, several divided dosages may be administered daily or the dose may be proportionally reduced as indicated by the particular therapeutic situation. Furthermore, lower amounts may be given but more frequently such as 0.1 to IQμ g per kilogram of body weight per day. Alternatively, larger amounts may be given but less frequently such as from 1 milligram to about 25 milligrams per kilogram of body weight per day. A decided practical advantage is tiiat the active compound may be administered in a convenient manner such as by the oral, intravenous (where water soluble), intramuscular, subcutaneously, intranasal, intradermal or suppository routes. The active compound may also be administered locally such as directly into tissue or via a slow release formulation. Depending upon the route of administration, the active ingredients may be required to be coated in a material to protect the ingredients from action of enzymes, acids and other natural conditons which may inactivate the ingredients. In order to administer cytokines by other than parenteral administration, they may be coated by or administered with, a material to prevent inactivation. For example, cytokines or in particular OSM, may be administered in an adjuvant formulation or co-administered with enzyme inhibitors or in liposomes. Adjuvants contemplated herein include resorcinols, non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether. Enzyme inhibitors mclude pancreatic trypsin inhibitor, diisopropylfluorophosphate (DEP) and trasylol. Liposomes include water-in-oil-in- water cytokine emulsions as well as conventional liposomes. Cytokines may also be administered parenterally or intraperitoneally. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microrganisms such as bacteria or fungi. The carrier can be a coolant of dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of super f actants. The prevention of the action of microrganisms can be brought about by various antibacterial and anti fungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thiomerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absoφtion, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incoφorating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilisation. Generally, dispersions are prepared corporating the various sterilised active ingredient(s) into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile filtered solution thereof. When the active ingredients are suitably protected as described above, die composition may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatine capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incoφorated with excipients and used in the form of ingestible tablets, buccal tables, troches, capsules, elixirs, suspension, syrups, waffers, and the like. Such compositions and preparations should contain at least 1 % on weight of active compound. The percentage of the compositions and preparations may of course be varied and may conventionally be between about 5 to about 80% of the weight of the unit. The amount of active compound(s) in the pharmaceutical compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared, so that an oral dosage unit form contains between about 0.5 nanogram and 320 milligram of active compound. The tablets, troches, pills capsules and d e like may also contain the following: a binder such as gum gragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical foπn of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, die active compound may be incorporated into sustained release preparations and formulations. As used herein "pharmaceutically acceptable carriers and/or diluents" include any and all solvents, dispersion media, aqueous solutions, coatings, antibacterial and antifungal agents isotonic and absoφtion delaying agents and d e like. The use of such media and agents for pharmaceutical active substance is well known in the art. Except insofar as any convential media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incoφorated into the compositions. The prefened cytokine for practice of die present invention is OSM. The OSM employed is preferably as described in United States Patent No. 5,428,012. Preferably, the OSM comprises an amino acid sequence as set forth in Figure 3 in US Patent No. 5,428,012 or is similar thereto or is a derivative or agonist thereof. In its most prefened form, the OSM comprises an amino acid sequence which has at least 40%, more preferably at least 50%, even more preferably at least 60%, still more preferably at least 70-80% and yet even more preferably at least 90-95%, similarity or identity to one or more regions of the amino acid sequence set forth in Figure 3 of US Patent No. 5,428,012. The cytokine may also contain single or multiple amino acid insertions, deletions and/or additions to the naturally occurring sequence and may be derivatised or fragmented to a part carrying die active site of the cytokine. All such derivatives or fragmented cytokine molecules are encompassed by die present invention and are included in the expression "cytokine", provided all such molecules have the effect of altering and preferably reducing growth, proliferation or promoting differentation of breast cancer cells. Administration may be by any suitable route such as intravenous, intranasal, subcutaneous, intraperitoneal, intramuscular, intradermal, infusion, suppository, implant and oral including slow release capsules. Where cytokines may have a relatively short serum half life, the injected preparation may need to be modified to reduce serum degradation and/or alternative routes of administration employed. Administration may also be by gene therapy including expression of the particular cytokine gene in vectors which are introduced to d e mammal to be treated. Alternatively, the cytokine gene can be expressed in bacteria which are tiien incoφorated into the normal flora of the host. The effective amount of cytokine and particularly OSM will depend on die animal and die condition to be treated. For example, amounts ranging from about 0.1 ng kg body weight/day to about 1000 μg kg/body weight/day are contemplated to be useful in breast cancer therapy. More preferably, the effective amount is lng/lkg body weight/day to 100 μg/kg body weight/day. Even more preferably, die effective amount is lOng kg body weight/day to 10 μg/kg body weight/day. Such effective amounts may reflect actual administration protocols or may reflect an average of an alternate administration protocol. The protocol may be varied to administer cytokine or particularly OSM per hour, week or month or in conjunction with other therapeutic agents. In all of the above cases, the present invention also extends to d e use of derivatives of cytokines. By derivatives is meant recombinant, chemical or other synthetic forms of OSM or other cytokines and/or any alteration such as addition, substitution and/or deletion to die amino acid sequence component of the molecule or to the carbohydrate or otiier associated molecule moiety of OSM or otiier cytokine provided the derivative possesses the ability to alter and particularly to slow growth, proliferation or enhancing differentiation of breast cells. Accordingly, reference herein to OSM or to a cytokine includes reference to its derivatives. The present invention is further described by reference