Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-05-11
2001-04-24
Clark, Deborah J. R. (Department: 1633)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C435S320100, C435S455000, C435S267000, C424S093200, C424S093210
Reexamination Certificate
active
06221848
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is directed generally to protecting an individual's tissues and cells against the damaging effects of an agent that elicits the production of a free radical, superoxide anion, or heavy metal cation when that individual is exposed to the agent. Specifically, the invention is directed to protection of the oral cavity, oropharynx, esophagus, stomach, small intestine and colon by transient expression of a protective protein through somatic gene transfer in vivo.
Therapeutic concentrations of anti-cancer drugs and clinical radiation therapy are known to damage a patient's normal tissues and cells. A need clearly exists for means to protect a patient's normal tissues during chemotherapy and/or radiation therapy. Previous methods of affording such protection include administration of sulfhydryl compounds such as thiols or other radical scavenger compounds.
The major way in which radiation damages biomolecules and cells is through its interaction with water to produce toxic free radicals (H&Circlesolid;, OH&Circlesolid;, e
aq
−
) and H
2
O
2
or, through interaction with oxygen, to produce the superoxide radicals (ÅO
2
−
) . In the late 1940's it was discovered that sulfhydryl compounds, such as cysteine and cysteamine, provide radiation protection in animals. Patt et al.,
Science
110: 213 (1949). Thiol groups scavenge radiation-produced free radicals by donating a hydrogen atom to damaged molecules. Despite extensive efforts to develop more effective protective agents, no thiol-based radioprotector has been found to be significantly better than cysteamine. Mitchell et al.,
Arch. Biochem. and Biophys.
289: 62 (1991). However, the use of thiol drugs to protect against radiation damage is limited by the toxicity of such compounds.
Antineoplastic agents, particularly the class of chemotherapeutic drugs known as alkylating agents, also produce free radicals that are cytotoxic due to their ability to form covalent bonds with nucleic acids. Most alkylating agents form positively charged carbonium ions that yield the charged alkylating intermediate R—CH
2
—CH
2
+
which attacks electron-rich sites on nucleic acids, proteins, small molecules and amino acids.
Several endogenous intracellular scavengers of free radicals, superoxide radicals and heavy metal cations have been identified. Induction or elevated activities of each of metallothionein (MT), gamma-glutamyl transpeptidase (&ggr;-GTP) and superoxide dismutase (SOD) are known to provide resistance to ionizing radiation damage in vitro. These proteins function intracellularly to scavenge free radicals, superoxide anions or heavy metal cations. U.S. Pat. No. 5,599,712, the contents of which are incorporated by reference in their entirety, describes a method for providing functional intracellular therapeutic levels of metallothionein, superoxide dismutase or gamma glutamyl transpeptidase to protect normal lung tissue from the adverse effects of a combination of chemotherapy and radiation therapy.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a method of protecting normal cells not at a tumor site against the damaging effects of an anticancer agent or ionizing radiation by providing genes encoding protein protective to normal somatic cells.
It is a further object of the present invention to provide a method of protecting normal cells, particularly cells of the oral cavity, oropharynx, esophagus, stomach, small intestine and colon, against the damaging effects of an anticancer agent or ionizing radiation by providing genes encoding protein protective to normal somatic cells.
It is another object of this invention to provide a safe and efficient method of transferring oxidation or cation-scavenging protein encoding genes directly into cells of the oral cavity, oropharynx, esophagus, stomach, small intestine and colon.
It is yet another object of this invention to transfer oxidation or cation-scavenging protein encoding genes directly into cells of the oral cavity, oropharynx, esophagus, stomach, small intestine and colon using an easily administrable method.
Another object of the present invention is to provide transient expression of the oxidation or cation-scavenging protein in the cells of the oral cavity, oropharynx, esophagus, stomach, small intestine and colon to protect these cells against an anticancer agent, wherein either the transferred polynucleotide or gene is cleared after therapeutic courses of ionizing radiation therapy or chemotherapy, or the transferred polynucleotide or gene is stably integrated within the genome, but its expression is temporary, and induced for a limited time by the ionizing radiation therapy or chemotherapy.
In accomplishing these and other objects, there has been provided, in accordance with one aspect of the present invention, a method for protecting the oral cavity, oropharynx, esophagus, stomach, small intestine or colon in a subject against an agent that elicits production of a toxic species when the subject is exposed to the agent. Alternatively, the present invention provides a method for protecting tissues of a subject against an agent that elicits production of a toxic species when the subject is exposed to the agent, wherein the tissues to be protected are at a site remote from the tissues to be treated with toxic species. The toxic species is selected from the group consisting of a free radical, a superoxide anion, and a heavy metal cation. Each of the methods comprises administering to the subject in vivo a pharmaceutical composition comprising (A) a polynucleotide that encodes a protein that is transiently expressed in the subject, wherein the protein is capable of neutralizing or eliminating the toxic species, and (B) a pharmaceutically acceptable vehicle for the polynucleotide. The agent may be ionizing radiation, clinical radiation therapy, or a chemotherapeutic drug. In a preferred embodiment of the invention, the proteins of the invention which neutralize or eliminate the toxic species are gamma glutamyl transpeptidase, manganese superoxide dismutase, or metallothionein. In one embodiment of the invention, the pharmaceutical composition of the invention comprises a mixture of polynucleotides selected from a polynucleotide encoding gamma glutamyl transpeptidase, a polynucleotide encoding manganese superoxide dismutase or a polynucleotide encoding metallothionein.
Liposomes, an adenovirus vector, or ligand-DNA conjugates can be used to introduce a polynucleotide according to the invention. Administration of the pharmaceutical composition preferably is performed prior to a subject's exposure to an agent. The present method is used during treatment of a variety of cancers, including lung cancer, prostate cancer, cervical cancer, endometrial cancer, ovarian cancer and bladder cancer.
Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
REFERENCES:
patent: 4980286 (1990-12-01), Morgan et al.
patent: 5240847 (1993-08-01), Heckl et al.
patent: 5599712 (1997-02-01), Greenberger
patent: 93/12756 (1993-07-01), None
patent: WO 94/19493 (1994-09-01), None
patent: WO 94/21283 (1994-09-01), None
patent: WO 98/00160 (1998-01-01), None
Mastrangelo et al., Seminars in Oncology, vol. 23, No. 1, pp. 4-21, Feb. 1996.*
Orkin et al., Report and Recommendations for the Panel to Assess the NIH Investment in Research on Gene Therapy, Dec. 1995.*
Epperly et al. “Prevention of late effects of irradiation lung damage by Manganese superoxide dismutase gene therapy” Gene Therapy, (1998 Feb) 5 (2) 196-208.
Epperly et al. “Protection of the lung from ionizing irrad
Chen Shin-Lin
Clark Deborah J. R.
Foley & Lardner
University of Pittsburgh
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