Methods of inhibiting tumor growth using adenosine receptor...

Details Methods of inhibiting tumor growth using adenosine receptor... Methods of inhibiting tumor growth using adenosine receptor...

1999-12-16

2004-01-20

Ungar, Susan (Department: 1642)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Animal or plant cell

C424S130100, C424S143100, C514S046000, C530S387100, C536S027600

Reexamination Certificate

active

06680052

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods of treating and or imaging tumors, and particularly to methods of treating and/or imaging tumors using A
1
adenosine-receptor activated cells, such as monocytes, macrophages and/or splenocytes.
BACKGROUND OF THE INVENTION
Purinergic receptors can be classified into the P
1
(adenosine) receptors and the P
2
(adenosine
5
′ triphosphate) receptors. Adenosine receptors can further be delineated into major subclasses, the A
1
, A
2
(A
a2
and A
a2b
) and A
3
adenosine receptors. These subtypes are differentiated by molecular structure, radioligand binding profiles, and by pharmacological and functional activity. Binding of adenosine, a naturally occurring nucleoside, to specific adenosine receptors leads to either stimulation (A
2
-receptor activation) or inhibition (A
1
-receptor activation) of adenylate cyclase activity resulting in an increase or decrease of intracellular cAMP, respectively. Most tissues and cell types possess either the A
1
or A
2
receptor, or both. Moreover, A
1
adenosine receptors have been identified in the nuclear fraction of splenocytes (Donnabella,
Life Sci.
46:1293 (1990)). Specific A
1
, A
2
, and A
3
antagonists and agonists are well-known in the art. See, e.g., Trivedi et al.,
Structure
-
Activity Relationships of Adenosine A
1
and A
2
Receptors, In:
Adenosine and Adenosine Receptors,
M. Williams, Ed., Humana Press, Clifton, N.J., USA (1990); Jacobson et al.,
J. Medicinal Chem.
35:407 (1992); Fredholm et al.,
Pharm. Rev.
46:143 (1994); Jacobson,
Abstracts from Purines
'96,
Drug Dev. Res.,
March 1996, page 112. Divalent ions (Mg
2+
and Ca
2+
) and allosteric enhancers enhance the binding of A
1
adenosine receptor agonists to A
1
adenosine receptors (Kollias-Baker,
Circ. Res.
75:961 (1994)). Allosteric enhancers enhance A
1
receptor mediated responses and are described in Bhattacharya,
Biochim. Biophys. Acta
1265:15 (1995).
Inflammatory cells, including monocytes and alveolar macrophages are known to express the A
1
, A
2
and A
3
receptor subtypes. Eppell et al.,
J. Immunology
143:4141 (1989); Lapin and Whaley,
Clin. Exp. Immunol.
57:454 (1984); Saijadi, et al.,
J. Immunol.
156:3435 (1996). Activation of the A
3
or A
2
receptors has been shown to inhibit monocyte function.
Mature monocytes enter the circulatory system from the bone marrow; some monocytes enter tissues and develop into macrophages in the spleen, lymph nodes, liver, lung, thymus, peritoneum, nervous system, skin and other tissues. Monocytes and macrophages can be identified by morphology, cell surface antigens, and the presence of characteristic enzymes. Both monocytes and macrophages play a role in inflammatory responses by eliminating bacteria and other pathogens by phagocytosis. Monocytes and macrophages also secrete various proteins active in immune and inflammatory responses, including Tumor Necrosis Factor (TNF) and Interleukin I (IL-1)). Upon stimulation, monocytes and macrophages can generate various oxygen metabolites, including superoxide anion and H
2
O
2
that are toxic to both pathogens and normal cells.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a method of inhibiting the growth of tumor cells in a subject, wherein a sample of treatment cells is taken from a subject and contacted with a priming agent, and then activated by contact with an A
1
adenosine receptor agonist, in order to induce cytotoxicity in the treatment cells. The cytotoxic treatment cells are then administered to the subject.
A further aspect of the present invention is a method of inhibiting the growth of tumor cells in a subject, wherein a macrophage priming agent is administered to tissue containing tumor cells, in an amount sufficient to prime resident macrophages. An A
1