to the following non-limiting Figures and/or Examples. In the Figures: Figure 1 is a photographic representation of an analysis of growtii factor/receptor expression in breast cancer cells assessed by reverse-transcriptase polymerase chain reaction, RT-PCR. Autoradiograph of RT-PCR products obtained from die analysis of breast cell mRNA. Products were transfeπed to nylon membranes prior to being probed with a 32 P-labelled oligonucleotide corresponding to die r spective growth factor /receptor (Table 1). Lanes 1- 12 contain DNA samples from the following cell lines respectively, 184, 184B5, BT-483, MCF-7M, MDA-MB-134, MDA-MB-361, T-47D, BT-20, BT-549, MDA-MB-231, SK-BR- 3 and HBL-100. Samples in lanes 1 & 2 are from normal breast epithelial cell lines, lanes 3-7 are from estrogen receptor (ER) positive breast cancer cell lines, and lanes 8-12 are from ER negative breast cancer cell lines. Lane 13 is a positive control containing DNA from bone manow and lane 14 is a negative control in which DNA was ommitted from the PCR. Rows A-K represent products detected when die membranes were hybridised to oligonucleotides specific for the following growth factors/receptors respectively, gpl30, IL- 6R, LIFR, IL-11R, CNTFR, G-CSFR, IL-6, LIF, IL-11, CNTF, G-CSF, OSM and β- ACTIN. Control samples, obtained when reverse transcriptase was ommitted from the initial cDNA synthesis of each sample, gave no detected signal. Figures 2A, B and C are graphical representations of MCF-7M cells in liquid culture. 10 MCF-7M cells were cultured in 500μl RPMI/10% bovine calf serum (BCS) (v/v) containing the indicated concentration of each of die growtii factors (OSM or LIF). After 7 days culture viable cells were counted using a hemacytometer. Cell numbers reported here are the result of one experiment, each performed in triplicate. Figure 3 is a graphical representation showing clonogenicity of MCF-7M cells. Following suspension culture MCF-7M cell viability was measured by agar culture. Cells were plated in agar with the indicated concentrations of each of the growth factors. After 14 days culture colonies of cells were counted. Cell numbers reported here are the results of 3 experiments, each performed in triplicate, and are expressed according to die number of cells that went into suspension culture. Figure 4 is a photographic representation showing moφhology of growtii factor stimulated MCF-7M cells. Following 1 week in suspension culture containing die various growth factors, MCF-7M cells were cytospun onto slides and subsequently stained with Giemsa. Figures 5A and B are graphical representations of BT-549 cells in liquid culture. IO 4 BT- 549 cells were cultured in 500μl RPMI/10% (v/v) BCS containing the relevant concentration of each of the growth factors (OSM, IL-11 and IL-6). After 10 days culture viable cells were counted using a hemacytometer. Cell numbers reported here in die two graphs are the results of 1 experiment performed in triplicate. Figure 6 is a graphical representation of primary normal breast cells in suspension culture. IO 4 primary normal breast cells were cultured in 500μl serum free breast media containing the indicated concentration of each of die growth factors (OSM and IL-6). After 7 days culture viable cells were counted using a hemacytometer. Cell numbers reported here are die results of 1 experiment, performed in triplicate. Figure 7 is a graphical representation showing inhibition of proliferation of MCF-7 cells by Oncostatin M (OSM). 10* MCF-7 cells were cultured in 500μl RPMI/10% (v/v) BCS with the indicated concentrations of OSM. At 2, 4 and 6 days, viable cells were counted using a hemacytometer. Results are from 3 experiments, each performed in triplicate. Figure 8 is a graphical representation showing that MCF-7 cells are inhibited in a dose- dependent fashion by Oncostatin M (OSM). IO 4 MCF-7 cells were cultured in 500/ RPMI/10% (v/v) BCS with the indicated concentrations of OSM. After 7 days viable cells were counted, and cell number expressed as a percentage of die conesponding untreated control value. Figure 9 is a graphical representation showing the effect of OSM on cell cycle. MCF-7 cells treated witii OSM while growing in serum-free medium were harvested by treatment with trypsin and stained for DNA content analysis by flow cytometry. Cell cycle distributions were calculated by computer fitting of the resultant histograms. Figure 10(a) represents a typical experiment indicating that the percentage of cells in S phase following treatment with OSM decreases from approximately 15 % to 8 % over a 72 hour time period. Figure 10(b) represents data from 2 experiments (performed in triplicate) where the number of cells in S phase are represented as a percentage of die conesponding untreated control value. Figure 10 is a graphical representation showing the effect of EGF and OSM on cell cycle. MCF-7 cells treated with OSM, Epidermal Growth Factor (EGF) or both OSM and EGF while growing in serum-free medium were harvested by treatment with trypsin and stained for DNA content analysis by flow cytometry. Cell cycle distributions were calculated by computer fitting of die resultant histograms. Results represent the combined data from 3 experiments (performed in triplicate) where the number of cells in S phase are represented as a percentage of the conesponding untreated control value. Figure 11 is a photographic representation showing cell moφhology after exposure to OSM. MCF-7 cells from control cultures and appearance of cells after 7 days in OSM. A) Control cells, 10X magnification. B) OSM treated cells, 10X magnification. C) OSM treated cells, 40X magnification. D) OSM treated cells, 100X magnification. Figure 12 is a photographic representation showing effect of OSM on the expression of Transforming Growth Factor α (TGFα), Epidemal Growth Factor Receptor (EGFR), Prolactin Receptor (PRLR), Estrogen Receptor (ER) and LIF mRNA. Cells growing in the presence of 10% (v/v) BCS were treated witii OSM (lOng/ml) and at the indicated time points duplicate 150 cm 2 flasks were harvested and mRNA extracted for Northern analysis. Results for control cells (C) are also shown. The same filter has been probed successively with a M P-labelled cDNA conesponding to each mRNA species. mRNA loading was evaluated by reprobing the filter with a fragment complementary to GAPDH. mRNA species of the following sizes were obtained: TGFα, 4.8 kb; PRLR, 10.5 and 8.6 kb; EGFR, 10.5 and 5.8 kb; ER, 6.5 and 3.8 kb and LIF, approx. 