Methods for anti-tumor therapy

Details Methods for anti-tumor therapy Methods for anti-tumor therapy

2000-02-10

2002-04-30

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

Reexamination Certificate

active

06380167

ABSTRACT:

BACKGROUND OF THE INVENTION
Approximately twenty percent of deaths from all causes in the United States are cancer-related. Although chemotherapy is a principal means of cancer treatment, the rate at which effective new drugs have become available for use in cancer chemotherapy has not increased (Horowitz et al., Journal of Clinical Oncology, Vol. 6, No. 2, pp. 308-314 (1988)). Despite many years of promising new therapies, cancer remains a major cause of morbidity and mortality. (Bailar et al., N. Engl. J. Med. 336:1569-1574, 1997) Accordingly, there is a substantial need for new drugs which are effective in inhibiting the growth of tumors.
Cardiac glycosides are potent and highly selective inhibitors of the active transport of Na
+
and K
+
across cell membranes and act by binding to the alpha subunit of the Na
+
K
+
-ATPase. The affinity of the alpha subunit for cardiac glycosides varies among species and among the three known mammalian alpha subunit isoforms, each of which is encoded by a separate gene. (Goodman and Gilman, “The Pharmacological Basis of Therapeutics, 9
th
edition, Hardman and Limbird eds, p. 810 (1996)). These compounds share a steroid nucleus containing an unsaturated lactone ring at the C17 position and one or more glycosidic residues at C3, and occur naturally in many plants and several toad species, usually acting as venoms or toxins that serve as protection against predators. (Id).
Cardiac glycosides have been used extensively as therapeutics in the treatment of heart failure. (Goodman and Gilman, “The Pharmacological Basis of Therapeutics, 9
th
edition, Hardman and Limbird eds, p. 810 (1996)). Digitoxin has been the most widely used cardiac glycoside, with a therapeutic plasma concentration of greater than 10 ng/ml (approximately 13 nM). However, digitoxin is toxic at concentrations of above 35 ng/ml (approximately 46 nM) (Id. at 1736). Thus, the therapeutic window for digitoxin in the treatment of heart failure is quite narrow.
Cardiac glycosides have also been shown to inhibit cell proliferation in a wide variety of cell lines in vitro. (See for example Kaneda et al., Planta Med. 58:429-431 (1992), Gil et al., J. Natural Products 58:848-856 (1995), Kitinaka et al., Chem. Pharm. Bull. 44(3):615-617 (1996), Baek et al., Planta Med. 60(1):26-29 (1994), Zhang et al., Chinese Medical Journal 109(6):478-481 (1996), Shiratori, GANN 58:521-528 (1967), Doskotch et al., J. Pharmaceutical Sciences 61(4):570-573 (1972), Kupchan et al., J. Med. Chem 17:803 (1964), Kupchan et al., Science 146:1685 (1964), Hyun et al., Planta Med. 61:294-295 (1995), Al-Said et al., Phytochemistry 27(10):3245-3250 (1988)). This in vitro activity was routinely shown to be non-selective, as the proliferation of almost all tumor cell lines were inhibited, and occurred at similar (generally toxic) doses across the different cell lines. Studies have also suggested that cardiac glycosides can be used to inhibit the export of leaderless proteins from cells (U.S. Pat. No. 5,891,855), as well as inhibiting inflammatory cytokine secretion (U.S. Pat. No. 5,545,623), but only at toxic doses.
Based on these in vitro findings, numerous cardiac glycosides have been screened for their ability to inhibit in vivo tumor growth. (See, for example, LeWinn, The Lancet Jun. 2, 1979, p. 1196-1197; Stenkvist et al., The Lancet Mar. 10, 1979 p. 563; Stenkvist et al., The Lancet Feb. 25, 1982, p. 484.) However, the results of these in vivo studies have uniformly proven disappointing, as any therapeutic activity was found only at toxic doses. (Repke et al., Anti-Cancer Drug Design 10:177-187 (1995)). Based on all of these studies, the use of cardiac glycosides as effective anti-neoplastic agents would be entirely unexpected.
SUMMARY OF THE INVENTION