adenosine receptor agonist is then administered to the tissue containing the tumor cells to induce cytotoxicity in the primed macrophages.
A further aspect of the present invention is a method of imaging tumor cells in vivo in a subject, wherein a sample of treatment cells is taken from a subject and contacted with a priming agent, and then labeled with a radiolabelled selective A
1
adenosine receptor ligand. The radiolabelled, primed treatment cells are then administered to the subject to provide a radioimage of any tumor cells present.
Fang et al. reported the inhibition of cell growth in hormone-refractory prostate cancer cell lines using P
2
purinergic receptor agonists. These authors concluded that human androgen-independent prostate carcinoma cells expressed functional P
2
-purinergic receptors, and proposed that agonists of such receptors be used to inhibit the growth of related neoplasms. Methods of treating prostate cancers by administration of a P
2
purinergic receptor agonist are provided in U.S. Pat. No. 5,415,873.
U.S. Pat. No. 4,880,918 (Rapaport) reports the use of low doses of extracellular adenosine 5′-diphosphate (ADP) or adenosine 5′-triphosphate (ATP) for the selective inhibition of growth and subsequent cell death of malignant cells. Such treatment is reported as inhibiting malignant cell growth without affecting normal cell activity. ATP and ADP are stated as able to permeate the plasma membrane of tumor cells (but not normal animal cells) without prior degradation to adenosine 5′-monophosphate (AMP) or adenosine. It is stated that the effects of ADP and ATP cannot be duplicated with the use of AMP or adenosine.
U.S. Pat. No. 5,049,372 (Rapaport) reports that administration of adenine nucleotides (AMP, ADP or ATP) into a host results in elevation of extracellular blood plasma ATP levels, which in turn inhibit tumor growth as well as ameliorating cancer cachexia in tumor-bearing hosts.
Tey et al.
Biochem. Biophys. Res. Comm.
187:1486 (1992) report that adenosine evoked a biphasic response in cultured human epidermoid carcinoma cells. A low concentration inhibited colony formation while higher concentrations progressively reversed the inhibition. When both A
1
and A
2
receptors were blocked, however, colony formation or growth was not inhibited at low concentrations of adenosine but was inhibited at high concentrations.
D'Ancona et al. reported the in vitro effects of NECA (5′-(N-ethyl)-carboxamidoadenosine), an A
1
, and A
2
adenosine receptor agonist, and 1,3-dipropyl-8-(2-amino-4-chloropheny)-xanthine (PACPX), a selective A
1
adenosine receptor antagonist, administered directly to human metastatic cell lines.
Anticancer Research
14:93 (1994). The drugs were reported as having an inhibitory effect on cell growth.
The foregoing and other objects and aspects of the present invention are explained in detail in the specification set forth below.
DETAILED DESCRIPTION OF THE INVENTION
A direct interaction of macrophages and tumor cells, in an approximately 20:1 ratio (macrophages:tumor cells), has been reported as required for the tumoricidal effect of macrophages to be seen. Alexander and Evans,
Nature New Biology
232:76 (1971). It is not fully understood how the actual cytotoxic effects of macrophages on tumor cells occurs.
Relatively low concentrations of bacterially derived endotoxic lipopolysaccharides (LPS) are known to activate macrophages, stimulating the macrophages to synthesize and secrete immunologically important cytokines, including interferon-&agr;/&bgr;, interleukin-1, and tumor necrosis factor. See Alexander,
Nature New Biology
232:76-78 (1971); Pace and Russell,
J. Immunol.
126:1863 (1981); Hamilton and Adams,
Immunology Today
8:151 (1987); Chen et al.,
Curr. Topics Microbiol. Immunol.
181:169 (1992). Exposure to LPS can result in fully activated macrophages capable of killing tumor cells. Saturable and specific binding of LPS to peritoneal macrophages has been reported. Haeffner-Cavaillon et al.,
J. Immunol.
128:1950 (1982). However, the biochemical sequence of events triggered by LPS interaction with macrophages which results in the tumoricidal activation of macrophages has not yet been defined. It

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