4.8 kb. Figure 13 is a photographic representation showing ER expression in OSM and EGF treated cells. MCF-7 cells were grown on chamber slides for 6 days in RPMI/10 % (v/v) BCS with the following growtii factors, prior to being stained with an antibody specific for ER. A) Control, B) OSM, C) EGF, D) OSM and EGF. Cells stained brown indicate ER positivity. Figure 14 is a photographic analysis of growth factor receptor expression in breast cancer cell lines assessed by RT-PCR. Autoradiograph of RT-PCR products obtained from the analysis of breast cell mRNA. Samples in lanes 1 & 2 are from normal breast epithelial cell lines, lanes 3-7 are from ER positive breast cancer cell lines, and lanes 8-12 are from ER negative breast cancer cell lines. Lane 13 is a positive control containing RNA from bone manow (BM) and lane 14 is a negative control in which RNA was ommitted from the PCR (-ve). Products were transfened to nylon membranes prior to being probed with a "P-labelied oligonucleotide conesponding to the receptor indicated on the left and β-Actin as a control. Lanes 1-12 contain RNA samples from die following cell lines respectively, 184, 184B5, BT- 483, MCF-7M, MDA-MB-134, MDA-MB-361, T-47D, BT-20, BT-549, MDA-MB-231, SK- BR-3 and HBL-100. Control samples, obtained when reverse transcriptase was ommitted from the initial cDNA synthesis of each sample, gave no signal. Figure 15 is a photographic representation showing cell moφhology after exposure to OSM. MCF-7 cells fiom control cultures (Panel A) and appearance of cells after culture for 14 days in OSM (10 ng/ml) (Panel B). MDA-MB-231 cells from control cultures (Panel C) and appearance of cells after culture for 7 days in OSM (Panel D). Figure 16 is a graphical representation showing inhibition of MCF-7 cells after 7 days in suspension culture. 10*MCF-7 cells were cultured in 500μl RPMI/10% (v/v) BCS with die indicated growth factor. After 7 days viable cells were counted using a hemacytometer. Results are from 9 experiments, each performed in triplicate. Figure 17 is a graphical representation showing clonogenicity of MCF-7 cells after 1 week in suspension culture. Following suspension culture clonogenicity of MCF-7 cells was assayed in agar culture. Cells were plated in agar with die indicated growth factor and maintained at 37°C in a humidified incubator with 5% CO 2 in air. After 14 days colonies of ceils were counted. Results are from 9 experiments using 1L-6, LIF and OSM, and 5 experiments using CNTF and IL-11. Each experiment was performed in triplicate, and colony numbers are expressed as a percentage of untreated controls. Figure 18 is a graphical representation showing BT-549 cells after 10 days in suspension culture. lO BT-549 cells were cultured in 500μl RPIvfl/10% (v/v) BCS with the indicated growtii factor. After 10 days culture viable cells were counted using a hemacytometer. Results are from 6 experiments, each performed in triplicate. Figure 19 is a graphical representation showing MDA-MB-231 cells after 7 days in suspension culture. 10 4 MDA-MB-231 cells were cultured in 500μl RPMI 10% (v/v) BCS with die indicated growth factor. After 7 days viable cells were counted using a hemacytometer. Results are from 8 experiments, each performed in triplicate. Figure 20 is a graphical representation showing Scatchard analyses ofthe saturation isotherms of LIF and OSM binding to breast cancer cell lines. Cells were incubated witii various concentrations of labelled or unlabelled ligand in d e presence or absence of a 10-100 fold excess of unlabelled ligand. After 18 hr on ice, bound and free ligand were separated by centrifugation through bovine calf serum. Bound and free 1 5 I-ligand was quantitated in a γ- counter and the data was depicted as a Scatchard transformation. Data was normalised for cell number and is shown as binding to 10 4 cells. A) Saturation isotherm of LIF binding to die MCF-7 cell line. This analysis indicates high affinity binding of LIF with a dissociation constant of 14.6 pM and an estimated 57 receptors per cell. B) Saturation isotherm of OSM binding to me MDA-MB-231 cell line. This analysis indicates high affinity binding of OSM with a dissociation constant of 92 pM and an estimated 124 receptors per cell. Figure 21 is a photographic analysis of growth factor receptor expression in primary breast cancer tissue assessed by RT-PCR- Autoradiograph of RT-PCR products obtained from the analysis of fresh breast tissue mRNA. Products were transfened to nylon membranes prior to being probed with a 12 P-labelled oligonucleotide conesponding to the respective receptor (Table 2). Lanes 1-15 contain RNA samples representative ofthe 50 cancerous breast tissue samples obtained at biopsy. These were examined for the growth factor receptors and β-Actin as indicated. Control samples, obtained when reverse transcriptase was ommitted from the initial cDNA synthesis of each sample, gave no signal. In some samples (CNTFR, ER and IL- 6R) a smaller hybridising PCR product was identified. These bands were attributed to alternative splicing (Koehorst etal., 1993; Horiuchi et al., 1994). EXAMPLE 1 Breast cell lines Cell lines 184 (Stampfer and Bartley, 1985) and 184B5 (Walen and Stampfer, 1989) were derived from non malignant breast epithelial cells; BT-483 (Lasfargues et ai, 1978), MCF- 7M (Soule et al, 1973), MDA-MB-134 (Cailleau etal., 1974), MDA-MB-361 (Cailleau et al., 1978) and T-47D (Keydar et al., 1979) cell lines originated from estrogen receptor (ER) positive breast cancer cells; BT-20 (Lasfargues and Ozzello, 1958), BT-549 (Lasfargues et al, 1978), MDA-MB-231 (Cailleau etal, 1974), SK-BR-3 (Trempe and Fogh, 1973) cell lines originated from ER negative breast cancer cells. The HBL-100 cell line is an ER negative transformed cell line, originating from normal lactating breast (Caron de Fromentel et al, 1985). EXAMPLE 2 Tissue culture Breast cell lines were grown in monolayer in RPMI- 1640 medium containing 10% (v/v) bovine calf serum ((v/v) BCS) at 37°C in a fully humidified atmosphere, containing 10% (v/v) CO 2 in air. Cell lines were passaged by treatment with 0.05% (w/v) trypsin and 0.02% (w/v) EDTA. EXAMPLE 3 Reverse transcriptase polymerase chain reaction Total RNA was extracted from the cell lines and primary breast cancer tissue as previously described (Buckley et al, 1993). First strand cDNA synthesis was performed on 1 μg of total RNA. Reverse transcription was canied out at 42°C for 60 min in 20 μl of 50 mM Tris.HCl pH 8.3, 20 mM KCI, 10 mM MgCL, 5 mM dithiothreitol, 1 mM of each dNTP, 20 μg/ml oligo(dT) and 12.5 units of AMV reverse transcriptase (Boehringer Mannheim). Control reactions were performed for each RNA sample under identical conditions except that reverse transcriptase was omitted from the reaction. The reverse transcription reaction mixture was diluted to 100 μl with water and 5 μl was used for each PCR reaction. PCR reactions were carried out in 50 μl of reaction buffer (Boehringer Mannheim) containing 200 μM of each dNTP, 1 μM of each primer and 2.5 units of Taq polymerase (Boehringer Mannheim). The oligonucleotides used for amplification of cDNA are shown in Table 2. After an initial denaturation of 2 min at 96°C PCR was performed for 30 cycles in a Hybaid Omnigene Thermal Cycler (Integrated Sciences). Each cycle consisted of 30 sec denaturation at 96°C, 30 sec annealing at 60°C and 2 min polymerisation at 72°C. 20 μl of the reaction mixture was electrophoresed on a 1% (w/v) agarose gel and DNA transfened to a nylon membrane (hybond-N+, Amersham). Southern blots were performed as described previously (Reed and Mann, 1987). Hybridisation was carried out with end-labelled oligonucleotides internal to the respective cDNA sequences (Table 2). EXAMPLE 4 Binding studies Receptor binding assays were performed using radioiodinated LIF ("'l-LIF) and OSM ( m I- OSM). The radioiodination of LIF and OSM and binding assays were essentially performed as previously described (Hilton etal., 1 91 ; Hilton and Nicola, 1992). Briefly, 50 μl aliquots ∞ntaining 1 x 10 7 cells, suspended in RPMI- 1640 medium containing 10% (v/v) BCS, were placed in Falcon tubes with 40 μl of