The present invention is based on the entirely unexpected finding that digitoxin can act as an effective anti-neoplastic agent. In one aspect, the present invention provides novel methods for treating tumors that involve administering an effective amount of digitoxin, or a pharmaceutical salt thereof, to a patient in need of such treatment, wherein the tumor is selected from the group consisting of mesotheliomas, sarcomas, carcinomas, stromal cell, and germ cell tumors.
In further aspects, the present invention provides pharmaceutical compositions comprising an effective amount for treating tumors of digitoxin, or a pharmaceutical salt thereof, in a suitable carrier, and an article of manufacture comprising packaging material and the above pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
All references cited herein are incorporated by reference in their entirety.
As used herein, the term “effective amount” means a dosage sufficient to produce adesired result. The desired result can be subjective or objective improvement in the recipient of the dosage, a decrease in tumor size, time to progression of disease, and/or survival.
As used herein the term “mesothelioma” is used to refer to a neoplasm derived from the cells lining the pleura, pericardium, or peritoneum, including but not limited to lung mesotheliomas.
As used herein the term “sarcoma” refers to tumors of mesenchymal origin, including but not limited to leiomyosarcomas, malignant fibrous histiocytoma, Ewing sarcoma, fibrosarcomas, chondrosarcomas, osteosarcomas, liposarcomas, rhabdomyo-sarcomas, hemangiocytomas, and myxosarcomas.
As used herein the term “carcinoma” is used to refer to a neoplasm derived from epithelial cells.
As used herein the term “ovarian carcinoma” refers to neoplasms derived from ovarian cells of epithelial origin, including but not limited to ovarian papillary serous cystadenoma, ovarian endometroid carcinoma, mucinous, clear cell and Brenner epithelial tumors;
As used herein the term “lung carcinoma” refers to neoplasms derived from lung cells including but not limited to squamous cell carcinomas, adenocarcinomas, oat cell carcinomas, carcinoid tumors, giant cell tumors, mucoepidermoid tumors, and adenoidcystic carcinomas.
As used herein the term “kidney carcinoma” refers to neoplasms derived from kidney cells including but not limited to renal cell carcinomas, Wilm's tumor, and hamartoma.
As used herein the term “germ cell tumors” refers to neoplasms including, but not limited to, dysgerminomas, and yolk sac tumors.
As used herein the term “stromal cell tumors” refers to neoplasms including, but not limited to granulosa cell, thecoma, and Sertoli-Leydig tumors.
In one aspect, the present invention provides new methods treating tumors that involve administering an effective amount of digitoxin, or a pharmaceutical salt thereof, to a patient in need of such treatment, wherein the tumor is selected from the group consisting of mesotheliomas, sarcomas, carcinomas, stromal cell, and germ cell tumors.
Digitoxin can be prepared by any of the methods known in the literature. Non-limiting examples of these methods include those disclosed in U.S. Pat. Nos. 3,514,441; 3,531,462; 3,843,628; 3,857,832; 3,939,156; 3,949,074; and 4,001,402, all references incorporated by reference herein in their entirety. Alternatively, digitoxin is commercially available (for example, Sigma Chemical Co., St. Louis, Mo.).
As disclosed herein, digitoxin and pharmaceutical compositions including digitoxin are useful in treating mesotheliomas, sarcomas, carcinomas, stromal cell and germ cell tumors. Examples of specific tumor types that the compounds may be used to treat include, but are not limited to solid tumors including ovarian papillary serous cystadenoma and ovarian endometroid carcinoma, lung mesothelioma, malignant fibrous histiocytoma, leiomyosarcoma, Ewing sarcoma, hemangiocytomas. Other ovarian tumors, such as mucinous, clear cell and Brenner epithelial tumors; germ cell tumors including dysgerminomas and yolk sac tumors; and stromal cell tumors including granulosa cell, thecoma, and Sertoli-Leydig tumors, are also treatable. Other sarcomas treatable with the compounds of the invention include fibrosarcomas, chondrosarcomas, osteosarcomas, liposarcomas, rh

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