Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2001-10-09
2004-06-15
Helms, Larry R. (Department: 1642)
Drug, bio-affecting and body treating compositions
Lymphokine
C424S198100, C424S277100, C435S002000, C435S007100, C436S500000
Reexamination Certificate
active
06749846
ABSTRACT:
The invention relates to the use of interferon-beta for the treatment of Ewing's family of tumors in mammals.
The family of Ewing's tumors represents the second most common type of bone tumors observed in children after osteosarcoma. The family includes Ewing's sarcoma (EWS or Ewing's tumor of bone), extraosseus Ewing's (EOE), primitive neuroectodermal tumors (PNET or peripheral neuroepithelioma) and Askin's tumors (PNET of the chest wall). These tumors are rare diseases in which malignant cells are found in the bone and soft tissues, and recent protocols use the same treatment for this family of tumors. EWS is mostly observed in adolescent and young adults, and the most common sites for the primary lesion are the pelvic bones, femur, humerous and ribs. Incidence of Ewing's sarcoma is estimated to be about 60% of the Ewing's family of tumors.
Studies using immunohistochemical markers, cytogenetics, molecular genetics, and tissue culture indicate that these tumors are all derived from the same primordial stem cell. Cytogenetic studies of the Ewing's family of tumors have identified a consistent alteration of the EWS locus on chromosome 22 band q12 that may involve other chromosomes, including 11 or 21. Characteristically, the amino terminus of the EWS gene is juxtaposed with the carboxy terminus of another chromosome. In the majority of cases (90%), this chromosomal translocation directs the fusion of the 5′ end of the EWS gene, encoding a protein capable of participation in RNA metabolism, with the 3′ end of the Fli-1 gene, a member of the Ets transcription factor family located on chromosome 11 band q24 (Delattre et al.,
Nature
359:162-165 (1992)). Several fusion genes can be generated according to the cleavage sites (between exons 7 and 11 of EWS and exons 3 to 9 from Fli-1).
The more frequent fusion, EWS-Fli-1 type I, fuses EWS exon 7 with Fli-1 exon 6 and represents 50% of cases. The type II fusion (25% of cases) ligates EWS exon 7 with Fli-1 exon 5. In addition to these two principal fusion types, about ten other combinations have been described.
In certain Ewing's tumor cases, EWS is not fused to Fli-1 but to another member of the Ets family, e.g. FEV. Other Ets family members which may combine with the EWS gene are ERG (located on chromosome 21), ETV (located on chromosome 7), and E
t
AF (located on chromosome 17), which result in the following translocations: t(21;22), t(7;22), and t(17;22) respectively.
These genetic alterations reach a constant biochemical consequence: Ewing cells always express a chimeric protein bearing the N-terminal region of EWS fused to a DNA binding domain of the Ets protein family. This constancy suggests that this fusion exerts a central role in Ewing's tumor development.
In Ewing's sarcoma, the role of the EWS/Fli-1 fusion protein has been experimentally demonstrated. This protein can transform mice fibroblasts, and these cells are able to generate tumors in nude mice.
From in vitro experiments, it was shown that the EWS/Fli-1 protein was able to activate certain gene transcription more efficiently than Fli-1. This fact suggests that the EWS/Fli-1 protein fusion exerts its oncogenic actions through the abnormal activation of certain cellular genes.
It was also shown that the PU-1 protein, also from the Ets family, is implicated in the control of interferon and cytokine regulated gene expression (Perez et al.,
Mol. Cell Biol
. 14:5023-5031 (1994)).
Important prognostic factors for the Ewing's family of tumors include the site and volume of the primary tumor and whether the disease is metastatic. Size of the tumor is also thought to be an important variable. With current treatment, studies suggest that 50%-70% of patients without metastatic disease have a long-term disease-free survival, compared to only 20%-30% for patients who present with metastatic disease. As such, there remains an acute need in the art for an effective method of treating the Ewing's family of tumors.
Accordingly, the present invention provides an effective method of treating the Ewing's family of tumors in a mammal. Other features and advantages of the present invention will be set forth in the detailed description of preferred embodiments that follows, and in part will be apparent from the description or may be learned by practice of the invention. These advantages of the invention will be realized and attained by the compositions and methods particularly pointed out in the written description and claims hereof.
Rosolen et al. (
Modern Pathology
, 1997, 10:55-61) reported that the treatment of a cell line derived from Ewing's sarcoma with interferon-alpha, induces an inhibition of cell growth in vitro.
The authors of the present invention have now shown that interferon-beta (IFN-&bgr;) which binds the same receptor as interferon-alpha (IFN-&agr;) but which is known to exert distinct activities (Runkel et al., 1998, the Journal of Biological Chemistry, 14:8003-8008), exhibits an antiproliferative action on Ewing's sarcoma.
They have more particularly shown that the antiproliferative action of IFN-&bgr; on cells derives from Ewing's sarcoma in vitro was distinctly superior than the one of IFN-&agr;.
Therefore, one embodiment of the present invention is directed to a method of treating Ewing's family of tumors in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of IFN-&bgr;. A second embodiment of the present invention is directed to a composition suitable for administration to a mammal for the treatment of Ewing's family of tumors comprising IFN-&bgr; in a therapeutically effective amount, together with a pharmaceutically acceptable carrier.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the invention as claimed.
Unless defined otherwise, all technical and scientific terms used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the relevant art.
As used herein, the term “Ewing's family of tumors” means a type of tumor found in bone and soft tissues characterized by small round cells and associated with an alteration of the EWS locus on chromosome 22. The family of tumors includes Ewing's sarcoma (Ewing's tumor of bone or ETB), extraosseus Ewing's (EOE), peripheral primitive neuroectodermal tumors (PNET or peripheral neuroepithelioma) and Askin's tumors (PNET of the chest wall).
The individual cells of Ewing's sarcoma and EOE contain round to oval nuclei with fine dispersed chromatin without nucleoli. Occasionally, cells with smaller, more hyperchromatic (and probably degenerative) nuclei are present giving a “light cell-dark cell” pattern. The cytoplasm varies in amount, but in the classic case it is clear and contains glycogen, which can be highlighted with a periodic acid-Schiff (PAS) stain. The tumor cells are tightly packed and grow in a diffuse pattern without evidence of structural is organization.
The histologic appearance of the PNET differs somewhat from Ewing's sarcoma and EOE. These tumors are typically composed of round to ovoid hyperchromatic cells with minimal cytoplasm. The tumor cells are typically arranged in nests and trabeculae with variable rosette formation. The rosettes may have a central lumen, but are often ill-defined, composed of tumor cells arranged around an empty space. The classic lobular growth pattern is best appreciated at low-power, and differs from the typical diffuse growth seen in EOE. Occasionally, groups of cytologically uniform, round cells with dispersed chromatin resembling those in EOE are seen interspersed in an otherwise typical PNET. This overlap of features lends confidence to the concept that these tumors are indeed the same tumor with a spectrum of differentiation.
As used herein, the term “mammal” indicates any mammalian specie
Sanceau Josiane
Wietzerbin Jeanne
Helms Larry R.
Institut National de la Sante et de la Recherche Medicale (INSER
Schulman B. Aaron
Stites & Harbison PLLC
Yaen Christopher
LandOfFree
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