Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-09-04
2002-07-30
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S422000, C424S445000, C424S449000, C514S547000
Reexamination Certificate
active
06426367
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods for selectively occluding blood vessels which supply neoplastic tissue, including tumors.
2. Description of the Related Art
The polyunsaturated fatty acids (PUFAs) are fatty acids having at least two carbon-to-carbon double bonds in a hydrophobic hydrocarbon chain which typically includes X-Y carbon atoms and terminates in a carboxylic acid group. The PUFAs are classified in accordance with a short hand nomenclature which designates the number of carbon atoms present (chain length), the number of double bonds in the chain and the position of double bonds nearest to the terminal methyl group. The notation “a:b” is used to denote the chain length and number of double bonds, and the notation “n-x” is used to describe the position of the double bond nearest to the methyl group. There are 4 independent families of PUFAs, depending on the parent fatty acid from which they are synthesized. They are:
(1) The “n-3” series derived from alpha-linolenic acid (ALA, 18:3, n-3).
(2) The “n-6” series derived from linoleic acid (LA, 18:2, n-6).
(3) The “n-9” series derived from oleic acid (OA, 18:1, n-9).
(4) The “n-7” series derived from palmitoleic acid (PA, 16:1, n-7).
The parent fatty acids of the n-3 and n-6 series can not be synthesized by the mammals, and hence they are often referred to as “essential fatty acids” (EFAs). Because these compounds are necessary for normal health but cannot be synthesized by the human body, they must be obtained through the diet.
It is believed that both LA and ALA are metabolized by the same set of enzymes. LA is converted to gamma-linolenic acid (GLA, 18:3, n-6) by the action of the enzyme delta-6-desaturase (d-6-d), and GLA is elongated to form di-homo-GLA (DGLA, 20:3, n-6), the precursor of the 1 series of prostaglandins. The reaction catalyzed by d-6-d is the rate limiting step in the metabolism of EFAs. DGLA can also be converted to arachidonic acid (AA, 20:4, n-6)) by the action of the enzyme delta-5-desaturase (d-5-d). AA forms the precursor of 2 series of prostaglandins, thromboxanes and the 4 series leukotrienes. ALA is converted to eicosapentaenoic acid (EPA, 20:5, n-3) by d-6-d and d-5-d. EPA forms the precursor of the 3 series of prostaglandins and the 5 series of leukotrienes. Conjugated linoleic acid (CLA; 18:2) is a group of isomers (mainly 9-cis, 11-trans and 10-trans, 12-cis) of linoleic acid. CLA is the product of rumen fermentation and can be found in the milk and muscle of ruminants (see, e.g., Brodie et al. (1999),
J. Nutr
. 129:602-6; Visonneau et al. (1997),
Anticancer Res
. 17:969-73. LA, GLA, DGLA, AA, ALA, EPA, docosahexaenoic acid (DHA, 22:6, n-3) and CLA are all PUFAs, but only LA and ALA are EFAs.
Under some well defined culture conditions GLA, AA, EPA and DHA showed a marked differential cytotoxic effect against tumor cells with little or no significant action on normal cells (Leary et al. (1987),
S. Afr. Med. J
. 62:681-683; Begin et al, (1985),
Prostaglandins Leukot. Med
. 19:177-186; Das (1999),
Nutrition
15:239-241; Das (1991),
Cancer Lett
. 56:235-243; Das (1990),
Nutrition
6:429-434; Seigel et al. (1987),
J. Natl. Cancer Inst
. 78:271-277; Sangeetha and Das (1992),
Cancer Lett
. 63:189-198; Begin et al. (1986),
J. Natl. Cancer Inst
. 77:1053-1062; Das (1992),
Asia Pacific J. Pharmacol
. 7:305-327). In mixed culture experiments, in which both normal and tumor cells were grown together, GLA showed more selective tumoricidal action compared to AA and EPA (Begin et al. (1986),
Prog. Lipid Res
. 25:573-576). In addition, direct intra-tumoral administration of GLA can regress human gliomas without significant side-effects (Naidu et al. (1992),
Prostaglandins Leukot. Essen. Fatty Acids
45:181-184; Das et al. (1995),
Cancer Lett
. 94:147-155).
