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Down-regulation of DNA repair to enhance sensitivity to p53-mediated suppression

a sensitivity and dna repair technology, applied in the field of cancer therapy, can solve the problems of major obstacles to cancer treatment, major obstacles to the development of resistance to such treatment, and half a million deaths per year, and achieve the effect of facilitating the function of the tumor suppressor, p53, and overcoming or restricting the therapy-inhibiting effect of dna repair

Inactive Publication Date: 2005-05-05
GJERSET RUTH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] It is, therefore, a goal of the present invention to provide improved methods for the treatment of cancer. More particularly, it is a goal to provide methods for overcoming or limiting the therapy-inhibiting effects of DNA repair in cancer cells. These methods facilitate the function of the tumor suppressor, p53, in the induction of apoptosis in cells sustain DNA damage.

Problems solved by technology

Disruption of this balance is thought to be a major event in the development of cancer.
The effects of cancer are catastrophic, causing over half a million deaths per year in the United States alone.
Though conventional therapies are available, development of resistance to such treatment is a major obstacle to treatment of cancer.
However, glioblastomas respond poorly to most chemotherapeutic agents, even though the blood brain barrier is broken down as a consequence of the disease.
Certain chemotherapeutic agents such as cisplatin, carmustine, procarbazine and 5-fluororacil are somewhat efficacious in the treatment of glioblastoma but the tumors are never completely eradicated by these methods.

Method used

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  • Down-regulation of DNA repair to enhance sensitivity to p53-mediated suppression
  • Down-regulation of DNA repair to enhance sensitivity to p53-mediated suppression
  • Down-regulation of DNA repair to enhance sensitivity to p53-mediated suppression

Examples

Experimental program
Comparison scheme
Effect test

example i

Materials and Methods

Cell Lines and Tissue Culture

[0175] T98G glioblastoma cells were obtained from ATCC and cultured at 37° C. 10% CO2 in Dulbecco's Modified Eagles Medium supplemented with 10% newborn calf serum. 9L rat glioblastoma cells were obtained from Carol Cruse (University of Colorado) and cultured at 37° C. in 10% CO2 in Dulbecco's Modified Eagles Medium supplemented with 10% fetal Calf serum. The T98G-LHCmjun clone (termed T98G mutant jun or T98G-mjun), as well as control empty vector modified clone (termed T98GLHCX) were obtained from Dr. Dan Mercola (Sidney Kimmel Cancer Center) and were cultured in the same way as were T98G cells except that 100 μg / ml hygromycin was added to the culture medium. The 98G-mjun is stably modified to express a dominant negative mutant of c-jun (the mutant was obtained by site-directed mutagenesis by M. Karin and colleagues and is described by Smeal et al. (1991). Mutant jun has ser→ala substitutions at positions 63 and 73, two sites of ...

example ii

The Effects of DNA Repair Inhibition on the Growth of Cancer Cells

[0185] The effects of DNA repair inhibition on the growth of two different types of cancer cells with varying status in wild-type p53 expression were tested.

[0186] In the first instance, the following three cell lines were tested: T98G, parental cell line; T98GLHXC, empty vector modified control; T98G-mutant jun, containing jun mutated at positions 63 and 73 from serine to alanine. The cells were infected with wild-type p53-expressing virus and the growth of the cells was measured after seven days (FIG. 1). The T98G-mutant jun cells had a significantly reduced viability compared to the T98G parental cells and the T98GLHXN empty vector control cells. Viability of the p53 adenovirus infected clones was measured relative to the viability of βgal adenovirus-infected control cells for each subclone.

[0187] The transcriptional activation of some DNA repair enzymes are controlled by the transcription factor AP-1, which is ...

example iii

The Combined Effects of DNA Damaging

Agents and DNA Repair Inhibitors on Tumor Cells

[0189] The effects of cisplatin alone and in combination with a synthetic retinoid SR11220 on tumor cells expressing wild-type p53 were tested.

[0190] In the first instance, viability of 9L rat glioblastoma cells infected with either βgal adenovirus or p53 adenovirus, and treated one day later in the absence or presence of 50 μM cisplatin was measured seven days after administration of cisplatin (FIG. 5). 9L rat glioblastoma cells infected with p53 adenovirus exhibited a significant decrease in viability compared to 9L cells infected with βgal adenovirus when exposed to cisplatin. The viability of 9L rat glioblastoma cells infected with either βgal adenovirus or p53 adenovirus in the absence of cisplatin did not significantly decrease. Thus tumor cells that have sustained DNA damage are more susceptible to growth suppression by p53.

[0191] In the second instance, T47D breast cancer cells were infect...

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Abstract

The present invention details methods for the treatment of cancer. In particular, it concerns the induction of apoptosis in cancer cells following treatment with inhibitors of DNA repair in combination with p53 gene therapy. Treatment of glioblastoma and breast tumor cells with inhibitors of DNA repair induced growth suppression that was a result of p53-mediated apoptosis. Thus it appears that inhibitors of DNA repair in combination with p53 gene therapy is involved in restoration of p53-mediated apoptosis.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] The present invention relates generally to the field of cancer therapy. More particularly, it concerns a method of inducing p53-mediated apoptosis in tumor cells by inhibiting DNA repair. [0003] 2. Description of Related Art [0004] Normal tissue homeostasis is achieved by an intricate balance between the rate of cell proliferation and the rate of cell death. Disruption of this balance is thought to be a major event in the development of cancer. The inhibition of apoptosis, or programmed cell death, has been linked to this disruptive event. The effects of cancer are catastrophic, causing over half a million deaths per year in the United States alone. [0005] Though conventional therapies are available, development of resistance to such treatment is a major obstacle to treatment of cancer. For example, glioblastoma multiforme is the most common intracranial brain tumor and is particularly resistant to therapy, and rapi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/166A61K31/203A61K31/7056A61K45/00A61K33/24A61P35/00
CPCA61K31/166A61K31/7056A61K31/7048A61K31/203A61P35/00
Inventor GJERSET, RUTH
Owner GJERSET RUTH
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