Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Patent
1997-06-27
2000-07-11
Bansal, Geetha P.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
4241381, 4241411, 4241431, 4241441, 4241451, 4241521, 4241551, 4241581, 4241721, 4241741, 5303871, 5303873, 53038822, A61K 39395, C07K 1624, C12P 2108, C09K 1628
Patent
active
060868740
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an antitumor agent effect enhancer comprising interleukin-6 antagonist that assists and enhances the effects of antitumor agents in the treatment of tumors.
BACKGROUND ART
Various drugs such as alkylating agents, metabolism antagonists, antitumor antibiotics and platinum compounds have been used in the past for chemotherapy on human tumors. In the case where remarkable therapeutic effects are not observed when these antitumor agents are used alone, therapeutic methods have been devised in which a plurality of antitumor agents are used concomitantly (Frei, E. III, Cancer Res., 32, 2593-2607, 1992). Tumor cells exhibit various sensitivities to antitumor agents, and certain cells are known to exhibit resistance to therapy by antitumor agents (Magrath, I., New Directions in Cancer Treatment, 1989, Springer-Verlag). Acquisition of resistance to therapy by tumor cells is said to be caused by, for example, the occurrence of multi-drug resistance (MDR) (Tsuruo, T. et al., Cancer Res., 42, 4730-4733, 1982), reduction in cell uptake of antitumor agent (Sherman, S. E. et al., Science, 230, 412, 1985), increased DNA repair activity (Borch, R. F., Metabolism and Action of Anticancer Drugs, Powis, G. & Prough, R. ed., Taylor & Francis, London, 1987, 163-193), or promotion of inactivation of antitumor agent in the cells (Teicher, B. A. et al., Cancer Res., 46, 4379, 1986). In such cases, there are many cases in which the expected therapeutic effects are not observed simply by administering antitumor agent.
Renal cell carcinoma exhibits resistance to therapy to antitumor agents such as cisplatin, adriamycin and vinblastine (Kakehi, Y. et al., J. Urol., 139, 862-864, 1988; Kanamaru, H. et al., J. Natl. Cancer Inst., 81, 844-847, 1989; Teicher, B. A. et al., Cancer Res., 47, 388-393, 1987). Platinum compounds such as cisplatin that possess antitumor effects bond with DNA and inhibit DNA synthesis and cell division (Pinto, A. L. et al., Biochica et Biophysica Acta, 780, 167-180, 1985).
The expression of glutathione-S transferase-.pi. (GST-.pi.), inhibition of the effects of cisplatin caused by an increase in intracellular levels of substances containing sulfidryl groups, increased DNA repair activities, or activation of oncogenes such as c-myc is considered to be involved in the resistance to therapy of renal cell carcinoma to cisplatin (Sklar, M. D. et al., Cancer Res., 51, 2118-2123, 1991; Mizutani, Y. et al., Cancer in press, 1994; Nakagawa, K. et al., Japan J. Cancer Res., 79, 301-305, 1988).
In addition, changes in membrane permeability and transport capabilities in tumor cells are said to cause a decrease in cisplatin uptake within the cells, thus increasing resistance to therapy to cisplatin (Richon, V. et al., Cancer Res., 47, 2056-2061, 1987; Waud, W. R. et al., Cancer Res., 47, 6549-6555, 1987). Glutathione, an example of a substance containing sulfidryl groups that is present in the largest amounts in mammalian animal cells, is reported to inactivate cisplatin in cells, and certain types of tumors have been shown to have higher intracellular glutathione and metallothionein levels (Hromas, R. A. et al., Cancer LETT., 34, 9-13, 1987; Taylor, D. M. et al., Eur. J. Cancer, 12, 249-254, 1976).
Glutathione is a tripeptide thiol. It plays an important role in the inactivation of DNA-bonding substances such as alkylating agents and cisplatin and in the repair of cell damage caused by these. One of the effects of GST-.pi. is that it promotes inactivation of antitumor agents by causing antitumor agents like those described above to bond to glutathione.
Since renal cell carcinoma produces interleukin-6 (IL-6) and expresses IL-6 receptor (IL-6R), it has been suggested that IL-6 plays some type of role in the growth activity of renal cell carcinoma (Miki, S. et al. FEBS Lett., 250, 607-610, 1989; Takenawa, J. et al., J. Natl. Cancer. Inst., 83, 1668-1672, 1991). Moreover, it has been reported that the level of IL-6 in the serum increases when the prognosis for treatment of r
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Mizutani et al., "Sensitization Of Human Renal Cell Carcinoma Cells To cis-Diamminedichloroplatinum (II) By Anti-Interleukin 6 Monoclonal Antibody Or Anti-Interleukin 6 Receptor Monoclonal Antibody", Cancer Research, Feb. 1, 1995, vol. 55, pp. 590-596.
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Mizutani Youichi
Yoshida Osamu
Bansal Geetha P.
Chugai Seiyaku Kabushiki Kaisha
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