Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
2001-05-24
2004-06-29
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C424S638000, C424S641000, C424S643000, C514S479000, C514S491000, C514S494000, C514S499000, C514S500000
Reexamination Certificate
active
06756063
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods and compositions for altering the viability of cells, particularly nonnormal or nonhealthy cells, such as those comprising various cancers in animals and humans. More particularly, the invention relates to the preparation and use of the compositions of the present invention to rapidly kill or weaken cancerous cells within or on the surface of an animal or human body. The invention also relates to methods to minimize metastatic growth potential of cancer cells derived from primary tumors during surgical intervention. Primarily intratumoral, but also systemic or parenteral treatments as well as pre-operative, post-operative, or topical treatment of cancers are contemplated. The present invention illustrates surprising and rapid effectiveness and relative specificity against a broad class of cancer cells and cancerous tissues over healthy cells.
BACKGROUND OF THE INVENTION
Despite vast advances in screening, lifestyle moderation, and therapeutic approaches, cancer continues to be one of the leading causes of death in the world. Drug toxicity, drug resistance, and the varying genetic backgrounds of different cancer sub-types have complicated the development of chemotherapeutics that are specifically cytotoxic to cancerous cells, yet minimally toxic to the patient.
Many currently available cancer treatments depend on the type, location, size and stage of the tumor, as well as numerous patient health-related issues. Typically, treatment may involve surgery, chemotherapy, and radiation, alone or in combination. Surgical removal of a cancerous tumor, for example breast tumors, is often desired in conjunction with chemotherapy and/or radiation, because the tumor may represent a burden to the patient's body.
During surgery, tumor cells often escape into the blood stream, leading to secondary tumors. Also the surgeon or radiologist may not succeed in removing/destroying the whole cancer tissue, leading to local recurrences. Therefore, even after seemingly successful treatment of a primary tumor, local recurrences and metastasis, i.e., the spread of malignant tumors to secondary sites, often represent further threats to the patient. It would be desirous to have methods and compositions that minimize the risk of metastasis and local recurrences, while at the same time present minimal toxic burden to the patient.
There remains a need for compositions with enhanced specificity and rapid cytotoxicity for a broad range of nonnormal or nonhealthy cells over healthy cells. In particular there remains a need for compositions and methods to treat and to prevent primary cancers and metastases that could be employed both locally, at the site of a primary tumor, and/or systemically, but that would present minimal toxic burden to the patient. Because of the heterogeneity of cancers, there further remains a need for a method to produce and to screen a library of active compositions from which a particular composition capable of altering the viability of a wide spectrum of cancerous cell types and sub-types may be chosen.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide methods and compositions that alter the viability of a wide spectrum of nonnormal or nonhealthy cells, particularly cancers, but preferably that minimally affect the viability of healthy human cells. It has been found that the compositions and methods of the present invention demonstrate a surprisingly rapid, relatively specific, cytotoxicity for a broad range of nonnormal cells, particularly cancers, including but not limited to breast (both estrogen receptor positive and negative), epidermal, melanomal, colorectal, bladder, cervical, neuroblastomal, prostate, ovarian, endometrial, and placental cancers.
In practice, the compositions of the present invention are formed from a set of components comprising one or more of the following: (A) a dithiocarbonyl, preferably dithiocarbamate, compound; (B) a divalent metal ion; (C) a modulator of cellular glutathione levels; and (D) an inhibitor of the phosphorylation of choline, which can significantly change the composition of biological membranes. The biologically effective compositions described herein induce a selective and rapid effect on the viability of preferably, nonnormal cells, by inducing apoptotic or necrotic cell death, or both, with the dominant pathway being apoptosis. Particularly preferred active compositions comprise all four components, although combinations of fewer components can be fully effective in certain tumors. Such compositions have been found to be useful against a broad spectrum of cancerous cell lines while exhibiting less toxicity to healthy cells. Such compositions are thereby useful to treat tumors in vivo that are typically heterogeneous. The multi-component embodiments can be thus effective against the entirety of such tumors, whereas conventional chemotherapies often have more limited specificity. Compositions comprising less than all four components are also able to alter the viability of one or more particular cell lines.
In one aspect of the invention, compositions of the present invention are prepared by incorporating one or more of the components A, B, C, and D into the composition. The dithiocarbonyl component A, preferably a dithiocarbamate compound, of the composition usually has the formula: (R
1
)
m
(R
2
)—Z—C(S)—S—Y wherein m is 0 or 1, but other structures can be envisioned. For example, a dithiocarbamate moiety can be inserted into fatty acid chains, or between the phosphate group and the polar headgroup, or at the end of the polar headgroup in a phospholipid molecule.
Y is chosen from the group consisting of hydrogen, a pharmaceutically acceptable cation, a physiologically cleavable leaving group, a targeting moiety, or a pharmaceutically active drug, including a chemotherapeutic drug. In a preferred embodiment, Y represents a pharmaceutically acceptable cation, and may represent all or a portion of the component B listed above.
Z may be preferably chosen from either O or N, but if Z is O, then m=0. R1 and R2 may be independently chosen from the group consisting of hydrogen; or C1-C24 straight, branched, or cyclic alkyl, alkenyl, aryl, acyl, alkaryl, aralkyl, or alkoxy groups, optionally substituted with ester, ether, halogen, sulfate, hydroxy, or phosphate groups. R1 and R2 may be optionally connected via a bridge such as —(CH)
n
—, wherein n is 3-8, so that the resulting structure is heterocyclic, and may be optionally substituted on any of the carbon atoms of the ring. Representative substitutents include, for example, C1-C10 straight, branched, or cyclic alkyl, aryl, aryalkyl, or alkaryl groups, optionally substituted with hydroxy, halo, phosphate, sulfate, or sulfonate groups.
Preferred dithiocarbonyl compounds of the present invention include diethyldithiocarbamate (DEDC); tricyclo-[5.2.1.O
2,6
]-decyl(9[8]-xanthogenate (also known commonly as D609); tetraethylthiuram disulfide (also known commonly as Disulfuram, ((C
2
H
5
)
2
NCS
2
.]
2
)); and pyrrolidinedithiocarbamate (PDC). Other representative dithiocarbonyl compounds are set forth in U.S. Pat. No. 5,783,596, incorporated herein by reference.
The present compositions also may incorporate a metal ion component B. In particular, the dithiocarbonyl components of the present invention may be complexed with the metal cation component B. Suitable metal cations include Cu
2+
and Zn
2+
. Most preferably, Zn
2+
is employed.
The compositions of the present invention may also incorporate a component C to affect the intracellular redox state of nonnormal or nonhealthy cells. In particular, it has been surprisingly discovered that chemical and enzymatic modulators of cellular glutathione (GSH) levels enhance the efficacy of the compositions of the present invention. Those compounds that deplete cellular glutathione are preferred as component C, including ethacrynic acid (EA), L-buthionine-S,R-sulfoximine (BSO), diethylmaleate, 2-cyclohexene-1-one, and 1-chlo
Faegre & Benson LLP
Krass Frederick
Zoltan Laboratories LLC
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