Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2003-05-06
2004-03-02
Carr, Deborah (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S613000, C514S627000, C514S109000, C554S040000, C564S015000
Reexamination Certificate
active
06699851
ABSTRACT:
The present invention concerns novel amides and their use, in particular their therapeutic use. These compounds have been synthesised and characterised by the present inventor, as disclosed herein. Further, their efficacy as anti-tumour agents has been shown in vitro and in animal studies, disclosed in the attached examples.
BACKGROUND OF THE INVENTION
Tumour cell drug resistance is a major problem in cancer chemotherapy. With resistance development follows the necessity of increasing doses, combination therapies and other treatment regimens, often associated with severe side effects for the patient.
Studies concerning the cytotoxicity of essential fatty acids on cancer cell lines have been published by several working groups. Moreover, several experimental studies have shown that exogenous polyunsaturated fatty acids (PUFAs) may sensitise tumour cells to anti-cancer drugs in cell culture or in tumours growing in animals.
No precise mechanism of action of PUFAs in the modulation of anti-cancer drug efficacy has yet been determined. It has been proposed that the enhanced tumour cell killing effect of anti-cancer drugs could result from alterations in the biophysical properties and functions of membranes brought about by PUFA supplementation.
In addition to the effects of PUFAs on membrane structure, the peroxidation of highly unsaturated fatty acids has been linked to cytotoxicity in neoplastic cells In response to oxidative stress, PUFAs undergo free-radical chain reaction breakdown, which results in the formation of fatty acid hydroperoxides and hydroxides as immediate products and aldehydes, among other end-products. Both in cultured tumour cells and in tumour-bearing animals, PUFA supplementation has been shown to cause a decrease in cell proliferation or in tumour growth correlated with a concomitant increase in the level of cellular lipid peroxidation. These observations suggest that PUFAs interfere with tumour cell proliferation in vitro and in vivo due to the formation of oxidation products. Little is however known about the involvement of lipid peroxidation in the modulation of drug efficacy by PUFAs.
The ability of PUFAs to increase the cytotoxic activity of several anti-cancer drugs has been well documented. The involvement of lipid peroxidation as a potential mechanism through which PUFAs modulate the efficacy of those cytotoxic drugs has been suggested from experimental studies in tumour-bearing animals (Shao Y., et al., Lipids, 30, 1035-1045, 1995) or in cell culture (Petersen E. S., et al., Cancer Res., 42, 6263-6269, 1992) and showing that PUFAs in conjunction with oxidants strongly increase the activity of a cytotoxic drug that generates an oxidative stress and that lipid peroxidation may be involved in this effect (Germain E., et al., Int. J. Cancer, 75, 578-583, 1998).
These results coupled with the observation that various fatty acids can alter the activity of cell membrane bound enzymes such as sodium-potassium-ATPase and 5′-nucleotidase, levels of various anti-oxidants, p53 expression and the concentrations of protein kinase C suggest that essential fatty acids and their metabolites can reverse tumour cell drug-resistance at least in vitro. (Das U. N., et al.,
Prostaglandins Leukot. Essent. Fatty Acids
, 58, 39-54, 1998).
The influence of different PUFAs on doxorubicin-induced cell toxicity has been examined (Germain E., et al., supra). In agreement with previous studies, it was observed that DHA was the most potent of all tested PUFAs at enhancing doxonibicin efficacy. For most of the PUFAs, the effect on drug activity increased with the double bond index. The only exception was 18:3n-6, which was more potent than 18:3n-3 and than fatty acids with 4 or 5 unsaturations (20:4n-6 or 20:5 n-3). This may be related to specific properties of 18:3n-6, as already documented in other cell lines.
In humans, little is known about the involvement of lipid peroxidation in drug efficacy. Exogenous PUFAs are readily incorporated into breast cancer cell membranes (Gore J., et al.,
Amer. J. Physiol
., 266, C110-C120, 1994).
