Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-06-11
2003-06-17
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S043000
Reexamination Certificate
active
06579857
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of medicine. More particularly, the invention relates to the field of oncology, especially the treatment of cancers of an epithelial origin.
DESCRIPTION OF RELATED ART
Purine nucleosides (e.g., adenosine, deoxyadenosine, guanosine, deoxyguanosine), which comprise bi-cyclic nitrogenous purine bases (adenine, guanine) linked to a pentose sugar (ribose, deoxyribose), are found in all cell types, e.g., serving as constituent nucleosides of both ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). At high concentrations, purines and their derivatives have been shown to arrest normal cell growth and cause apoptosis in certain cell types, such as endothelial cells, macrophages, and lymphocytes. It has been hypothesized that cell death usually occurs through conversion of adenosine into nucleotides (via phosphorylation) and/or into S-adenosylhomocysteine, which in turn induce pyrimidine starvation or inhibit cellular methylation. The high concentrations of adenosine necessary to cause cell death are difficult to maintain, however, due to the many cellular processes by which adenosine can be converted to other products. See Bynum,
Cancer Res.
40: 2147-2152 (1980); Archer et al.,
J. Cell. Phys.
124:226-232 (1985); Henderson et al.,
Pharmac.& Ther.
8: 539-571 and 573-604 (1980).
Adenosine (Ado) is reportedly released from cells in response to alterations in oxygen supply or demand, and has been reported to be a potent vasodilator involved in the metabolic regulation of blood flow. At less than toxic concentrations, adenosine has been reported to have both cardio-protective and neuro-protective properties [Olafsson et al.,
Circulation,
76: 1135-1145 (1987); Dragunow and Faull,
Trends in Pharmacol Sci.,
9: 193 (1988).]
Adenosine deaminase (ADA) is the hydrolytic enzyme that catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, and thus is one of the enzymes involved in controlling adenosine/deoxyadenosine levels. ADA is found at especially high levels in the spleen, thymus, and B and T lymphocytes. Adenosine monophosphate deaminase (AMP deaminase, AMPDA) is functionally related to adenosine deaminase, converting adenosine monophosphate to inosine monophosphate. ADA plays an essential role in leukocytes and its absence is associated with a severe, inherited combined immunodeficiency disease.
Interestingly, although ADA is capable of deaminating both adenosine and 2-deoxyodenosine (dAdo), it is principally dAdo that accumulates in plasma following dosing with an ADA inhibitor, such as deoxycoformycin (dCF). Apparently, deamination of adenosine occurs principally at the monophosphate level by the enzyme AMP deaminase. The dAMP moiety is a poor substrate for AMP deaminase, so deamination of dAdo is largely dependent on ADA, and ADA-inhibition results in dAdo accumulation. [Plunkett and Gandhi,
Hematol. Cell Ther.
38: S67-S74 (1996).]
Inhibitors of ADA have been recognized as potential immunosuppressive agents, and many early studies of the cytotoxicity of adenosine deaminase inhibitors have involved human lymphocytes. [See, e.g., O'Dwyer et al.,
Annals Int. Med.
108: 733-743 (1988).] For example, dCF, a powerful ADA inhibitor (K
i
for erythrocyte ADA of 2×10
−12
), has been used to treat lymphatic leukemias and is FDA-approved (Pentostatin) to treat hairy cell leukemia. Coformycin, the ribosyl analog of dCF, also acts as an ADA inhibitor. The pharmacology and efficacy of dCF and two other prominent nucleoside analogs 2-chlorodeoxyadenosine, (CDA, cladribine) and arabinosyl-2-fluoroadenine monophosphate (F—ara—AMP, fludarabine) for treating lymphoid malignancies are reviewed in Plunkett and Gandhi,
Hematol. Cell Ther.
38: S67-S74 (1996), and Diliman, R.,
Seminars in Hematoloogy,
31: 16-27 (1994), incorporated herein by reference. The toxicity of ADA inhibitor compounds appears to relate to their causing an accumulation of toxic intracellular levels of dAdo, which (through conversion to dATP via successive phosphorylations) inhibits ribonucleotide reductase. The lethal effects of dAdo on blood cells has been extensively studied and reported in the literature.
