Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
1997-06-02
2002-11-05
Kunz, Gary L. (Department: 1647)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C514S04400A, C424S093210
Reexamination Certificate
active
06475791
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to risk-assessment of suspected genotoxins, evaluation of novel chemotherapeutic agents, and novel chemotherapeutic methods for cancer management.
BACKGROUND OF THE INVENTION
Cancer arises when a normal cell undergoes neoplastic transformation and becomes a malignant cell. Transformed (malignant) cells escape normal physiologic controls specifying cell phenotype and restraining cell proliferation. Transformed cells in an individual's body thus proliferate, forming a tumor (also referred to as a neoplasm). When a neoplasm is found, the clinical objective is to destroy malignant cells selectively while mitigating any harm caused to normal cells in the individual undergoing treatment. Currently, three major approaches are followed for the clinical management of cancer in humans and other animals. Surgical resection of solid tumors, malignant nodules and or entire organs may be appropriate for certain types of neoplasia. For other types, e.g., those manifested as soluble (ascites) tumors, hematopoeitic malignancies such as leukemia, or where metastasis of a primary tumor to another site in the body is suspected, radiation or chemotherapy may be appropriate. Either of these techniques also is commonly used as an adjunct to surgery.
Harrison's Principles of Internal Medicine,
Part 11 Hematology and Oncology, Ch. 296, 297 and 300-308 (12th ed. 1991).
Chemotherapy is based on the use of drugs that are selectively toxic (cytotoxic) to cancer cells. Id. at Ch. 301. Several general classes of chemotherapeutic drugs have been developed, including drugs that interfere with nucleic acid synthesis, protein synthesis, and other vital metabolic processes. These generally are referred to as antimetabolite drugs. Other classes of chemotherapeutic drugs inflict damage on cellular DNA. Drugs of these classes generally are referred to as genotoxic. Two widely used genotoxic anticancer drugs that have been shown to damage cellular DNA by producing crosslinks therein are cisplatin [cis-diamminedichloroplatinum(II)] and carboplatin [diammine(1,1-cyclobutanedicarboxylato)platinum(II)]. Bruhn et al. (1990), 38
Prog. Inorg. Chem.
477, Burnouf et al. (1987), 84
Proc. Natl. Acad. Sci. USA
3758, Sorenson and Eastman (1987), 48
Cancer Res.
4484 and 6703, Pinto and Lippard (1985), 82
Proc. Natl. Acad. Sci., USA
4616, Lim and Martini (1984), 38
J. Inorg. Nucl. Chem.
119, Lee and Martin (1976), 17
Inorg. Chim. Acta
105, Harder and Rosenberg (1970), 6
Int. J. Cancer
207, Howle and Gale (1970), 19
Biochem. Pharmacol
2757. Cisplatin and/or carboplatin currently are used in the treatment of selected, diverse neoplasms of epithelial and mesenchymal origin, including carcinomas and sarcomas of the respiratory, gastrointestinal and reproductive tracts, of the central nervous system, and of squamous origin in the head and neck.
Harrison's Principles of Internal Medicine (
12th ed. 1991) at Ch. 301. Cisplatin currently is preferred for the management of testicular carcinoma, and in many instances produces a lasting remission. Loehrer and Einhorn (1984), 100
Ann. Int. Med.
704. Susceptibility of an individual neoplasm to a desired chemotherapeutic drug or combination thereof often, however, can be accurately assessed only after a trial period of treatment. The time invested in an unsuccessful trial period poses a significant risk in the clinical management of aggressive malignancies.
The repair of damage to cellular DNA is an important biological process carried out by a cell's enzymatic DNA repair machinery. Unrepaired lesions in a cell's genome can impede DNA replication, impair the replication fidelity of newly synthesized DNA or hinder the expression of genes needed for cell survival. Thus, genotoxic drugs generally are considered more toxic to actively dividing cells that engage in DNA synthesis than to quiescent, nondividing cells. Indeed, cells carrying a genetic defect in one or more elements of the enzymatic DNA repair machinery are extremely sensitive to cisplatin. Fraval et al. (1978), 51
Mutat. Res.