Thus, it is known in the art that certain polyunsaturated fatty acids (PUFAs) have cytotoxic properties towards tumor cells in vitro, and that PUFAs provide the substrates for the generation of lipid peroxidation products which have an inhibitory action on cell proliferation. In addition, tumor cells are known to have low d-6-d activity, which is necessary for the desaturation of LA and ALA to their respective products. Moreover, it has been shown that hepatocarcinogens, diethylnitrosamine (DEN) and 2-acetylamino-fluorine (2-AAF), can suppress the activity of d-6-d and d-5-d resulting in low levels of GLA and AA, EPA and DHA in the tumor cells.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides methods of selectively interrupting the blood supply to a neoplastic region, such as a tumor region, causing necrosis of the neoplastic tissue without substantial necrosis of adjoining tissues. The invention also provides methods of selectively causing anti-angiogenic action in a neoplastic region, such as a tumor region, with the result that new blood vessels and collaterals are not formed to sustain the neoplasia.
In particular, the invention provides methods for selectively reducing blood supply to at least a portion of a neoplastic region, in which (a) a proximal artery which carries blood to at least a portion of said region is located and (b) a therapeutically effective amount of a solution of at least one PUFA is intra-arterially injected into the artery, thereby selectively reducing the blood supply in a period of less than one hour or in a period less than ten minutes. In preferred embodiments, the amount of the solution is sufficient to cause occlusion of the artery in a period of less than one minute. In preferred embodiments, the therapeutically effective amount is between 0.5 mg and 50 gm, most preferably between 250 mg and 5 gm.
In some embodiments of the invention, in addition to the PUFA, a lymphographic agent is intra-arterially injected to visualize the proximal artery and blood supply to the neoplastic region. The lymphographic agent may be combined with the PUFA solution and they may be injected together. The progress of the lymphographic agent through the proximal artery and neoplastic region can be observed to determine when the blood supply is effectively reduced and when injection of the PUFA solution can be stopped. In some embodiments, the lymphographic agent is covalently conjugated to the PUFA.
In some embodiments, the PUFA is an EFA. In certain preferred embodiments, the EFA is selected from linoleic acid, gamma-linolenic acid, arachidonic acid, docosahexaenoic acid, eicosapentaenoic acid, di-homo-gamma-linolenic acid, alpha-linolenic acid, linoleic acid, and conjugated linoleic acid.
In preferred embodiments, the PUFA is administered in the form of free acid or a salt, such as a lithium salt, a sodium salt, magnesium salt, a manganese salt, an iron salt, a copper salt or an iodide salt. In some preferred embodiments, the PUFA is in the form of a fatty acid derivative, such as a glyceride, ester, ether, amide, or phospholipid, or an alkylated, alkoxylated, halogenated, sulfonated, or phosphorylated form of the fatty acid.
In some embodiments of the inventions, the neoplastic tissue is a tumor. In particular, the neoplastic tissue may be a glioma, hepatoma, lung cancer, colon cancer, breast cancer, ovarian cancer, kidney cancer, skin cancer, Kaposi's sarcoma, esophageal cancer, stomach cancer, leukemia, or lymphoma. In other embodiments, the neoplastic tissue may result from a non-cancerous cell proliferative disorder.
In some embodiments of the invention, in addition to the PUFA, a therapeutically effective amount of a compound selected from tumor necrosis factor, anti-cancer drugs, lymphokines, and specific polyclonal or monoclonal antibodies is intra-arterially injected. In preferred embodiments, the lymphokine is alpha interferon or gamma interferon.
In some embodiments, the PUFA is covalently conjugated with a pharmaceutical agent chosen from TNF, alpha-interferon, gamma-interferon, an antibody, vincristine, adriamycin, doxorubicin, cyclophospham-ide, cis-platinum, L-asparaginase, procarbazine, camnptothecin, taxol or busulfan.
In anothe
EFA Sciences LLC
Fay Zohreh
Hale and Dorr LLP
Kwon Brian-Yong
LandOfFree
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