Not all of the studies involving ADA inhibitors have focused on lymphoid malignancies. Camici et al.,
Int. J. Cancer,
62: 176-183 (1995) reported an assessment of the effect of deoxycoformycin (.001 to 1 &mgr;M) and 2′-deoxyadenosine (0 to 500 &mgr;M) on the growth of two cultured human colon carcinoma cell lines and on Chinese hamster ovary (CHO K-I) cells. Neither compound was reported to be toxic when used alone, whereas their combination was reported to cause cell growth inhibition, with the CHO cells more sensitive than the colon carcinoma cells. At the concentrations tested, 50-150 &mgr;M deoxyadenosine was required to approach full cell growth inhibition. The authors suggest that phosphorylation of deoxyadenosine by adenosine kinase plays a central role in the toxicity of the combination therapy, and observed that the cytotoxic effect was almost completely reversed in the three cell lines when inhibitors of adenosine kinase were added to the cell culture medium. Introduction of dipyridamole to inhibit deoxyadenosine uptake also was reported to reverse the toxicity.
Svendsen et al.,
Cancer Chemotherapy & Pharmacology
21(1): 35-39 (1988) reported that simultaneous administration of 3′deoxadenosine N1-oxide and either ERNA or dCF to mice bearing Ehrlich ascites tumor cells resistant to 3′-deoxyadenosine N1-oxide resulted in 80-90% inhibition of tumor growth in vivo.
Rowland et al.,
Arch. Biochem. Biophys.,
239(2): 396-403 (1985) developed a rat hepatoma cell line that was ADA-dependent and dCF sensitive. The authors observed that dCF-resistant variants developed and determined that such cells have progressively increasing concentrations of ADA activity, apparently resulting from ADA gene amplification. A dCF-resistant CHO cell line developed by the authors also demonstrated extreme increases in ADA activity, but this change was not attributable to gene amplification.
Wakade et al.,
J. Biol. Chem.,
270(30): 17986-17992 (1995) have shown that dAdo (which increases in concentration in the presence of an ADA inhibitor) causes neuronal cell toxicity in a dose-dependent manner (maximal at 300 &mgr;M). Neuronal death was correlated to a dramatic increase in the dATP content of the neurons. Nanomolar concentrations of 5′-Iodotubercidin (ITu) were reported to completely and dose-dependently inhibit formation of dATP and protect against toxicity of sub-millimolar concentrations of dAdo. Interestingly, neither dCF nor another ADA inhibitor [erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA)] at concentrations of 3-30 &mgr;M were found to modify the toxic effects of dAdo in the neuronal model. [See also Kulkarni and Wakade,
J. Neurochem.,
67(2): 778-786 (1996).] Wakade et al.,
J. Neurochemistry
67(6):2273-2281 (December, 1996) reported that 100 &mgr;M dAdo (but not adenosine) in combination with 3 &mgr;M dCF was toxic to chromaffin cells. The toxicity, which was associated with dATP accumulation, was eliminated by co-culture with nanomolar concentrations of ITu.
There also exists suggestions in the literature for using AMP deaminase inhibitors for therapeutic purposes. For example, Gruber and colleagues have suggested using AMP deaminase inhibitors to treat or prevent a variety of cardiovascular and other disorders. [See U.S. Pat. Nos. 5,731,432 and 4,912,092.]
The treatment of parasitic (e.g., fungal, trypanosomal) infections with ADA inhibitors in combination with 3′-deoxypurine nucleosides (e.g., cordycepin) has been suggested. See McCaffrey et al., U.S. Pat. Nos. 5,679,648 and 5,663,155 and International Patent Publication No. WO 96/16664.
Extracellular adenosine and adenosine triphosphate (ATP) have also been reported to cause cytotoxicity. For example, Dawicki et al.,
Am. J. Physiol.,
273: L485-L494
Barry Catherine P.
Lind Stuart E.
Evanston Northwestern Healthcare Research Institute
Goldberg Jerome D.
Marshall Gerstein & Borun
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