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`PCT/EP97 /03036
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`14
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`pharmaceutical composition comprising a rapamycin macrolide. The kit or package
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`may also contain instructions to use the pharmaceutical compositions in accordance
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`with the present invention.
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`According to the invention, the combination of a compound of the somatostatin class
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`and a rapamycin macrolide is indicated for the prevention or treatment of malignant
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`tumor growth, e.g. breast, lung, GEP tumors, pituitary adenomas, lymphomas, etc .. for the
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`prevention or treatment of proliferative vascular diseases, e.g. biologically or
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`mechanical1y induced vascular injury causing intimal thickening, e.g. restenosis,
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`atherosclerosis, vascular occlusion, injury following percutaneous transluminal coronary
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`angioplasty, vascular surgery or transplantation surgery, transplant vasculopathies, for
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`example chronic rejection of various tissues and organs such as heart, kidney, pancreas,
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`lung, liver, bowel, trachea and combined heart-lung.
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`The combination is particularly indicated for preventing intimal smooth muscle cell
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`hyperplasia, restenosis and vascular occlusion in a mammal.
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`Utility of the combination in the treatment of disorders and diseases as hereinbefore
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`specified, may be demonstrated for example in accordance with the method hereinafter
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`described.
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`A. In vitro Assay
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`AR42J cell cultures are propagated in DMEM supplemented with I 0 % fetal calf
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`serum (FCS) at 5 % C02. Ce11s are grown in the absence of antibiotics or antifungal
`agents. Subconfluent AR42J ce1ls growing in DMEM and supplemented with 10 % FCS
`are trypsinized, diluted in DMEM + 2.5 % PCS and seeded in uncoated 96-we11 plates
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`(5'000 to 10'000 cells per well in 180 µI). After a 48-hr incubation period (Day 0), the
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`number of cells in a separate control plate is determined both by counting cells in a
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`Coulter counter and by the sulforhoda~ine B (SRB) staining assay. The cells are then
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`exposed either to the somatostatin analogue alone, e.g. octreotide, or to rapamycin or a
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`derivative thereof alone or to a combination of the somatostatin analogue and rapamycin
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