the respective radioiodinated ligand at 1 x 10 s cpm per 40 μl, with or without greater than a 40-fold excess of unlabelled ligand. Incubation was carried out at room temperature for 60 min and cells were resuspended and layered over 180 μl of (v/v) BCS. Cell associated and free radioiodinated ligand were separated by centrifugation. The pellet and supernatant were subsequently counted in a γ-counter. Specific binding was estimated by subtraction of non specific binding from binding with 1M I-ligand (total binding). Number of cell surface receptors and dissociation constant were calculated by Scatchard analysis. EXAMPLE 5 Biological assays Proliferation of die cell lines was measured in monolayer culture in 24 well Costar cluster plates. Cells were plated at an initial density of 10 000 cells/ml and cultured in 500 μl RPMI- 1640 supplemented with 10 % (v/v) (v/v) BCS and with each growth factor as indicated (LIF, 1000 U/ml; IL-6, 100 ng/ml; OSM, 10 ng/ml; CNTF, lOOng/ml; J -11, lOOng/ml). These concentrations are maximally active in other systems (Nandurkar et al, 1996; Hilton et al., 1994; Zhang et al, 1994; Tanigawa et al, 1995). After 7 or 10 days at 37°C in a fully humidified atmosphere ∞ntaining 10% (v/v) CO 2 in air, cells were trypsinised and counted using a haemocytometer and an inverted microscope. Cell viability was assessed using eosin exclusion. Results were expressed as a percentage of the conesponding untreated ∞ntrol value for that experiment. EXAMPLE 6 Clonogenic assays Clouogenic potential of cells foilowing monolayer culture was assessed in a semi-solid culture medium. Cells were cultured in triplicate in 35 mm Petri dishes ∞ntaining 1 ml Iscove's modified Dulbec∞'s medium (IMDM) supplemented with 25% (v/v) (v/v) BCS, 0.3% (w/v) agar with final concentration of growth factor as outlined above, and with 200 cells per ml for ∞ntrol cultures. Cultures were maintained at 37°C in a humidified incubator with 5% (v/v) CO 2 in air. After 14 days, colonies were enumerated using a dissecting microscope. A colony was defmed as a clone of greater than 40 cells. All cultures were performed in triplicate. EXAMPLE 7 Cytokines Human LIF was produced using the pGEX system, essentially as described (Gearing et al, 1989), human IL-6 was from Ludwig Institute for Cancer Research, (Melbourne, Australia), human CNTF was purchased from AMRAD Operations Ltd. (Melbourne, Australia) and human OSM and IL-11 were purchased from PeproTech (Rocky Hill, NJ, USA). EXAMPLE 8 Statistical analysis Statistical analysis of data was performed using the paired and unpaired Student's T-test. EXAMPLE Growth of primary breast tissue Sterile normal breast tissue was obtained from reduction mammoplasty surgery. Fat was dissected away and die remaining ductal tissue minced finely, suspended in 'dissociation media' (DME/Hams F12 ∞ntaining 10 ng/ml EGF, 1 μg/ml insulin, 0.5 μg/ml hydro∞rtisone, 10 ng/ml cholera toxin, 300 U/ml collagenase, 100 U/ml hyaluronidase and 1 mg/ml BSA) and agitated overnight at 37"C . After 18 hours the mixture was centrifuged at 600 RCF/5 min, the supernatant discarded and the remaining cell pellet washed twice in RPMI- 1640 supplemented witii 10 % (v/v) (v/v) BCS. An alliquot of the cells was then placed in an 80 cm 2 tissue culture flask (Nunc) in 'breast media' (DME/Hams F12 ∞ntaining 10 ng/ml EGF, 1 μg/ml insulin, 0.5 μg/ml hydro∞rtisone, 10 ng/ml cholera toxin, 1 mg/ml BSA supplemented with 10% (v/v) (v/v) BCS) for 24 hour at 37"C in a fully humidified atmosphere, ∞ntaining 10% (v/v) CO 2 in air. Single cells adhered to the culture flasks and from these islands of cells epithelial cells grew. The media was subsequently removed and replaced with serum-free breast media. Partial tiTpsinisation removed any ∞ntaminating fibroblasts and the cells remaining were 95-100% epithelial. Cells were subsequently grown for approximately 30 days in die serum free breast media. EXAMPLE 10 Cell Cycle Analysis Cell cycle analysis was performed in serum-free medium (Sigma). Analysis was performed 2-4 days after cells were washed and re-cultured in serum-free medium. Growth factors were added to the medium as indicated. At the times shown thereafter, cells were harvested with 0.05 % (w/v) tipsin-0.02% (w/v) EDTA. The cells were resuspended in serum-free tissue culture medium and after cell counting using a hemacytometer, stained for later DNA analysis by the addition of 0.25% prothidium iodide in the presence of 0.2% (v/v) Triton X-100. DNA histograms were obtained by using a FACScan flow cytometer (Becton Dickinson Immunocytochemistry Systems) and die cell cycle phase distribution was estimated by using the manufacturer's DNA analysis software (Cellfit). Each histogram ∞ntained 10,000 events. EXAMPLE 11 RNA isolation and Northern Analysis Cells havested from duplicate flasks were pooled and poly A+ mRNA extracted by an oligo-dT cellulose procedure (Boehringer Mannheim). Northern analysis was performed using 5μg RNA per lane. Membranes (Hybond-C extra-Amersham) were hybridised (42 "C overnight) with probes labelled with a- 32 ? dCTP (bresatec). The membranes were washed at a stringency of 0.2 X SSC (30 mM NaCl, 3 mM sodium citrate, pH 7.0) -0.1 % (w/v) sodium dodecyl sulfate at 65 β C and exposed to Kodak X-Omat film at -70°C. mRNA loading was estimated by hybridising membranes with a 1.3 kb cDNA complementary to GAPDH. EXAMPLE 12 Analysing growtii factor/receptor expression by RT-PCR Initial experiments have examined expression of several receptors, including gp 130, LIF, G- CSF, GM-CSF, CNTF, IL-2, 3, 6, 7 tfe 11 and their associated ligands (Figure 1). Preliminary results have indicated die expression of both ligand and receptor in die case of IL-6, LIF and CNTF. The expression of IL-11 receptor was observed in most of the breast samples. The signalling molecule gpl30 was also expressed (as expected). The expression of such receptors as G-CSF, GM-CSF and IL-2 appeared to be less consistent in the breast samples. EXAMPLE 13 Function of growth factors/receptors on breast cell growth The function of the growth factors and receptors identified in initial mRNA and protein studies of breast cancer cells have also been investigated. Breast cell lines were initially examined for changes in cell proliferation in suspension cultures ∞ntaining the growth factors of interest. Preliminary experiments have examined the growth of several of the breast cancer cell lines in cultures with maximal ∞ncentrations of LIF, IL-6 and OSM. These cultures have indicated tiiat two of these growtii factors have inhibitory effects on cell proliferation. Figures 2A, 2B and 2C show the proliferation of MCF-7M cells following 1 week in suspension culture. This proliferation data indicates that OSM and LIF may inhibit cell growth. Figure 3 shows the viability of the MCF-7M cells following a clonogenic assay. Results indicate that the effects of the two growth factors are enhanced after this assay. This inhibition of cell proliferation by OSM has been demonstrated in cell lines MCF-7M and BT549. LIF induced inhibition in cell line MCF-7M. It is interesting to note that IL-6 did not appear to be able to induce inhibition when compared to the ∞ntrol (Figure 2A). Figure 4 depicts four photomicrographs of MCF-7M breast cancer cells treated with maximal concentrations of IL-6, OSM