Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-07-17
2001-07-17
Hauda, Karen M. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C424S093210, C424S093200
Reexamination Certificate
active
06262032
ABSTRACT:
The present invention relates to the field of the therapy of hyperproliferative pathologies. It relates more especially to a new method of treatment of hyperproliferative pathologies based on the combined use of two types of therapeutic agents.
More specifically, the present invention relates to a new method of treatment of hyperproliferative pathologies based on the combined use of genes that block oncogenic cell signalling pathways and chemotherapeutic and or radiotherapeutic agents. The combined treatments according to the present invention have especially effective effects for the destruction of hyperproliferating cells, at relatively low doses. The present invention thus provides an especially effective new method of treatment of hyperproliferative pathologies (cancer, restenosis and the like) with limited side-effects.
In spite of the very substantial progress made in this field, the methods currently available for the treatment of cancer still have limited efficacy. Radiotherapy and chemotherapy admittedly have a very favourable impact on the development of cancers. However, an acute problem in the treatment of cancer is the insensitivity of certain primary tumours and/or the appearance of tumour cells which are resistant, after a first cycle of effective treatments, both to radio- and to chemotherapy.
Numerous studies have attempted to elucidate the molecular mechanisms which may be the source of these events. Generally speaking, the investigations have been directed towards the manner in which chemotherapeutic agents entered the cells and the manner in which they reacted with their cell targets (Chin et al., Adv. Cancer Res. 60 (1993) 157-180; Chabner and Meyers in Cancer/Principles and practices of Oncology, De Vita et al. Eds., J. B. Lippencott Co. pp. 349-395, 1989). For example, high levels of expression of the mdr1 gene can limit the intracellular concentration of various chemotherapeutic agents and might contribute to the expression of the multiple drug resistance (Chin et al., see above).
A more complete elucidation of the mechanisms of resistance to chemotherapy and to radiotherapy involves a better knowledge of the processes of cell death induced by these agents. Since ionizing radiation and many anticancer agents induce damage in the DNA, the effect of these therapeutic agents has been attributed to their genotoxic power. However, the cell damage caused by these agents does not enable their therapeutic activity to be explained completely (Chabner and Meyers, see above). In the last few years, the exploration and understanding of the mechanisms of programmed death or apoptosis have enabled the mechanisms by which tumour cells acquire or lose their sensitivity to cytotoxic agents to be reconsidered. Numerous toxic stimuli induce apoptosis, even at doses which are insufficient to induce metabolic dysfunctions. The capacity to induce an apoptotic response in tumour cells might determine the efficacy of the treatment.
The applicant has now developed a new method of treatment which is especially effective for the destruction of hyperproliferative cells. As mentioned above, the method of treatment according to the invention is based essentially on the combined use of two types of therapeutic agents: genes that block oncogenic cell signalling pathways and chemotherapeutic and/or radiotherapeutic agents. The present invention is, in effect, the outcome of the demonstration of an especially large synergistic effect associated with the combined use of these two types of agents.
A first subject of the present invention hence relates to a medicinal combination of one or more nucleic acids that at least partially inhibit oncogenic cell signalling pathways and an anticancer therapeutic agent, for use simultaneously, separately or spread over time for the treatment of hyperproliferative pathologies.
As mentioned above, the invention is based essentially on the demonstration of a synergistic effect between the product of certain genes and anticancer therapeutic agents. This combined use produces more powerful effects at lower doses of agents. This invention thus affords an especially advantageous means for the treatment of hyperproliferative pathologies.
As mentioned later, depending on the gene and the chemo- or radiotherapeutic agent which are chosen, the two components of the combined treatment of the present invention may be used simultaneously, separately or spread over time. In the case of a simultaneous use, both agents are incubated with the cells or administered to the patient simultaneously. According to this embodiment of the present invention, the two agents may be packaged separately and then mixed at the time of use before being administered together. More commonly, they are administered simultaneously but separately. In particular, the administation see of the two agents can be different. In another embodiment, the two agents are administered spaced over time.
The nucleic acid used in the context of the present invention can be a deoxyribonucleic acid (DNA) or a ribonucleic acid (RNA). Among DNAs, possible alternatives include a complementary DNA (cDNA), a genomic DNA (gDNA), a hybrid sequence or a synthetic or semi-synthetic sequence. A further possibility is a nucleic acid modified chemically, for example, for the purpose of increasing its resistance to nucleases, its cell penetration or cell targeting, its therapeutic efficacy, and the like. These nucleic acids can be of human, animal, plant, bacterial, viral, synthetic and the like, origin. They may be obtained by any technique known to a person skilled in the art, and in particular by screening of libraries, by chemical synthesis or alternatively by mixed methods including the chemical or enzymatic modification of sequences obtained by screening of libraries. As mentioned later, they can, moreover, be incorporated in vectors such as plasmid, viral or chemical vectors.
As mentioned above, the nucleic acid according to the present invention is a nucleic acid capable of at least partially inhibiting oncogenic cell signalling pathways. These nucleic acids are designated hereinafter by the term “oncogene intracellular neutralization elements” or OINE. The signalling pathways leading to cell transformation are manifold. Cell proliferation involves a multitude of factors, such as membrane receptors (G proteins), oncogenes, enzymes (protein kinases, farnesyl transferases, phospholipases, and the like), nucleosides (ATP, AMP, GDP, GTP, and the like), activating factors [guanosine exchange factors (GRF, GAP, RAF, and the like), transcription factors, and the like], Disturbances, for example in the structure, activity, conformation, and the like, of these different factors have been associated with phenomena of deregulation of cell proliferation. Thus, 90% of adenocarcinomas of the pancreas possess a Ki-ras oncogene mutated on the twelfth codon (Almoguera et al., Cell 53 (1988) 549). Similarly, the presence of a mutated ras gene has been demonstrated in adenocarcinomas of the colon and thyroid cancers (50%), or in carcinomas of the lung and myeloid leukaemias (30%, Bos, J. L. Cancer Res. 49 (1989) 4682). Many other oncogenes have now been identified (myc, fos, jun, ras, myb, erb, and the like), mutated forms of which appear to be responsible for a disturbance of cell proliferation. Similarly, mutated forms of p53 are observed in many cancers, such as, in particular, colorectal cancer, breast cancer, lung cancer, stomach cancer, cancer of the oesophagus, B-cell lymphomas, ovarian cancer, bladder cancer, and the like. The nucleic acids used in the context of the invention are nucleic acids capable of interfering with one of these factors involved in cell proliferation, and of at least partially inhibiting its activity. The factors towards which the nucleic acids of the invention are preferentially directed are those which appear preferentially or specifically during disturbances of cell proliferation (activated oncogenes, mutant of tumour suppressor, and the like).
Nucleic acids used in the context of the i
Aventis Pharma S.A.
Beckerleg Anne Marie S
Brobeck Phleger & Harrison LLP
Hauda Karen M.
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