Purification and administration of DNA repair enzymes

Details Purification and administration of DNA repair enzymes Purification and administration of DNA repair enzymes

1990-12-26

1994-03-22

Patterson, Jr., Charles L.

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Liposomes

424 445, 424 446, 435193, 435196, A61K 3722, A61K 3752, A61K 3759

Patent

active

052962318

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to DNA repair enzymes and, in particular, to 1) methods for purifying DNA repair enzymes, and 2) methods and means for administering DNA repair enzymes to living cells in situ, e.g. human skin cells, so that the enzymes can enter the cells and enhance the repair of damaged DNA in the cells.
2. Description of the Prior Art
Skin cancer is a serious human health problem. The incidence of non-melanoma skin cancer in the United States is 500,000 per year, and 23,000 per year for melanoma. Annual deaths are 2,000 and 6,000 respectively, and 800,000 deaths from skin cancer are predicted in the next 88 years if current trends continue.
The causal link between non-melanoma skin cancer and ultraviolet light exposure from the sun has been clearly established, and sun exposure is an important causative factor in melanoma. The target for ultraviolet light damage leading to cancer is widely accepted as DNA.
Xeroderma pigmentosum is a human genetic disease in which patients develop solar damage, pigmentation abnormalities and malignancies in sun-exposed skin. A review of the disease was authored by J. H. Robbins, K. H. Kraemer, M. A. Lutzner, B. W. Festoff and H. G. Coon, entitled "Xeroderma Pigmentosum: An Inherited Disease with Sun Sensitivity, Multiple Cutaneous Neoplasms, and Abnormal DNA Repair", and published in the ANNALS OF INTERNAL MEDICINE, volume 80, number 2, pages 221-248, February, 1974. The disease occurs in 1 of 250,000 worldwide. Cells from xeroderma pigmentosum patients are deficient in repair of ultraviolet damage to DNA, which results in a cancer incidence 4,800 times the frequency of the general U.S. population. There is no cure, and treatment consists of avoiding sun exposure and excising skin lesions. Death occurs 30 years earlier in these patients than among the general U.S. population.
Research into the basic mechanisms of DNA repair has established outlines of biochemical pathways which remove ultraviolet damage in DNA. Bacterial repair systems have been demonstrated to differ significantly from repair in human cells. However, the enzyme endonuclease V (also referred to herein as T4 endonuclease V and denV endonuclease V) has the ability to enhance DNA repair in human cells as evidenced by increased UV-specific incision of cellular DNA, increased DNA repair replication, and increased UV survival after treatment with the enzyme.
The endonuclease V enzyme is produced by the denV gene of the bacteriophage T4. It has been established that this enzyme catalyzes the rate limiting, first step in the removal of UV-induced DNA damage, namely, single strand incision of DNA at the site of damage. In particular, the enzyme exhibits glycosylase and apurinic/apyrimidinic endonuclease activities and acts at the site of ultraviolet induced pyrimidine dimers. See "Evidence that the UV Endonuclease Activity Induced by Bacteriophage T4 Contains Both Pyrimidine Dimer-DNA Glycosylase and Apyrimidinic/Apurinic Endonuclease Activities in the Enzyme Molecule" by H. R. Warner, L. M. Christensen and M. L. Persson, in JOURNAL OF VIROLOGY, 1981, Vol. 40, pages 204-210; "denV Gene of Bacteriophage T4 Codes for Both Pyrimidine Dimer DNA Glycosylase and Apyrimidinic Endonuclease Activities" by S. McMillan, H. J. Edenberg, E. H. Radany, R. C. Friedberg and E. C. Friedberg, in JOURNAL OF VIROLOGY, 1981, Vol. 40, pages 211-223, and "Physical Association of Pyrimidine Dimer DNA Glycosylase and Apurinic/Apyrimidinic DNA Endonuclease Essential for Repair of Ultraviolet-damaged DNA" by Y. Nakabeppu and M. Sekiguchi, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, 1981, Vol. 78, pages 2742-2746.
Other enzymes having the ability to repair DNA damage have also been identified. These enzymes include O.sup.6 -methylguanine-DNA methyltransferases, photolyases, uracil- and hypoxanthine-DNA glycosylases, apyrimidinic/apurinic endonucleases, DNA exonucleases, damaged-bases glycosylases (e.g., 3-methyladenine-DNA glycosylase), correndonucleases alone or in compl

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