Drug – bio-affecting and body treating compositions – Identification or warning feature – Taste or smell or chemical irritation to the eye – nose – or...
Patent
1987-07-02
1990-02-13
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Identification or warning feature
Taste or smell or chemical irritation to the eye, nose, or...
424164, 514 34, A61K 3304, A61K 3170
Patent
active
049005383
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a composition for increasing the anti-carcinogenic activity of adriamycin or daunomycin and reducing side effects caused by them.
Currently agents which react with intracellular DNAs are the main stream of agents for treating cancers. However, carcinostatic agents which attack said DNAs have side effects such as cardiotoxicity, hepatotoxicity, nephrotoxicity and hematogeneous obstacles. Moreover, the carcinostatic agents have mutagenicity and some of them (e.g. adriamycin and daunomycin) have been proved to be carcinogenic. From the above facts there is fear that secondary carcinogenesis occurs after treating cancers with such carcinostatic agents. Therefore, reduction of side effects including mutagenicity is a main theme in the development of carcinostatic agents and treatment of cancers.
Suwa, one of the inventors, investigated the inactivation of mutagenicity of beverages (both alcoholic and nonalcoholic, e.g. coffee) and tobacco and discovered factors for inactivating mutagenicity and disclosed said factors and safe beverages (both alcoholic and non-alcoholic) and tobacco, and foods in Japanese Patent application No. 144272/81. In this application it is disclosed that sulfite ion or hydrogensulfite ion inactivates mutagenicities of coffee, tobacco tar and spirits.
The inventors searched for a method of inactivation of mutagenicities of carcinostatic agents and succeeded in creating a composition comprising adriamycin or daunomycin as an active ingredient the mutagenicity of which is reduced. Further, according to the present invention, reduction of acute toxicity and remarkable increase in anti-carcinogenic activity, as well as reduction of mutagenicity, can be attained. In result, the range of effective dose of adriamycin or daunomycin was expanded in comparison with adriamycin or daunomycin alone and therefore more an effective treatment of cancer has become possible.
Disclosure or the Invention
The present invention relates to an agent and method for increasing anti-tumor activity of a carcinostatic agent selected from adriamycin and daunomycin and for reducing toxicity and includes administration of said carcinostatic agent in combination with a compound for increasing the potency of the carcinostatic agent and reducing its toxicity which is selected from the group consisting of sulfite, acid sulfite, pyrosulfite, dithionite and anhydrous sulfite and is referred to hereafter as "a sulfite compound". Adriamycin is alternatively named doxorubicin (U.S. Pat. No. 3,590,028), and daunomycin is also named daunorubicin (GB Patent No. 1,003,383). These antibiotics are anthracyclinic antibiotics.
Daunomycin was isolated from a culture of Streptomyces peuceticus (A. Grein, C. Spalla, A. Di Marco & G. Canevazzi: Giorn. Microbiol., Vol. 11, 109, 1963). Adriamycin was initially synthesized from daunomycin and subsequently isolated from a culture of a mutant of Streptomyces peuceticus, Streptomyces peuceticus var. caesius (F. Arcamone, G. Cassinelle, G. Fantini, A. Grein, P. Orezzi, C. Pol & C. Spalla: Biotechnol. Bioeng., Vol. 11, 1101, 1969). Both adriamycin and daunomycin react with 3 base pairs of DNA per one molecular (intercalation). Therefore, the effects of these antibiotics are considered to be mainly due to the inhibition of RNA and DNA polymerases which use DNA as a mould. Incidentally, there is a report that DNA cleavage induced by free radicals such as quinone radicals (. AH) which are produced by reductive oxidation of the quinone moieties, O.sub.2 .sup.- and OH, contributes to anti-tumor activities. These antibiotics can be adapted for acute or chronic leukemia, carcinoma, sarcoma, lymphoma malignum etc. However, said antibiotics have side effects such as vomiturition, vomition, pyrexia, epilation, depression of bone marrow etc. and one particular side effect, cardiotoxicity, is severe. Therefore it is earnestly desired to reduce the side effects of these antibiotics.
On the other hand, sulfite ion and hydrogensulfite ion are produced in
REFERENCES:
patent: 4327083 (1982-04-01), Alvarez
patent: 4548927 (1985-10-01), Eaton
Chemical Abstracts, vol. 83, No. 7, Aug. 8, 1975, p. 46, Abstract 53458a, Columbus, OH, U.S. by K. Handa et al.
Abstract and Chemical Abstracts, Ninth Collective Index, Chemical Substances, pp. 23962-23963, in relation to 83:53458a.
Chemical Abstracts, vol. 98, No. 5, Jan. 31, 1983, p. 548, Abstract 33245k, Columbus, OH, U.S., Y. Suwa et al.
Chemical Abstracts, vol. 93, No. 25, Dec. 22, 1980; p. 204, Abstract 232249m, Columbus, OH, U.S., A. DiMarco et al.
Chemical Abstracts, vol. 67, No. 13, Sep. 25, 1967; p. 5877, Abstract 62632g, Columbus, OH, U.S., A. DiMarco et al.
Kirk Othmer, Encyclopedia of Chemical Technology, vol. 19, 1969.
Kiyota Noriko
Senoh Shiro
Suwa Yoshihide
Yoshizumi Hajime
Goldberg Jerome D.
Suntory Limited
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