and LIF for 1 week in liquid culture. Cells grown in the presence of IL-6 appeared moφhologically similar to the ∞ntrol; several of the cells grown in LIF appeared larger than the ∞ntrol cells; the cells grown in the presence of OSM showed more abundant cytoplasm and vacuolation. This moφhological change in the OSM treated cells was consistent with features of cell differentiation. These findings suggested that ligand-induced growth inhibition in breast cancer cell lines may be associated with an apparent induction of differentiation. Figures 5A and 5B show cells from the BT-549 cell line that have been grown in liquid culture in the presence of IL-11. As well as the growth inhibition seen previously on other cell lines with OSM, the BT-549 cell proliferation was inhibited by IL-11. EXAMPLE 14 Examination of breast tissues The inventors developed culture techniques that allow the growth of normal breast cells in vitro. A total of 4/4 normal breast samples have been successfully cultured and ∞ntinued to proliferate for several weeks. RT-PCR analysis from three of these primary normal breast samples have indicated that gp 130, LIFR, LIF and OSM are expressed in these cells. Figure 6 shows the growth of one of these primary samples in suspension culture with the various growth factors. These data show that OSM profoundly inhibited the proliferation of these normal cells. EXAMPLE 15 Inhibition of proliferation of MCF-7 cells by Oncostatin M (OSM). The results are shown in Figure 7. IO 4 MCF-7 cells were cultured in 500μl RPMI/10% (v/v) BCS with the indicated ∞ncentrations of OSM. At 2, 4 and 6 days, viable cells were ∞unted using a hemacytometer. Results are from 3 experiments, each performed in triplicate. These data demonstrate that while ∞ntrol cells grow in a exponential fashion over the 6 day time period, there was inhibition of cellular proliferation as a result of treatment with OSM. EXAMPLE 16 MCF-7 cells are inhibited in a dose-dependent fashion by Oncostatin M (OSM). The results are shown in Figure 8. IO 4 MCF-7 cells were cultured in 500μl RPMI/10% (v/v) BCS with the indicated ∞ncentrations of OSM. After 7 days viable cells were ∞unted, and cell number expressed as a percentage of the conesponding untreated ∞ntrol value. Results are from 5 experiments each performed in triplicate. Results indicate that treatment of MCF-7 cells with pg/ml quantities of OSM results in decreases in cellular proliferation while a concentration of 10 ng/ml OSM results in optimal inhibition. EXAMPLE 17 Effect of OSM on cell cycle. The results are shown in Figure 9. MCF-7 cells treated witii OSM while growing in serum-free medium were harvested by treatment with trypsin and stained for DNA ∞ntent analysis by flow cytometry. Cell cycle distributions were calculated by ∞mputer fitting of the resultant Figure 9A represents a typical experiment indicating tiiat the percentage of cells in S phase following treatment with OSM decreases from approximately 15 % to 8 % over a 72 hour time period. Figure 9B represents data from 2 experiments (performed in triplicate) where the number of cells in S phase are represented as a percentage of the ∞nesponding untreated ∞ntrol value. At the initial time point of 12 hour there is a marked decrease in die S phase cells in OSM treated cells. By 24 hour the number of cells in S phase was 50 % of ∞ntrol cells. There was a concomitant increase in the percentage of cells in G. phase, demonstrating that OSM is inhibiting a rate limiting step in progression through G,. Similar results were seen when cells were grown in RPMI ∞ntaining 10 % (v/v) BCS. EXAMPLE 18 Effect of EGF and OSM on cell cycle. The results are shown in Figure 10. MCF-7 cells treated with OSM, Epidermal Growtii Factor (EGF) or both OSM and EGF while growing in serum-free medium were harvested by treatment with trypsin and stained for DNA content analysis by flow cytometry. Cell cycle distributions were calculated by computer fitting of the resultant histograms. Results represent the ∞mbined data from 3 experiments (performed in triplicate) where the number of cells in S phase are represented as a percentage of the ∞nesponding untreated ∞ntrol value. The S phase fraction is decreased in cells treated with OSM, and this is maintained over a 6 day time period. Cells treated with EGF (thought to be a mitogenic stimuli in some breast cancers) and OSM also demonstrate a 50 % decrease in S phase fraction. EXAMPLE 19 Cell morphology after exposure to OSM. The results are shown in Figure 11. MCF-7 cells from control cultures and appearance of cells after 7 days in OSM. A) Control cells, 10X magnification. B) OSM treated cells, 10X magnification. C) OSM treated cells, 40X magnification. D) OSM treated cells, lOOX magnification. Striking changes in the moφhology of cells treated with OSM are apparent. MCF-7 cells exposed to OSM appeared to draw apart from neighbouring cells, and to develop a more fibroblastic phenotype. This was associated with the appearance of decreased intercellular adhesion and the development of pseudopodia-like processes. EXAMPLE 20 Effect of OSM on the expression of Transforming Growth Factor a (TGFατ, Epidemal Growth Factor Receptor (EGFR), Prolactin Receptor (PRLR) , Estrogen Receptorm (ER) and LIF mRNA. The results are shown in Figure 12. Cells growing in the presence of 10% (v/v) BCS were treated with OSM (lOng/ml) and at the indicated time points duplicate 150 cm 2 flasks were harvested and mRNA extracted for Northern analysis. Results for ∞ntrol cells (C) are also shown. The same filter has been probed successively with a S2 P-labelled cDNA ∞nesponding to each mRNA species. mRNA loading was evaluated by reprobing the filter with a fragment ∞mplementary to GAPDH. mRNA species of the following sizes were obtained: TGFα, 4.8 kb; PRLR, 10.5 and 8.6 kb; EGFR, 10.5 and 5.8 kb; ER, 6.5 and 3.8 kb and LIF, approx. 4.8 kb. Northern analysis demonstrates that as a result of cells being exposed to OSM the abundance of EGFR mRNA is elevated at least 5-fold between 4-12 hours. The EGFR transcript decreases to ∞ntrol levels by 24 hour. The abundance of Transforming Growth Factor α (TGFα) transcript in OSM treated cells appears to be equivalent to ∞ntrol cells over this time period. However, OSM appears to down regulate the level of expression of both Estrogen Receptor (ER) and Prolactin Receptor (PRLR) mRNA. After only 2 hours exposure to OSM the levels of these two receptors is down regulated and this is maintained for 48 hours. OSM also upregulates the level of LIF transcript in MCF-7 cells over the 1-4 hour time period. EXAMPLE 21 ER expression in OSM and EGF treated cells. The results are shown in Figure 13. MCF-7 cells were grown on chamber slides for 6 days in RPMI/10 % (v/v) BCS with the following growth factors, prior to being stained with an antibody specific for ER. A) Control, B) OSM, C) EGF, D) OSM and EGF. Cells stained brown indicate ER positivity. Results indicate that 90 % of ∞ntrol cells have stained positive for ER and cells treated with EGF have approximately 60 % ER positivity. Cells treated with OSM show 50 % of cells staining very weakly for ER, indicating a down regulation of ER protein levels after treatment with OSM. Furthermore, this down regulation of ER protein is more dramatic when cells are treated with both OSM and EGF