Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1995-10-26
1997-09-09
Marschel, Ardin H.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 691, 436501, 436 63, 514 2, 514 44, 935 77, 935 78, C12Q 168
Patent
active
056655533
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 filing of PCT/US94/04383, filed Apr. 29, 1994.
FIELD OF THE INVENTION
The present invention relates generally to diagnostic and prognostic methods for assessing the cancer status of a subject and methods for modifying that status. More particularly, the invention provides methods for determining the cancer status (healthy, precancerous, or cancerous) of a subject by analyzing the cellular redox potential as it affects cellular DNA and provides methods for modulating the cellular redox potential so as to affect cancer formation.
BACKGROUND OF THE INVENTION
The mechanism generally responsible for cellular replication is DNA transcription whereby genetic information about an organism as embodied in the DNA is transferred to each subsequently formed cell. It is during this replicating process that errors in the genetic code, in the form of miscoding or base pair errors (base lesions), may be passed from one cell to further generations. Some such lesions, or groups thereof, are detrimental and may result in death of the organism or neoplasia. Other lesions may have little detectible effect or may be readily repaired by enzymes produced by or introduced into the organism. Still other base lesions are beneficial and promote diversity and adaptation. It is the first category which is of great interest to the human population.
Because destruction or alteration of DNA sequences can have catastrophic consequences, e.g. cancer, much research has been conducted into identifying why and how such alterations take place. It has been shown that exposure to high levels of radiation or oxidizing chemicals causes destruction of DNA to varying degrees. For example, it has been shown that DNA misreplication occurred when bacteria were exposed in vitro to high levels of radiation so as to cause oxidatively modified nucleotide base lesions to appear. As a consequence of this and other research, it has been proposed that a primary promoter of DNA misreplication is the formation of oxidatively modified nucleotide bases. Experiments conducted by the inventor have extended this concept to show that such modifications to DNA actually occurred in vivo. Thus, it has been established that exposure to oxidative molecules in general and oxygen radicals in particular induced DNA lesions in the form of oxidatively modified nucleotide bases, and that these lesions were linked to carcinogenesis.
Further experiments conducted by the inventor have shown that exposure to known environmental toxins also caused oxidatively modified nucleotide bases to appear in vivo. In these further experiments, feral fish were taken from an environment known to contain carcinogenic compounds. Assays were conducted for DNA lesions and the resulting data showed that high levels of certain oxidatively modified nucleotide bases were present in cancerous tissues. The data indicated that cancerous tissues contained abnormally high levels of modified purine bases: 4,6-diamino-5-formamidopyrimidine (Fapy-A) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-G), and 8-hydroxyguanine (8-OH-Gua) and 8-hydroxyadenine (8-OH-Ade). From this research, the initiator of these modifications was identified--the hydroxyl radical (.cndot.OH).
From the foregoing findings, a determination of a cancerous or precancerous state could be made by assaying for elevated concentration levels of the aforementioned oxidatively modified nucleotide bases. This discovery is the subject of pending U.S. patent application Ser. No. 07/806,487 which is incorporated herein by reference. The significance of this discovery is that for the first time, it was shown that a broad-based indicator of a cancerous state or elevated cancer risk could be utilized by conducting an assay for abnormally high concentration levels of oxidatively modified nucleotide bases. Moreover, by identifying the .cndot.OH radical as the molecule responsible for most oxidative modifications of DNA which produced genotoxic lesions, treatments could be carried out to reduce or eliminate its presence,
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Marschel Ardin H.
Pacific Northwest Research Foundation
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