121, Beck and Brubaker (1973), 116
J. Bacteriol
1247. Normal cells of many body tissues, however, are quiescent and commit infrequently to re-enter the cell cycle and divide. Greater time between rounds of cell division generally is afforded for the repair of DNA damage in normal cells inflected by chemotherapeutic genotoxins. As a result, some selectivity is achieved for the killing of cancer cells. Many treatment regimes reflect attempts to improve selectivity for cancer cells by coadministering chemotherapeutic drugs belonging to two or more of these general classes.
In some tissues, however, normal cells divide continuously. Thus, skin, hair follicles, buccal mucosa and other tissues of the gut lining, sperm and blood-forming tissues of the bone marrow remain vulnerable to the action of genotoxic drugs, including cisplatin. These and other classes of chemotherapeutic drugs can also cause severe adverse side effects in drug-sensitive organs, such as the liver and kidneys. These and other adverse side effects seriously constrain the dosage levels and lengths of treatment regimens that can be prescribed for individuals in need of cancer chemotherapy.
Harrison's Principles of Internal Medicine
(12th ed. 1991) at Ch. 301. See also Jones et al. (1985), 52
Lab. Invest.
363-374 and Loehrer and Einhorn (1984), 100
Ann. Int. Med.
704-714. Such constraints can prejudice the effectiveness of clinical treatment. For example, the drug or drug combination administered must contact and affect cancer cells at times appropriate to impair cell survival. Genotoxic drugs are most effective for killing cancer cells that are actively dividing when chemotherapeutic treatment is applied. Conversely, such drugs are relatively ineffective for the treatment of slow growing neoplasms. Carcinoma cells of the breast, lung and colorectal tissues, for example, typically double as slowly as once every 100 days.
Harrison's Principles of Internal Medicine
(12th ed. 1991) at Table 301-1. Such slowly growing neoplasms present difficult chemotherapeutic targets.
Moreover, cancer cells can acquire resistance to genotoxic drugs through diminished uptake or other changes in drug metabolism, such as those that occur upon drug-induced gene amplification or expression of a cellular gene for multiple drug resistance (MDR).
Harrison's Principles of Internal Medicine
(12th ed. 1991) at Ch. 301. Resistance to genotoxic drugs also can be acquired by activation or enhanced expression of enzymes in the cancer cell's enzymatic DNA repair machinery. Therapies that employ combinations of drugs, or drugs and radiation, attempt to overcome these limitations. The pharmacokinetic profile of each chemotherapeutic drug in such a combinatorial regime, however, will differ. In particular, permeability of neoplastic tissue for each drug will be different. Thus, it can be difficult to achieve genotoxically effective concentrations of multiple chemotherapeutic drugs in target tissues.
Needs remain for additional chemotherapeutic drugs with improved selectivity for destroying transformed cells in situ, without significantly impairing viability of untransformed cells. Needs remain also for enhancing effectiveness of chemotherapeutic drugs, such that satisfactory cell killing can be achieved with lower doses thereof than are currently needed. Thus, needs remain for improved, more accurate methods of testing whether a given chemotherapeutic drug will be effective for killing a particular colony of transformed cells in situ. Poignant needs remain for chemotherapeutic drugs with improved selectivity for destroying transformed cells. Particularly poignant needs remain for ways to render transformed cells selectively more vulnerable to killing through chemotherapy.
SUMMARY OF THE INVENTION
It is an object of this invention to provide a method for assessing whether a suspected genotoxic agent forms lesions in DNA that are
Brown Steven J.
Bruhn Suzanne L.
Donahue Brian A.
Essigmann John M.
Kellett Patti J.
Hayes Robert C.
Kingsley Taft Foley Hoag LLP
Kunz Gary L.
Massachusetts Institute of Technology
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