Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-27
2004-11-30
Weber, Jon P. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S472000, C540S465000, C540S145000, C514S410000
Reexamination Certificate
active
06825186
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel methods and pharmaceutical formulations for treating atheroma, tumors and other neoplastic tissue, as well as other conditions that are responsive to the induction of targeted oxidative stress. This invention also relates to novel methods for determining the radiation sensitization potential of a compound.
2. Publications Cited by Reference
Certain publications are cited in this application through the use of the following superscript numbers:
1
Buettner, et al., Radiation Research,
Catalytic Metals, Ascorbate and Free Radicals: Combinations to Avoid,
145:532-541 (1996)
2
Isoda, et al., J. Cancer Research,
Change in Ascorbate Radical Production in an Irradiated Experimental Tumor with Increased Tumor Size,
56:5741-5744 (1996)
3
Riley, Int. J. Radiat. Biol.,
Free Radical in biology: oxidative stress and the effects of ionizing radiation,
65(1):27-33 (1994)
4
Sessler, et al., J. Phys. Chem. A,
One
-
Electron Reduction and Oxidation Studies of the Radiations Sensitizer Gadolinium
(
III
)
Texaphyrin
(
PCI
-120)
and Other Water Soluble Metallotexaphyrins,
103: 787-794 (1999)
5
Adams, et al., Radiation Res., 67:9-20 (1976)
6
Riley, Int. J. Radiat. Biol.,
Free Radicals in Biology: Oxidative Stress and the Effects of Ionizing Radiation,
65(1):27-33 (1994)
7
Magda, et al., U.S. Pat. No. 5,798,491,
Multi
-
Mechanistic Chemical Cleavage Using Certain Metal Complexes
, issued Aug. 25, 1999
8
Young, et al., U.S. Pat. No. 5,776,925
, Methods for Cancer Chemosensitization
, issued Jul. 7, 1998
9
Sessler, et al., U.S. Pat. No. 5,622,946
, Radiation Sensitization Using Texaphyrins
, issued Apr. 22, 1997
10
Sessler, et al., U.S. Pat. No. 5,457,183
, Hydroxylated Texaphyrins
, issued Oct. 10, 1995
11
Sessler, et al., Accounts of Chem. Res.,
Texaphyrins: Synthesis and Applications,
27:43-50 (1994)
12
Hemmi, et al., U.S. Pat. No. 5,599,928
, Texaphyrin Compounds Having Improved Functionalization
, issued Feb. 4,1997
13
Young, et al., Investigative Radiology, 29:330-338 (1994)
14
Mosmann, J. Immunol. Methods, 65:55-63 (1983)
15
Lin, et al., Analytical Biochemistry,
The Cytotoxic Activity of Hematoheme: Evidence for Two Different Mechanisms,
161:323-331 (1987)
16
Volpin, et al., WO097/03666, EP 0 786 253 A1, U.S. Pat. No. 6,004,953, Agent for Suppressing Tumor Growth
All of the above publications are herein incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference in its entirety.
3. Background Information
The treatment of solid mammalian tumors with Ionizing radiation involves the in situ generation of hydroxyl radicals and other reactive oxygen species which, due to the focusability of the ionizing radiation are primarily located in the tumor, i.e., in tumor cells. These reactive species possess extreme oxidizing properties which oxidize biomolecules in vivo thereby interfering with cellular metabolism.
1
For example, it is reported that ionizing radiation, such as X-rays and &ggr;-rays, induces irreversible damage to cellular DNA through production of hydroxyl radicals and other reactive oxygen species in the cell leading to cell death
2.3
or initiation of the mechanism of apoptosis.
4
One generally accepted mechanism of the cellular effect of ionizing radiation is initial damage inflicted to the cell's DNA by reactive oxygen species generated by the ionizing radiation. In the presence of molecular oxygen, this damage is largely irreparable. Contrarily, in the absence of molecular oxygen (such as hypoxic cells), cellular antioxidants such as ascorbate and NAD(P)H can act to repair damage to the tumor DNA.