as only approximately 10 % of cells have stained positively for ER. Moφhologically it can be seen that cells treated with OSM appear larger and more vacuolated than ∞ntrol cells. The moφhological changes are more striking when cells are treated with OSM and EGF: cells are larger than control cells and have more abundant cytoplasm and cytoplasmic processes. EXAMPLE 22 RT-PCR analysis of receptor expression on breast cancer cell lines Initial experiments examined the expression of various receptors on 12 breast cell lines. These receptors included the LIF receptor (LIFR), IL-6R, IL-1 IR, CNTFR, the common gpl30 signalling molecule and receptors for IL-2, 3, 6, 7 & 11, G-CSF, GM-CSF, growth hormone (GH) and prolactin (PRL) (Figure 14). Both GHR and PRLR were expressed primarily in estrogen receptor (ER) positive cell lines with in∞nsistent expression in ER negative cells. GHR was also expressed in the breast cell lines derived from normal tissue, whereas PRLR was not expressed in these cells. All cell lines expressed the signalling molecule gpl30, and expression of the specific receptor components for IL-6, LIF, IL-11 and CNTF was observed in the majority of cell lines studied. Expression ofthe LIFR was ubiquitous and appeared equivalent to the level of gp 130 as assessed by RT-PCR. IL-1 IR expression was also observed in all of the cell lines except SK-BR-3 (a line originating from an ER negative breast carcinoma). However, expression ofthe IL-6R in die cell lines appeared variable, ∞nsistent with die variable biological effects reported for IL-6. For example expression of the IL-6R in MCF-7, T-47D and SKBR3 cell lines is consistent with previous reports of variable effects of IL-6 in these cell lines. Equally the lack of IL-6R expression in the MDA-MB-231 cell line conelates well with reports describing its lack of activity on these cells (Danforth and Sgagsis, 1993). The CNTFR was readily detected in cell lines that expressed the ER, but with no expression observed in cell lines derived from normal breast nor ER negative cell lines. The pattern of expression was thus similar to PRLR expression. In contrast to the widespread expression of gpl30 and associated receptors, expression of receptors for G-CSF, GM-CSF, BL-2 and IL-3 was highly variable in these breast cell lines. G-CSFR was expressed only in the BT-483 cell line. While the β ∞mmon signaUing subunit shared by GM-CSF, IL-3 and IL-5 was detected in 6 cell lines the specific GM-CSFR α and IL-3R α chains were expressed in only 2 cell lines. The IL-2R γ ∞mmon signalling subunit, shared by IL-2, 4, 7, 9 and 13, was expressed in 2 of the breast cell lines, while for example, the LL-7R α chain was not expressed in any cell lines. Because of the widespread expression pattern ofthe gpl30 molecule and associated receptors in the majority of breast cell lines compared with the variable expression of other cytokine receptors, we elected to focus on the gpl30 sub-family in this study. EXAMPLE 23 Action of cytokines on growth of breast cell lines The action of B -6, LIF, OSM, CNTF and IL-11 was examined on 4 breast cancer cell lines grown in monolayer culture. Striking changes in the moφhology of cells were observed. Figure 15 compares moφhology of untreated cells with cells exposed to OSM. MCF-7 cells exposed to OSM appeared to draw apart from neighbouring cells, and to develop a more fϊbroblastic phenotype. This was associated with the appearance of decreased intercellular adhesion or cellular ∞ntraction. These changes were quite marked by day 14. Transformation to a fibroblastic phenotype was also observed in the BT-549 and MDA-MB-231 cell lines exposed to OSM, with elongation of cells and loss of intercellular contact. In contrast, T-47D cells cultured with OSM, became more rounded in appearance. Experiments were performed to determine whether these moφhological changes were associated with alterations in cell growth. The proliferation of four breast cancer cell lines was examined in monolayer cultures ∞ntaining either IL-6, LIF, OSM, CNTF or IL-11. In this assay, significant inhibition of cellular proliferation by OSM in 3/4 cell lines, IL-11 in 2/4 cell lines and by IL-6 and LIF in 1/4 cell lines was observed. The MCF-7 cell line exhibited a biological response following treatment with this family of growth factors. Results of 9 experiments examining action of IL-6, LIF and OSM, and 5 experiments examining action of CNTF and IL-11 on the MCF-7 cell line are presented in Figure 16. In ∞ntrol cultures of MCF-7 cells the absolute cell number increased from lOVml to 5xl0 . lxlOVml during the 1 week culture period. The most dramatic effect on cell proliferation was seen after 7 days exposure to OSM, with up to 94% inhibition and a mean of 85% inhibition in 9 experiments (p< 0.001). This action of OSM was maximal at ∞ncentrations of greater than 10 ng/ml. Exposure to LIF for 7 days resulted in an average of 37% growth inhibition (p<0.01). The effect of IL-11 and IL-6 was less marked. The mean inhibition observed in response to IL-6 was 23% (p<0.01). In five experiments using IL-11 a mean of 27% inhibition (p= 0.02) was observed. In ∞ntrasζ there was no effect on cellular proliferation in five experiments in which cells were treated with CNTF. To further address die inhibitory effect of these molecules on MCF-7 cells we also examined the clonogenic potential of cells following growth in monolayer cultures for 7 days. The frequency of clonogenic MCF-7 cells in ∞ntrol cultures was 20-60% (n=9 experiments). With OSM, LIF and LL-6 the growth inhibitory effect observed in monolayer culture were also detected in agar cultures. Results of 9 experiments (Figure 17) showed significant reduction of ∞lony formation by cells which had been exposed to IL-6 (ρ< 0.01), LIF (p< 0.01) and OSM (p< 0.01). In 5 experiments exposure to IL-11 in monolayer culture did not have detectable effect on subsequent clonogenicity (p= 0.65). As in the monolayer cultures, exposure to CNTF had no effect on clonogenic potential of these cells. Results of treatment ofthe cell line BT-549 with growth factor for 10 days are presented in Figure 18 (n=6 experiments). The number of BT-549 cells in ∞ntrol cultures increased from 1 OVml to 4- 9x 1 OVml during the 10 day culture period. Mean growth inhibition of 60% followed treatment with OSM, with up to 80% inhibition observed (p<0.01). This inhibition was also apparent at 7 days (mean 60%, p<0.01). Similarly, inhibition of up to 63% (mean 56%, p<0.01) in response to EL-11 was observed at 10 days however after 7 days in culture this effect was less evident (mean 30%, p=0.17 ). As expected from he results shown in Figure 14 with no detectable mRNA for EL-6R and very low levels of CNTFR mRNA. Figure 19 depicts 8 experiments using die ER negative cell line, MDA-MB-231. Inhibition of proliferation of up to 65% (mean 54%, p< 0.01) was observed in cells exposed to OSM. Treatment with LIF did not result in significant effects on cellular proliferation. These cells did not express CNTFR (Figure 14) and did not respond to CNTF. Similarly the level of IL-6R expression was barely detectable (Figure 14). EXAMPLE 24 Analysis of receptor protein expression The response of BT-549 and MDA-MB-231 cells to OSM but not to LIF was unexpected given tiiat 5 both growtii factors utilize the LIF-gpl30 