Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-08-06
2001-04-10
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S255060
Reexamination Certificate
active
06214824
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of Invention
This invention pertains to the art of methods for suppressing the invasion and spread of cancer cells and more particularly to the use of amiloride, alone or in combination with other agents, to inhibit the proliferation and invasive capability of epithelial based cancers which are dependent on the plasmin enzymatic cascade.
2. Background of the Invention
Cancer cells proliferate through a series of events such as separation of cells from the primary tumor mass, migration of the separated cells through solid tissue, penetration of the vascular system with embolization at a distant site (intravasation), escape of embolic cells from the confines of the capillary bed involved (extravasation), and parasitization of blood supply at the target site.
The mechanisms which allow these events to occur are perversions of normal physiologic processes and are dependent on a cascade of enzymatic activity which is initiated by the intracellular chemistry of the cancer cell. The trigger for this cascade is the activation of plasminogen to plasmin. This activation is a physiologic function which normally allows for the dissolution of blood clots within the vascular system, allows for the migration of blood cells through solid tissue to fight infection or to reject foreign material, and allows for the penetration of the ovum by the sperm cell.
In the cancer cell, large amounts of plasminogen activator, uPA, are produced. This activator binds to its own cell surface receptor sites. The surface-bound activator captures plasminogen from the circulatory system and converts it to the active form of plasmin. In turn, plasmin lyses the basement matrix, allowing the liberated cell to migrate through solid tissue. Plasmin also activates other tissue enzymes which dissolve connective tissue and the binding molecules of the cell wall of capillaries.
The end result of this complex activity is the local invasion of specific cancer cells as well as the capacity of those cells to invade the circulatory system and spread to distant sites. The types of cancer cells so affected are those derived from epithelial cells. These cancer types include the most commonly found in man, such as breast, colon, stomach and lung.
One trigger mechanism for the enzymatic cascade is the activation of plasminogen to plasmin by the specific activating enzyme Urokinase Plasminogen Activator or uPA. The capacity of the cancer cell to invade and spread may be depressed by inhibition of this trigger mechanism.
One substance which has been found to inhibit the activator, uPA, is a acylguanidine, known under the proprietary name, Amiloride. This drug is a potassium sparing diuretic which has been marketed for years for the purpose of controlling hypertension. It is used most often in conjunction with more powerful diuretics. Amiloride prevents the loss of potassium which occurs with those diuretic agents.
In 1988, an article by J. A. Kellen et. al. (Antimetastatic Effect of Amiloride in an Animal Tumor Model, Anticancer Res, 8, 1373-1376) presents a study using Fisher rats inoculated with breast cancer cells. The in vivo study showed that continuous administration of Amiloride via drinking water prevented the formation of lung cancer in the study animals.
The present invention confirms the suppression of experimentally induced metastases through the use of amiloride. In addition, a time and dose-dependency relationship of amiloride administration is demonstrated in the present invention.
Because known inhibitors in the art will suppress, but not eliminate the invasive capability of the cancer cells, one may surmise that more than the above-mentioned trigger mechanism in the enzymatic cascade should be targeted. A combination of inhibitors which attack separate parts of the chain reaction forms a part of the present invention.
In addition to the use of amiloride alone, the present invention is directed to the combination of the action of amiloride, which is a uPA inhibitor, with a metalloprotease inhibitor such as Batimistat which is a proprietary name of British Biotech, and/or hydrochlorothiazide, which promotes the excretion of potassium which could be retained by the other inhibitors.
SUMMARY OF THE INVENTION
Amiloride has been found to exhibit other remarkable pharmacological effects as well as inhibiting uPA. Amiloride inhibits the ability of the cancer cell to attract new blood supply. It blocks the Na+/H+ transporter, the required mechanism for cell multiplication, and inhibits still another enzyme, ornithine decarboxylase which controls DNA synthesis. Therefore, it has been found that amiloride inhibits the spread of cancer cells in at least four separate and distinct ways.
In accordance with the present invention, there is provided a method for treating cancer comprising the step of administering to a host an effective amount of amiloride.
In accordance with one aspect of the invention, the amiloride is administered to a host that has a cancer from epithelial cells including breast cancer, colon cancer, stomach cancer, and lung cancer.
According to another aspect of the invention, there is provided a method for treating diseases in which cell proliferation is a primary or secondary cause comprising the step of administering to a host in need of treatment an effective amount of amiloride.
According to another aspect of the invention, there is provided a method for suppressing an invasive capacity of cancer cells comprising the step of administering to a host an effective amount of amiloride.
According to another aspect of the invention, there is provided a method for treating a host having cancer cells derived from epithelial cells due to an enzymatic cascade triggered by the activation of plasminogen to plasmin by the specific activation of Urokinase Plasminogen Activator (uPA) comprising the step of administering to the host an amount of amiloride sufficient to adversely affect the action of the uPA and thereby suppress evasion and spread of cancer cells in the host.
According to another aspect of the invention, the method further comprises the step of administering a secondary agent to the host in combination with the amiloride.
According to another aspect of the invention, the secondary agent is effective to suppress a different step in the enzymatic cascade than the action of the uPA.
According to another aspect of the invention, the secondary agent is batimistat.
According to another aspect of the invention, the secondary agent promotes the excretion of potassium.
One advantage of the invention is that amiloride is a drug which has already been shown to be tolerated by humans in the treatment of other conditions.
Another advantage of the invention is that amiloride is readily available.
Another advantage of the invention is that amiloride does not depend on a toxic effect on human cells in order to be effective.
Another advantage of the invention is that use of secondary agents increases the benefit to the host as compared to the use of amiloride alone.
Another advantage of the invention is the suppression of the migratory capability of cancer cells.
Still other benefits and advantages of the invention will become apparent to those skilled in the art to which it pertains upon a reading and understanding of the following detailed specification.
REFERENCES:
Pashinskii, Byull. Eksp. Biol. Med., 74(11), 82-4 Abstract Only, 1972.*
Pashinskii, Farmakol. Toksikol., 36(5), 602-5 Abstract Only, 1973.*
Tatsuta et al., Carcinogenesis, 16(4), 941-2 Abstract Only, 1995.
Evans Douglas McCullough
Sloan-Stakleff Kimberly Denise
Evans Douglas M.
Goldberg Jerome D.
Lacher Frederick K.
Lacher Marcella R.
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