Tumor treatment via the use of ionizing radiation can be enhanced by increasing the radiosensitivity of the tumor cells. One method suggested for enhancing radiosensitivity has been the external administration of a compound having a high affinity for electrons, which ideally localizes in the tumor. Proposed radiation sensitizers include compounds such as halogenated pyrimidines, nitroimidazoles and gadolinium (III) complexes of the pentadentate macrocycle texaphyrin.
4
Motexafon gadolinium (a gadolinium (III) texaphyrin complex) is currently in Phase III clinical trials for the treatment of brain metastases.
4
Phthalocyanine and naphthalocyanine polydentate ligands of the transition metals cobalt and iron have been described as suppressing the growth of tumor cells when administered in combination with a biogenic reductant such as ascorbic acid.
16
The observation that radiation sensitization occurs as a function of redox potential gave rise to the proposal that such compounds function by interception of aqueous electrons, thus preventing their recombination with cytotoxic radicals.
5
Subsequent evidence showing a lack of radiation sensitization activity for lutetium (III) texaphyrin in animal models notwithstanding the rapidity of reaction between this complex and hydroxyl radicals under pulsed radiolytic conditions and minimal apparent nuclear localization suggest that this proposal might not fully explain the mechanism by which the gadolinium texaphyrins act as radiosenstizers.
4
In view of the above, an understanding of the mechanism for radiosentization of tumor cells would be particularly helpful. Such an understanding could be used for testing in the discovery of new compounds useful as radiation sensitizers as well as in maximizing the therapeutic effect achieved by use of such compounds in the presence or the absense of ionizing radiation.
SUMMARY OF THE INVENTION
This invention is premised upon the unexpected observation that the known motexafin gadolium radiation sensitizer acts to catalyze the oxidation of NAD(P)H, ascorbate and other reducing agents under approximate physiological conditions, leading to reactive oxygen species generation. Depletion of these reducing agents will inhibit biochemical pathways that in vivo utilize reducing agents to effect repair of the damage inflicted by reactive oxygen species. Additionally, since hydrogen peroxide is recognized as probably the most significant of the reactive oxygen species
6
, the generation of hydrogen peroxide will facilitate oxidative attack on the tumor or other tissue where it is produced.
Moreover, this discovery that motexafin gadolium acts to catalyze the oxidation of reducing agents under approximate physiological conditions to produce one or more reactive oxygen species such as superoxide and hydrogen peroxide, serves as a basis to assess the radiation sensitizing potential of other compounds. Specifically, a candidate compound can be screened to determine its ability to generate one or more reactive oxygen species under appropriate conditions. In turn, the amount of reactive oxygen species so produced is then correlated to the radiation sensitizing ability of the compound. Accordingly, in one of its method aspects, this invention is directed to a method for determining the radiation sensitization potential of a compound by the steps of:
a) introducing a compound to be tested into an aqueous solution of a cellular metabolite having a standard biochemical reduction potential more negative than the standard biochemical reduction of oxygen/hydrogen peroxide;
b) monitoring the solution for the occurrence of a reaction that produces one or more reactive oxygen species; and
c) determining whether the compound has potential radiation sensitization activity, wherein the potential for radiation sensitization activity correlates to the occurrence of a reaction that produces one or more reactive oxygen species.
The reaction that produces a reactive oxygen species can be monitored in numerous manners as is well known to the skilled artisan, by measuring one or more of: depletion of oxygen, production of hydrogen peroxide, decreased concentration of the cellular metabolite, or generation of an oxidation product of the cellular metabolite. The cellular metabolite is preferably a compound sele
Magda Darren
Sessler Jonathan L.
Kathardekar Vinit G.
Lukton David
Pharmacyclics Inc.
Weber Jon P.
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