It remains to be determined to what extent the toxic side effects of known cytotoxic drugs (such as their hematological or cardiac toxicity) would be affected. This is required before any intervention trial involving such a strategy can be considered in human patients.
The problems underlying the present invention are manifold. One problem is how to modulate and preferably increase the efficacy of presently known cytotoxic agents with unchanged or preferably reduced side effects. The avoidance of systemic toxic effects and complications, such as hematological or cardiac toxicity is another problem of great importance.
Yet another problem is how to prevent the development of tumour cell drug resistance, which presently is a major complication in cancer chemotherapy. Further problems include how to locally focus the effect of cytotoxic drugs to the tumour cells or affected organs, and thus increase the efficacy of the treatment without negative consequences to the patient. Also knowing that some PUFAs have the ability to increase the cytotoxic activity of several anti-tumour drugs, it remains a problem to find and synthesize new, specific compounds, exhibiting either the ability to increase the cytotoxic activity of existing drugs or having a cytotoxic effect in themselves.
Further, it remains a problem how to design new combinations of specific compounds, both presently known and hitherto unknown compounds, exhibiting an enhanced anti-tumour effect.
SUMMARY OF THE INVENTION
The present inventor has surprisingly shown, that the disclosed amides of the docosahexaenoic acid and eicosapentaenoic acid and arachidonic acid, and &agr;-linolenic acid or &ggr;-linolenic acid with cysteamine-S-phosphate exert a significant cytotoxic action against tumour cells in vitro. During the priority year, these results have been confirmed in animal studies.
Combinations of the all-trans-retinoic acid and/or amides of the 13-cis-retinoic acid with 0-phospho-L-tyrosine, and N-docosahexaenoyl-cysteamine-S-phosphate, N-eicosapentaenoyl-cysteamine-S-phosphate, N-arachidonoyl-cysteamine-S-phosphate, N-&agr;-linolenoyl-cysteamine-S-phosphate, and N-&ggr;-linolenoyl-cysteamine-S-phosphate and their analogues N-docosahexaenoyl-O-phospho-2-aminoethanol, N-eicosapentaenoyl-O-phospho-2-aminoethanol, N-arachidonoyl-O-phospho-2-aminoethanol, N-&agr;-linolenoyl-O-phospho-2-aminoethanol, N-&ggr;-linolenoyl-O-phospho-2-aminoethanol in different compositions exhibit a marked cell-growth inhibiting effect and display anti-tumour activity in in vivo and in vitro experiments.
The invention will be disclosed in closer detail in the following description and examples, to be read in connection with the attached claims, which are hereby incorporated in their entirety.
DESCRIPTION OF THE INVENTION
In the following description, the term “cancer” is used to define any uncontrolled cell growth, malignant or benign. The term “treatment” is used with the aim of comprising both active or curative treatment, as well as pallative treatment.
The term “cytotoxic agent” is used to define any pharmacologic compound that inhibits the proliferation of cells within the body, and in particular existing and future pharmaceuticals used in cancer theraphy. Doxorubicin (DXR) is a well known anthracyclin antibiotic, used in the treatment of a variety of malignant neoplastic diseases. In the present description, DXR is used as an example of a cytotoxic agent.
The novel compounds according to the present invention are amides of docosahexaenoic acid and eicosapentaenoic acid and arachidonic acid, and &agr;-linolenic acid or &ggr;-linolenic acid, with cysteamine-S-phosphate.
Specific novel compounds according to the present invention are for example (the compound number is given in parenthesis for easier reference):
N-docosahexaenoyl-cysteamine-S-phosphate (C1)
N-eicosapentaenoyl-cysteamine-S-phosphate (C2)
N-arachidonoyl-cysteamine-S-phosphate (C3)
N-&agr;-linolenoyl-cysteamine-S-phosphate (C4)
N-&ggr;-linolenoyl
Ardenia Investments Ltd.
Carr Deborah
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