Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1993-08-24
1997-02-04
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
A61K 3816
Patent
active
055997899
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/AU92/00683 filed Dec. 24, 1992.
The present invention relates generally to the use of leukaemia inhibitory factor and pharmaceutical compositions comprising same in the treatment of undifferentiated tumours and sarcomas in mammals. The present invention is particularly directed to the treatment of Ewing's Sarcoma, Rhabdosarcoma and other sarcomas of connective tissue, bones, bladder, kidneys, liver, lungs, parotids or spleen.
Leukaemia inhibitory factor (hereinafter referred to as "LIF") was purified (1,2) and cloned (3) on the basis of its capacity to induce differentiation in and suppress the M1 mouse myeloid leukaemic cell line (see International Patent Application No. PCT/AU88/00093) and has been shown to possess a variety of actions: it releases calcium from bone tissues (5), is the factor preventing spontaneous differentiation in normal embryonic stem cells (6,7), is a molecule stimulating DA1 cell proliferation (4), stimulates liver cells to produce acute phase proteins (8,9), and is a lipoprotein lipase inhibitor (10).
The present invention arose in part from an investigation of the effect of LIF on Ewing's Sarcoma, the second most common malignant bone tumour of children and young adults, accounting for approximately 7% of all malignant tumours of bone. The predominant localisation of these tumours is in the metaphyses of long bone and the pelvic region, although the extremities, ribs and spine or any other bone may be affected and they can also metastise to the lungs.
Macroscopically, the tumours are a jelly-like mass with foci of haemorrhage on their cut surface. Microscopically, they are made up of sheets of densely packed, undifferentiated, small round cells, divided into small groups or nests by fibrous-tissue septa.
With current treatment, patients with small localised tumours have an approximately 50% chance of survival, however, those with large or metastatic tumours have a poor prognosis (12). Recent studies have demonstrated that Ewing's Sarcoma cells have the capacity to undergo differentiation into neural cells, suggesting that the precursor cell for this tumour originates from the neural lineage (13). The cytogenetic study of these tumours has revealed that the majority are associated with a t(11:22) translocation (14). At present the molecular basis of this translocation remains unknown, and although a number of candidate oncogenes located close to the translocation have been extensively studied, none have been found to be involved in Ewing's Sarcoma (including C-sis, c-ets, proto-oncogenes). Furthermore, to date only a few Ewing's Sarcoma cell lines have been reported (15,16).
In work leading to the present invention, the effects of various growth factors on the proliferation of sarcoma cell lines were studied. In accordance with the present invention, it has been surprisingly discovered that LIF can cause a significant reduction in tumour size indicating its potential as an anti-tumour agent in the treatment of undifferentiated tumours and sarcomas.
Accordingly, one aspect of the present invention contemplates a method for the treatment of mammals carrying undifferentiated tumours and/or sarcomas which method comprises administering to said mammal an effective amount of LIF and/or active fragments or derivatives thereof for a time and under conditions sufficient to destroy or reduce the size of undifferentiated tumours and/or sarcomas.
Another aspect of the present invention further comprises the simultaneous or sequential administration of one or more other cytokines, derivatives thereof and/or one or more chemotherapeutic agents and/or the simultaneous or sequential treatment by radiotherapy. By "simultaneous or sequential" is meant that LIF is co-administered with another cytokine or chemotherapeutic agent or together with radiotherapy or where LIF administration is preceded or followed by non-LIF treatment. Where "sequential" therapy is occurring, the time difference between LIF administration and non-LIF treatment may be minutes, hours, days, w
REFERENCES:
patent: 5187077 (1993-02-01), Gearing et al.
Amrad Corporation Limited
Goldberg Jerome D.
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