heterodimer. Experiments were, therefore, performed to document LIFR expression and binding of LIF to the surface of these cells. Binding assays were performed to monitor in∞rpσration ofthe respective radio-labelled ligand. Four breast cancer cell lines (T-47D, MDA-MB-231, MCF-7 and HBL-100) were examined with m I-LIF and '"I-OSM. Table 3 shows the specific binding of OSM and LIF. All four ofthe cell lines demonstrated specific 10 binding. Three ofthe cell lines showed increased binding of OSM ∞mpared with LIF. Binding of radiolabelled LIF was comparable for all cell lines. In contrast there was approximately 10-fold reduced binding of radiolabelled OSM to HBL-100 cells ∞mpared with the other cell lines (a cell line derived from normal lactating breast). Thus the failure of BT-549 cells and MDA-MB-231 cells to respond to LIF ∞uld not be attributed to lack of expression of LIFR mRNA (Figure 14) nor 15 to lack of receptor protein expression (Table 3). Binding of ,ϊ3 I-LIF to the MCF-7 cell line (Figure 20A) revealed a single class of high affinity binding sites for LIF with an estimated 57 receptors per cell and a dissociation ∞nstant of 14.6 pM. In contrast, and in keeping with the results presented in Table 3, MCF-7 cells showed an estimated 20 990 receptors per cell and a dissociation ∞nstant of 2 nM for l2$ I-OSM. Results obtained with the HBL-100 cell line also demonstrated high affinity binding of 125 I-LIF. HBL-100 cells showed an estimated 27 receptors per cell and a dissociation ∞ntstant of 7.49 pM. The number of LIF binding sites observed on these cells is comparable with estimates of receptor number for other tissues (Hilton etal., 1991). Figure 21B shows a Scatchard analysis depicting binding of 12J I-OSM to the 25 MDA-MB-231 cell line. MDA-MB-231 cells also showed a single class of high affinity binding sites for OSM, with an estimated 124 receptors per cell and a dissociation ∞nstant of 92 pM. EXAMPLE 25 Receptor expression by RT-PCR on primary breast cancer samples Based on the aforementioned results, the inventors sought to determine whether the gpl30 sub- family of receptors might also be expressed on fresh tumor samples. Although it was possible that these receptors might be expressed on normal breast cells contaminating these tissue samples, the concordance between results from primary samples and analysis of cell lines suggested that this was not the case. Typical results for expression of the gpl30 sub-family of receptors from 50 clinical samples of malignant breast tissue are shown in Figure 21. This analysis showed a strikingly similar pattern of expression of gpl30 associated receptors to that observed on breast cancer cell lines. Expression of gpl30, LIF and IL-11 receptors was detected on 96%, 96% and 98% ofthe samples respectively. By comparison, IL-6 receptor was detected in only 80% ofthe samples. This was ∞nsistent with the variable expression pattern of this receptor relative to LIF and IL-11 receptors that was observed on cell lines. CNTFR expression was observed in 94% of the primary breast cancer samples. This was more frequent than CNTFR expression in the cell lines, and the ∞nelation with ER (only 68% of samples were ER positive) was less marked. It was interesting, however, that the three samples tiiat were CNTFR negative were also ER negative. Thus the widespread expression of members ofthe gpl30 sub-family of receptors was observed not only in breast cancer cell lines but in the majority of samples obtained from malignant breast tissue. Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, ∞mpositions and compounds refened to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features. TABLE 2 Sequence of Olignniiclentides Gene size cDNA 5' sequence/3' sequence internal sequence Reference 0ml f5'-3'.. '-3'ϊ gp !30 811 GAGGTGTGAGTGGGATGGTGG GGGCAACAC ACAAGTTTGCTGATTG 2 Hibi et al. , 1991 GCTGCATCTGATTTGCCAAC' IL-6R 748 GTTTCAGAACAGTCCGGCCG CAGGAGCCGTGCCAGTATTCCCAGG 4 Yamasaki et al , 1988 CTTGCCTTCGTTCAGAGCCC 5 LIFR 660 CCCTCTGGAACAGGCCGTGG GAAGTTTGC ATTGAAAAC AGGTCCCG* Gearing et al , 1991 CAAGGGGCAGTTTGTATGGCC 5 O IL-11R 509 CTGAGTTCTGGAGCCAGTAC GTGACTGAGGTGAACCCACTGGGTG' Nandurkar et al, 1996 GGTGTGGTTGGAGGGAGGGC 7 CNTFR 649 GTGGGCCTGCTGTGCTGTGC CGCCGCAGTTGTCTACGCCCAGAG 10 Davis et al , 1991 CCAGCCGGCGAGGGTTGCTG 9 G-CSFR 1034 GCTGCATCTAAAGCACATTG GACCTGGGCACAGCTGGAGTGGGTG 12 Fukunaga et a/., 1990 GAGATGGTGAGAGCCTGGGCTG 11 PLR 670 CAGACTACATAACCGGTGGC CAAGCAGTACACCTCCATGTGGAGG' 4 Boutin et al. , 1989 TGGCATCCCAAGGCACTCAG 1 ' GHR 702 CAGATCCACCCATTGCCCTC GGCGAGTTCAGTGAGGTGCTCTATG Jβ Leung et al, 1987 CGCCATCCTTCACCCCTAGG" TABLE 2 (continued...) GM-CSFR β 710 CCACCAGGTACTGGGCCAGG GCACCGGCTACAACGGGATCTGGAG 1, Hayashida et al , 1990 GAGGGACCAGTTGCACCTGC 17 GM-CSFR α 928 GGAAGGGAGGGTACCGCTGC CTGTACCTGGGCGAGGGGTCCGACG 20 Crosier et al. 1991 CTTGACCACCACCCTGCCTC 19 IL-2R γ 776 CCCCTCCCAGAGGTTCAGTG CAGCAGCTCTGAGCCCCAGCCTACC* Takeshita et al , 1992 AGACACACCACTCCAGGCCG" IL-3R α 888 GCCGACTATTCTATGCCGGC CCGTCCGAGTGGCC AACCC ACC ATT 24 Kitamura et al. , 1991 CGTTTTGGAAGCTGTCACCG 23 I ER 711 GTGTACAACTACCCCGAGGG CGCCAACGCGCAGGTCTACGGTCAG* Green et al, 1986 CTCATGTCTCCAGCAGACCC* β-ACTIN 721 CTTCCCCTCCATCGTGGGGC CGACGAGGCCCAGAGCAAGAGAGGC 2 * Ponte et al. 1984 GTTTCGTGGATGCCACAGGAC" 1-28 Corresponds to SEQ ID Nos. 1-28 TABLE 3 BINDING OF hOSM AND hLIF TO HUMAN BREAST CANCER CELL LINES specific bmding(cpm)/10 6 cells Cell line OSM LIF T47D 1400+/-20 380+/-10 MDA-MB-231 2980+/-460 450+/-120 MCF-7M 1250+/-90 350+/- 100 HBL-100 140+/-10 590+/-30 BIBLIOGRAPHY: Antman, K. H. 1992. Dose intensive therapy in breast cancer. 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D., Turner, K., Shoyab, M., Taga, T., (v/v) BCS, T., Bataille, R. and Klein, B. (1994) J. Exp. Med., 177: 1337-1342. SEQUENCE LISTING (1) GENERAL INFORMAΗON: (i) APPLICANT: (Countries other than US) AMRAD OPERATIONS PTY LTD (US only) DOUGLAS, AM and BEGLEY, CG (ii) TITLE OF INVENTION. A METHOD OF TREATMENT (ϋi) NUMBER OF SEQUENCES: 28 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: DAVIES COLLISON CAVE (B) STREET: 1 LITTLE COLLINS STREET (C) CITY: MELBOURNE (D) STATE: VICTORIA (E) COUNTRY: AUSTRALIA (F) ZIP: 3000 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Patentin Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: PCT INTERNATIONAL (B) FILING DATE: 25-OCT-1996 (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: PN6242 (B) FILING DATE: 27-OCT-1995 (A) APPLICAΗON NUMBER: PN6243 (B) FILING DATE: 27-OCT-1995 (A) APPLICATION NUMBER. PN8966 (B) FILING DATE: 27-MAR-1996 (A) APPLICATION NUMBER: PO0364 (B) FILING DATE: 07-JUN-1996 (viii) ATTORNEY/AGENT INFORMATION: (A) NAME: HUGHES DR, E JOHN L (C) REFERENCE/DOCKET NUMBER: EJH EK (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: +61 3 9254 2777 (B) TELEFAX: +61 3 9254 2770 (2) INFORMATION FOR SEQ ID Nθ:l: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:l: GAGGTGTGAGTGGGATGGTGGGCTGCATCTGATTTGCCAAC 51 (2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: GGGCAACACA CAAGTTTGCT GATTG 25 (2) INFORMATION FOR SEQ ID NO:3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: GTTTCAGAAC AGTCCGGCCG CTTGCCTTCG TTCAGAGCCC 50 (2) INFORMATION FOR SEQ ID Nθ:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA - 52 - (xi) SEQUENCE DESCRIPTION: SEQ ID Nθ:4: CAGGAGCCGTGCCAGTATTCCCAGG 