Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-08-11
1995-05-16
Richter, Johann
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 4506, A61K 3702
Patent
active
054160910
DESCRIPTION:
BRIEF SUMMARY
The instant case is a 371 of PCT/GB91/02248, file Dec. 17, 1991.
1. Field of the Invention
The present invention relates to the use of .alpha.-aryl-4-substituted piperidinoalkanol derivatives such as terfenadine, 11-(4-piperidylidene)-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridines such as Loratadine, and N-heterocyclyl-4-piperidinamines wherein said heterocyclic radical is an optionally substituted 1H-benzimidazol-2-yl or 3H-imidazo[4,5-b]pyridin-2-yl radical compound, such as astemizole, as adjuvant chemotherapy for neoplasias resistant to multiple drugs. The present invention also relates to the use of such compounds as agents for enhancing the therapeutic effect of multiple antitumor agents.
2. Background of the Invention
Complete cures of various tumors like leukemias, lymphomas and solid tumors by the use of chemotherapeutic agents are rare because of heterogeneous sensitivity of tumor cells to each antitumor agent. Cancer chemotherapy also fails because of intrinsic resistance of tumors to multiple drug therapies. In other cases, a tumor may become resistant to the antitumor agents used in a previous treatment. The therapeutic effects of these agents are then eliminated. An even graver problem is that recurrent cancers are resistant not only to the cancer suppressants used in previous treatments, but also manifest resistance to other antitumor agents, unrelated to the agent used previously either by chemical structure or by mechanism of action. These phenomenon are collectively referred to multiple drug resistance (mdr) and contribute widely to cancer treatment failures in the clinic.
The major documented cause of multiple drug resistance is overexpression of a membrane glycoprotein (the multiple drug transporter) responsible for pumping structurally diverse antitumor drugs from cells. See D. Houseman et al., A Molecular Genetic Approach to the Problem of Dr. Resistance in Chemotherapy, 504-517 (1987) (Academic Press, Inc.); R. Fine and B. Chabner, Multidrug Resistance, in cancer Chemotherapy , 117-128 (H. Pinedo and B. Chabner eds. 1986).
Tumor cells expressing elevated levels of the multiple drug transporter accumulate far less antitumor agents intracellularly than tumor cells having low levels of this enzyme. The degree of resistance of certain tumor cells has been documented to correlate with both elevated expression of the drug transporter and reduced accumulation of antitumor drugs. See M. Gottesman and I. Pastan, J. Biol. Chem. 263, 12163 (1988); see also A. Fojo et al., Cancer Res. 45, 3002 (1985). This form of multiple drug cross-resistance involves agents derived from natural products, such as the vinca alkaloids, the anthracyclines, the epipodophyllotoxins, actinomycin D and plicamycin. See I. Pastan and M. Gottesman, New England J. Med. 1388, 1389 Table 1 (May 28, 1987).
Adenocarcinomas derived from adrenal, kidney, liver, small intestine, and colon tissue are notorious for exhibiting inherent cross-resistance to chemically unrelated chemotherapeutic agents. See M. Gottesman and I. Pastan, supra at 12165; see also A. Fojo et al., J. Clin. Oncol. 5, 1922 (1987). These tissues normally express higher levels of the multidrug transporter. Other tumors documented to express high levels of the multidrug transporter include pancreatic, carcinoid, chronic myelogenous leukemia in blast crisis, and non-small cell lung carcinoma. Tumors documented to initially be drug-sensitive but to then become drug resistant include neuroblastoma, pheochromocytoma, multiple myeloma, acute lymphocytic leukemia in adults, acute nonlymphocytic leukemia in adults, nodular poorly differentiated lymphoma, breast cancer and ovarian cancers. It is estimated by the National Cancer Institute that approximately half a million tumor samples a year will be drug resistant because of aberrant levels of expression of the multidrug transporter. See L. Goldstein et al., Expression of Multidrug Resistance Gene in Human Cancers, J. National Cancer Institute 81, 116 (1988).
Elevated levels of expression of the mdr drug transporter in th
REFERENCES:
patent: 4282233 (1981-08-01), Vallani
L. C. Iorio, et al., Interaction studies in mice of SCH 29851, a potential non-sedating antihistamine, with commonly used therapeutic agents Agents and Actions 18, 5,6 (1986).
Burroughs Wellcome Co.
Peabody John
Richter Johann
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