25 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TCrOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: CCCTCTGGAA CAGGCCGTGG CAAGGGGCAG TTTGTATGGC C 51 (2) INFORMATION FOR SEQ ID NO:6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 26 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: GAAGTTTGCA TTGAAAACAG GTCCCG 26 (2) INFORMATION FOR SEQ ID NO:7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: CTGAGTTCTG GAGCCAGTAC GGTGTGGTTG GAGGGAGGGC 50 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: GTGACTGAGGTGAACCCACTGGGTG 25 (2) INFORMATION FOR SEQ ID NO: 9 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 baβe pairs (B) ΓE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: GTGGGCCTGC TGTGCTGTGC CCAGCCGGCG AGGGTTGCTG 50 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 24 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: CGCCGCAGTTGTCTACGCCCAGAG 24 (2) INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 52 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:ll: GCTGCATCTAAAGCACATTG GAGATGGTGAGAGCCTGGGCTG 52 (2) INFORMATION FOR SEQ ID NO:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: GACCTGGGCACAGCTGGAGTGGGTG 25 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: CAGACTACAT AACCGGTGGC TGGCATCCCA AGGCACTCAG 50 (2) INFORMATION FOR SEQ ID NO:14: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: CAAGCAGTACACCTCCATGTGGAGG 25 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: CAGATCCACC CATTGCCCTC CGCCATCCTT CACCCCTAGG 50 (2) INFORMATION FOR SEQ ID NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: GGCGAGTTCA GTGAGGTGCT CTATG 25 (2) INFORMATION FOR SEQ ID NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: CCACCAGGTA CTGGGCCAGG GAGGGACCAG TTGCACCTGC 50 (2) INFORMATION FOR SEQ ID NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: GCACCGGCTACAACGGGATCTGGAG 25 (2) INFORMATION FOR SEQ ID NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: βingle (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: GGAAGGGAGG GTACCGCTGC CTTGACCACC ACCCTGCCTC 50 (2) INFORMATION FOR SEQ ID NO:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: CTGTACCTGG GCGAGGGGTC CGACG 25 (2) INFORMATION FOR SEQ ID NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: CCCCTCCCAG AGGTTCAGTG AGACACACCA CTCCAGGCCG 50 (2) INFORMATION FOR SEQ ID NO:22: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: CAGCAGCTCTGAGCCCCAGCCTACC 2 5 (2) INFORMATION FOR SEQ ID NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: GCCGACTATT CTATGCCGGC CGTTTTGGAA GCTGTCACCG 50 (2) INFORMATION FOR SEQ ID NO:24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe paire (B) TYPE: n'-cleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: CCGTCCGAGTGGCCAACCCACCATT 25 (2) INFORMATION FOR SEQ ID NO:25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 50 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: GTGTACAACT ACCCCGAGGG CTCATGTCTC CAGCAGACCC 50 (2) INFORMATION FOR SEQ ID NO:26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: CGCCAACGCG CAGGTCTACG GTCAG 25 (2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO.-27: CTTCCCCTCC ATCGTGGGGC GTTTCGTGGA TGCCACAGGA C 51 (2) INFORMATION FOR SEQ ID NO:28: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 25 baβe pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: DNA (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: CGACGAGGCCCAGAGCAAGAGAGGC 25

Claims: CLAIMS: 1. A method for the treatment or prophylaxis breast cancer in a mammal, said method comprising administering to said mammal an effective amount of one or more cytokines or functional derivatives or agonists of said one or more cytokines for a time and under conditions sufficient to ameliorate the effects of or to delay onset of said cancer. 2. A method according to claim 1 wherein the cytokines are selected from the list consisting of oncostatin M (OSM), interleukin-6 (IL-6), interleukin- 11 (IL-11), leukaemia inhibitory factor (LIF) and epidermal growtii factor (EGF) or other members of die EGF family. 3. A method according to claim 1 wherein the cytokine is OSM. 4. A method according to claim 1 wherein die cytokine is LIF. 5. A method according to claim 2 or 3 or 4 wherein d e cytokine is of human or murine origin. 6. A method according to claim 1 or 2 wherein the breast cancer is metastic breast cancer. 7. A method according to claim 1 or 2 wherein the breast cancer is early breast cancer. 8. A method according to any one of die preceding claims further comprising the simultaneous or sequential administration of at least one other therapeutic agent. 9. A method according to claim 8 wherein the other therapeutic agent is a chemotherapeutic agent or a hormone. 10. A method according to claim 9 wherem the chemotherapeutic agent is selected from cyclophosphamide, vincristine, methotrexate, cisplatin, melphalan and adriamycin. 11. A method according to claim 9 wherein the hormone is tamoxifen or other anti-estrogens. 12. A method according to claim 1 wherein the cytokine is administered in an amount from about 0.5 μg to about 2 mg per kilogram of body weight of mammal. 13. A method according to claim 1 wherein the mammal is a human. 14. A pharmaceutical composition effective in ameliorating the effects of breast cancer or delaying onset of breast cancer in a mammal comprising at least one cytokine or a functional derivative or agonist thereof and one or more pharmaceutically acceptable carriers and/or diluents. 15. A pharmaceutical composition according to claim 14 comprising a cytokine selected from IL-6, OSM, IL-11, LIF and EGF or other members of the EGF famdy. 16. A pharmaceutical composition according to claim 14 where the cytokine is OSM. 17. A pharmaceutical composition according to claim 14 wherein the cytokine is LIF. 18. A pharmaceutical composition according to claim 14 or 15 or 16 further comprising a chemotherapeutic agent or a hormone. 19. A pharmaceutical composition according to claim 18 wherein the chemoti erapeutic agent is selected from cyclophosphamide, vincristine, methotrexate, cisplatin, melphalan and adriamycin. 20. A pharmaceutical composition according to claim 18 wherein the hormone is tamoxifen or other anti-estrogens. 21. Use of a cytokine or a functional derivative or agonist tiiereof in the manufacture of a medicament for die treatment or prophylaxis of breast cancer in a mammal. 22. Use according to claim 21 wherein the cytokine is IL-6, OSM, EGF, IL-11 or LIF. 23. Use according to claim 22 where die cytokine is OSM. 24. Use according to claim 22 wherein the cytokine is LIF. 25. Use according to claim 22 wherein die mammal is a human. 26. An agent comprising a cytokine or a functional derivative or agonist thereof for the treatment or prophylaxis of breast cancer in a mammal 27. An agent according to claim 26 wherein the cytokine is IL-6, OSM, IL-11 , LIF or EGF or other members of the EGF famdy. 28. An agent according to claim 26 wherein the cytokine is OSM 29. An agent according to claim 26 wherein the cytokine is LIF.

Inventors: BEGLEY COLIN GLENN, DOUGLAS ANDREA MARGARET, BEGLEY, COLIN, GLENN, DOUGLAS, ANDREA, MARGARET
Applicants: AMRAD OPERATIONS PTY LTD, BEGLEY COLIN GLENN, DOUGLAS ANDREA MARGARET, AMRAD OPERATIONS PTY. LTD., BEGLEY, COLIN, GLENN, DOUGLAS, ANDREA, MARGARET
Application year: 1996
Main classification: A61K38
IPC codes: A61K38